{"gene":"MAPK8IP1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2004,"finding":"Crystal structure of human JNK1 complexed with the JIP1 peptide (pepJIP1) revealed that Pro157, Leu160, and Leu162 of pepJIP1 make van der Waals contacts and Arg156 of pepJIP1 forms a hydrogen bond with Glu329 of JNK1, conferring selectivity for JNK1 over other MAPKs. Peptide binding induces a hinge motion between N- and C-terminal domains of JNK1, distorting the ATP-binding cleft and reducing ATP affinity (allosteric inhibition mechanism).","method":"X-ray crystallography of JNK1–pepJIP1 binary complex and JNK1–pepJIP1–SP600125 ternary complex","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structures with direct identification of contact residues; mechanistic conclusions about allostery structurally validated","pmids":["15141161"],"is_preprint":false},{"year":2001,"finding":"JIP1 scaffold protein is required for stress-induced JNK activation in vivo: JIP1-knockout mice are refractory to JNK activation caused by excitotoxic and anoxic stress. Under stress, JIP1 redistributes from neurites to the soma together with activated JNK and phosphorylated c-Jun.","method":"Homologous recombination gene knockout in mice; live-imaging of JIP1 localization in primary hippocampal neurons; JNK activation assays in brain","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined biochemical readout (JNK phosphorylation) in vivo; replicated with in vitro stress models","pmids":["11562351"],"is_preprint":false},{"year":2013,"finding":"JIP1 coordinates bidirectional APP axonal transport by switching between anterograde (kinesin-1) and retrograde (dynein) motor complexes. JIP1 binds kinesin heavy chain (KHC) directly and relieves KHC autoinhibition; dynactin subunit p150Glued competes with KHC for JIP1 binding and inhibits KHC activation. JNK-dependent phosphorylation of JIP1 at Ser421 acts as a molecular switch: phosphorylation promotes retrograde while dephosphorylation promotes anterograde transport.","method":"Single-molecule motility assays; co-immunoprecipitation; live imaging of APP transport in neurons; phosphomutant (S421A/S421D) analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted in single-molecule assays, competitive binding in vitro, and validated with phosphomutants in neurons; multiple orthogonal methods","pmids":["23897889"],"is_preprint":false},{"year":2014,"finding":"JIP1 binds directly to the autophagosome adaptor LC3 via a conserved LIR motif. This interaction is required for retrograde autophagosome transport initiation and sustenance in axons. LC3 binding to JIP1 competitively disrupts JIP1-mediated kinesin-1 activation, and dephosphorylated JIP1-S421 (maintained by autophagosome-associated MKP1 phosphatase) favors retrograde transport, ensuring robust retrograde autophagosomal movement.","method":"Direct binding assay; live-cell imaging of autophagosome transport; JIP1 depletion and rescue with phosphomutants (S421A, S421D); competitive binding assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding established, LIR motif identified, phosphomutant rescue in neurons, MKP1 phosphatase involvement demonstrated; multiple orthogonal methods","pmids":["24914561"],"is_preprint":false},{"year":2001,"finding":"JIP1 binds the cytoplasmic intracellular domain (AID) of APP. This interaction was confirmed in vitro, in vivo by FRET, and in mouse brain lysates, linking APP processing by γ-secretase to JNK stress-kinase signaling pathways.","method":"Yeast two-hybrid; in vitro binding assay; FRET in cells; co-immunoprecipitation from mouse brain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal methods (yeast two-hybrid + in vitro + FRET + brain Co-IP); independently confirmed in subsequent studies","pmids":["11724784"],"is_preprint":false},{"year":2003,"finding":"JNK binding to JIP1 is necessary for stimulus-induced dissociation of DLK from JIP1, DLK oligomerization, and JNK module activation. JNK phosphorylates JIP1 on Thr-103; this phosphorylation is specifically required for DLK dissociation and subsequent module activation, not other JNK-dependent phosphorylation sites on JIP1.","method":"Mutagenesis of JIP1 phosphorylation sites; in vitro kinase assays; co-immunoprecipitation; DLK oligomerization assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of specific residue combined with multiple functional readouts; single lab but orthogonal methods","pmids":["12756254"],"is_preprint":false},{"year":1998,"finding":"IB1 (rat homolog of JIP-1) is a DNA-binding nuclear protein expressed in pancreatic beta-cells that binds the GTII cis-regulatory element of the GLUT2 promoter in vitro and transactivates the GLUT2 gene. An activation domain was mapped to the first 280 amino acids. IB1 localizes to both cytoplasm and nucleus of insulin-secreting cells.","method":"Expression cloning; in vitro DNA binding assay; transactivation reporter assay; immunocytochemistry; GAL4 domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods establishing DNA binding, transactivation, and subcellular localization in a single study","pmids":["9442013"],"is_preprint":false},{"year":2000,"finding":"IB1/JIP-1 overexpression in insulin-producing cells prevents JNK-mediated phosphorylation of c-Jun, ATF2, and Elk1 and decreases IL-1β- and ΔMEKK1-induced apoptosis. Reducing IB1 content (antisense RNA) increases c-Jun phosphorylation and apoptosis. A missense mutation (559N) abolishes IB1's ability to counteract JNK-pathway inhibition of insulin transcription and to prevent MEKK1-induced apoptosis.","method":"Antisense RNA knockdown in beta-cell lines; overexpression with viral gene transfer; kinase activity assays; apoptosis measurement; functional mutation analysis (559N)","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, overexpression, functional mutation), two beta-cell line systems","pmids":["10700186"],"is_preprint":false},{"year":2004,"finding":"JIP1 scaffold protein is essential for JNK activation in adipose tissue during obesity. JIP1 deficiency prevents JNK-dependent phosphorylation of IRS-1 on Ser307, thereby protecting against obesity-induced insulin resistance.","method":"Jip1 gene knockout mice fed high-fat diet; JNK activity assays in adipose tissue; IRS-1 phosphorylation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with defined biochemical (kinase activity, IRS-1 phosphorylation) and physiological readouts","pmids":["15314024"],"is_preprint":false},{"year":2009,"finding":"Hyperphosphorylated Tau interacts with JIP1 under pathological conditions, sequestering JIP1 in the cell body and impairing JIP1 transport into axons. Tau competes with kinesin light chain for JIP1 binding. This pathological Tau/JIP1 interaction requires Tau phosphorylation.","method":"Co-immunoprecipitation from K3 (K369I mutant Tau) transgenic mouse brain and AD human brain; immunofluorescence; primary neuronal culture transfection","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in transgenic mouse and human AD brain, localization by immunofluorescence, competition assay; single lab","pmids":["19491104"],"is_preprint":false},{"year":2005,"finding":"Drosophila APLIP1 (JIP-1 homolog) genetically interacts with kinesin-1 and dynein: Aplip1 mutation causes reduced anterograde and retrograde vesicle transport and reduced retrograde mitochondria transport, with synthetic phenotypes when combined with Dynein heavy chain heterozygous mutation, indicating APLIP1 is part of motor-cargo linkage complexes for both motors.","method":"Genetic screen; Aplip1 mutant analysis (larval paralysis, axonal swelling); quantitative axonal transport assays; double-mutant epistasis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with two separate motors, quantitative transport assays, defined phenotypic readouts; Drosophila ortholog of MAPK8IP1","pmids":["16332540"],"is_preprint":false},{"year":2008,"finding":"JIP1 localizes specifically to a single neurite before polarization and accumulates in the emerging axon after specification in cortical neurons. JIP1 is required for normal axonal development and promotes axonal growth dependent on kinesin-1 binding and via a newly discovered interaction with c-Abl tyrosine kinase. JIP1 is phosphorylated by c-Abl, and mutation of the c-Abl phosphorylation site on JIP1 abrogates its ability to promote axonal growth.","method":"Live-cell imaging; JIP1 knockdown and rescue; co-immunoprecipitation with c-Abl; phosphorylation-site mutagenesis; axon length quantification","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, new binding partner identified by Co-IP, phosphomutant validation; multiple orthogonal methods, single lab","pmids":["18261906"],"is_preprint":false},{"year":2014,"finding":"JIP1 interacts with the GTP-locked active form of Rab10 and directly connects Rab10 to kinesin-1 light chain (KLC), forming a kinesin-1/JIP1/Rab10 complex required for anterograde transport of plasmalemmal precursor vesicles (PPVs) during axonal growth and neuronal polarization in vitro and in vivo.","method":"Co-immunoprecipitation; JIP1 knockdown; live imaging of PPV transport; in vivo neuronal polarization assay in rat cortex","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP, in vitro knockdown and in vivo validation; single lab","pmids":["24478353"],"is_preprint":false},{"year":2006,"finding":"IB1/JIP1 homodimerizes through a unique SH3–SH3 interaction. X-ray crystallography showed the dimer interface covers the region normally engaged in PxxP-mediated ligand recognition. Point mutations disrupting dimerization reduce IB1-dependent basal JNK activity and impair GLUT2 expression and glucose-dependent insulin secretion in beta-cells.","method":"X-ray crystallography; site-directed mutagenesis; JNK activity assay; GLUT2 expression; glucose-stimulated insulin secretion","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus functional cellular readouts in a single study; strong mechanistic evidence","pmids":["16456539"],"is_preprint":false},{"year":2001,"finding":"LZK (a mixed lineage kinase) binds the C-terminal region of JIP-1 through its kinase catalytic domain, and LZK-induced JNK activation is markedly enhanced when co-expressed with JIP-1. LZK directly phosphorylates and activates MKK7.","method":"Co-immunoprecipitation; in vitro kinase assay; co-transfection/overexpression JNK activity assay","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding by Co-IP, kinase assay for LZK→MKK7, functional enhancement shown; single lab","pmids":["11726277"],"is_preprint":false},{"year":2005,"finding":"Akt1 interacts with JIP1 and its catalytic activity is inhibited when bound. JNK2-mediated phosphorylation of JIP1 causes dissociation of Akt1 from JIP1, restoring Akt1 activity. Dissociated Akt1 then binds SEK1 and inhibits it by phosphorylation on Ser-80, forming a negative regulatory feedback loop during glucose deprivation.","method":"Co-immunoprecipitation; kinase activity assays; siRNA knockdown of JIP1, SEK1, and Akt1; phosphorylation assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus siRNA knockdowns plus kinase assays; multiple readouts but single lab","pmids":["15998799"],"is_preprint":false},{"year":2008,"finding":"VRK2 stably interacts with JIP1, TAK1, and MKK7 (but not JNK), and its binding to the JIP1 signalosome prevents JNK association, reducing JNK phosphorylation and AP-1-dependent transcription in response to IL-1β. Knockdown of JIP1 eliminates the AP-1 transcriptional response to IL-1β.","method":"Co-immunoprecipitation; shRNA and siRNA knockdown; AP-1 reporter assays; JNK phosphorylation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RNAi knockdown plus transcriptional reporter; multiple methods, single lab","pmids":["18286207"],"is_preprint":false},{"year":2007,"finding":"Src family kinases directly bind and tyrosine-phosphorylate JIP1 under basal conditions, increasing JIP1 affinity for DLK and maintaining the JIP-JNK module in a catalytically inactive state.","method":"Co-immunoprecipitation; in vitro kinase assay; tyrosine phosphorylation detection; multiple cell systems","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and phosphorylation shown with Co-IP and kinase assay in multiple systems; single lab","pmids":["17242197"],"is_preprint":false},{"year":2003,"finding":"JIP1 serves as a scaffold for MLK3, MKK7, and JNK in beta-cells; cytokine-induced reduction of IB1/JIP-1 content increases JNK activity and apoptosis rate. Overproducing IB1/JIP-1 prevents cytokine-induced apoptosis by inhibiting caspase-3 cleavage. Haploinsufficient mice (one disrupted Jip1 allele) show increased JNK activity and basal apoptosis in isolated pancreatic islets.","method":"Adenoviral gene transfer (overexpression and knockdown); JNK activity assay; caspase-3 cleavage assay; apoptosis measurement; heterozygous knockout mice","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell models plus in vivo haploinsufficient mice; orthogonal overexpression and loss-of-function with caspase-3 mechanistic readout","pmids":["12640031"],"is_preprint":false},{"year":2001,"finding":"The transcriptional repressor REST controls the tissue-specific expression of MAPK8IP1/IB1. REST binds the NRSE element in the IB1 promoter (confirmed by EMSA), represses IB1 transcription in non-beta, non-neuronal cells, and this repression requires histone deacetylase activity (abolished by trichostatin A).","method":"Luciferase reporter assay; EMSA (mobility shift assay); REST transfection; NRSE mutagenesis; trichostatin A treatment","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — EMSA demonstrating direct DNA binding, reporter assay, NRSE mutagenesis, and pharmacological validation; multiple orthogonal methods","pmids":["11585908"],"is_preprint":false},{"year":2010,"finding":"JIP1-mediated JNK activation (via Thr103 phosphorylation of JIP1) is required for obesity-induced insulin resistance. A Jip1 point mutation (T103A) that selectively blocks JIP1-mediated JNK activation severely impairs high-fat-diet-induced JNK activation and protects mice from obesity-induced insulin resistance.","method":"Germ-line Jip1 T103A knock-in mice; high-fat diet challenge; JNK activation assay; insulin tolerance/glucose tolerance tests","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model with specific point mutation isolating JIP1 scaffold function; defined biochemical and metabolic phenotype","pmids":["20679483"],"is_preprint":false},{"year":2011,"finding":"JIP1 is cleaved by caspase-3 at two sites during TRAIL- and staurosporine-induced apoptosis, leading to disassembly of the JIP1/JNK scaffold complex and subsequent JNK inactivation. Inhibition of caspase-3-mediated JIP1 cleavage sustains JNK activation. Maximal JNK activation correlates with intact JIP1, while JIP1 cleavage correlates with JNK inactivation.","method":"Cell apoptosis assays (TRAIL, staurosporine); Western blot detection of caspase-3-mediated JIP1 cleavage; caspase-3 inhibitor (DEVD.fmk); co-immunoprecipitation of JIP1/JNK complex","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — caspase cleavage sites identified, pharmacological inhibition demonstrates mechanistic link to JNK activity; single lab","pmids":["21237154"],"is_preprint":false},{"year":2013,"finding":"RALA GTPase, activated by RLF (in complex with JIP1 and JNK), promotes assembly and activation of MLK3, MKK4, and JNK onto the JIP1 scaffold following oxidative stress. This pathway mediates ROS-induced JNK-dependent FOXO activation and is conserved in C. elegans (ral-1 and jip-1 depletion both impair FOXO/DAF16 nuclear translocation).","method":"Co-immunoprecipitation; siRNA/RNAi knockdown; FOXO reporter assays; C. elegans genetic analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi, and cross-species genetic validation; single lab","pmids":["23770673"],"is_preprint":false},{"year":2012,"finding":"IL-1β stimulates Lys-63-linked ubiquitination of MLK3 by TRAF6 via a conserved pentapeptide motif in the MLK3 catalytic domain. This ubiquitination is required for dissociation of monomeric MLK3 from the JIP1/IB1 scaffold, enabling MLK3 dimerization, autophosphorylation, and activation. Preventing MLK3 ubiquitination (or adding A20 deubiquitinase) blocks MLK3 activation and BAX translocation in cytokine-stimulated beta-cells.","method":"Ubiquitination assays; co-immunoprecipitation; MLK3 dimerization assays; BAX translocation assay; A20 expression; mutagenesis of TRAF6-binding motif","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical reconstitution of ubiquitination, mutagenesis of motif, deubiquitinase rescue, and functional readout; multiple orthogonal methods","pmids":["23172226"],"is_preprint":false},{"year":2006,"finding":"Vaccinia virus B1R kinase binds the central region of JIP1 (independent of B1R kinase activity), increasing the amount of MKK7 and TAK1 bound to JIP1 (more stable or higher affinity), increasing JNK phosphorylation in the complex, and thereby enhancing c-Jun transcription factor activity.","method":"Co-immunoprecipitation; kinase activity assays; reporter assays for c-Jun activity; kinase-dead B1R mutant","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with kinase-dead mutant separates binding from catalytic activity; c-Jun reporter as functional readout; single lab","pmids":["16840345"],"is_preprint":false},{"year":2005,"finding":"SHIP2 interacts with JIP1 (confirmed in overexpression and native cells), positively modulates MLK3/JIP1-mediated JNK1 activation, and increases tyrosine phosphorylation of JIP1. This SHIP2 effect on JNK activity and JIP1 tyrosine phosphorylation is independent of SHIP2 phosphoinositide 5-phosphatase activity and is prevented by Src/Abl kinase inhibitors (PP2, Glivec).","method":"Co-immunoprecipitation in overexpression and endogenous systems; JNK activity assay; phosphatase-dead SHIP2 mutant; kinase inhibitor treatment","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in native cells plus catalytic-dead mutant to separate docking from enzymatic function; single lab","pmids":["18486448"],"is_preprint":false},{"year":2017,"finding":"JIP1 and JIP3 cooperate to relieve kinesin-1 autoinhibition: JIP1 binds KHC (kinesin heavy chain) and KLC, while JIP3 binds KLC. Together they mediate anterograde axonal transport of TrkB. This cooperative mechanism is required for BDNF-induced TrkB retrograde signaling.","method":"JIP1 knockout mice; sciatic nerve ligation analysis; live imaging; microtubule-binding assays; microfluidic chamber assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus reconstitution-like motor assays and live imaging; single lab but multiple complementary methods","pmids":["28638935"],"is_preprint":false},{"year":2014,"finding":"JIP1b has two novel regions in its central domain that interact with the coiled-coil domain of KLC1 (in addition to the conventional C-terminal 11-amino acid/C11 region that binds KLC1-TPR). The novel regions are required for high-frequency APP anterograde transport, while the C11 domain (regulated by the second novel region) is required for fast-velocity APP transport. KLC1 Thr466 phosphorylation abolishes C11/KLC1-TPR interaction and fast-velocity transport.","method":"Quantitative live-imaging of APP transport in JIP1-deficient neurons; truncation/domain mapping; co-immunoprecipitation; phosphomutant analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative transport assays plus domain mapping in neurons; single lab, multiple complementary methods","pmids":["25165140","29093025"],"is_preprint":false},{"year":2010,"finding":"JIP1 binds RBP-Jκ (a Notch1 transcriptional effector) via the C-terminal SH3 domain of JIP1 interacting with the proline-rich domain of RBP-Jκ, causing cytoplasmic retention of RBP-Jκ and suppressing Notch1 activity. Conversely, RBP-Jκ inhibits JIP1-mediated JNK1 activation and cell death.","method":"Co-immunoprecipitation; subcellular fractionation; Notch1 reporter assay; domain-mapping by deletion mutants","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus reporter assay plus fractionation; single lab","pmids":["20508646"],"is_preprint":false},{"year":2007,"finding":"IB1/JIP1 selectively stabilizes the short splice variants of JNK (not the long variants) against proteasomal degradation, increasing their steady-state protein levels. This represents a mechanism by which IB1 regulates the JNK pathway independent of direct kinase cascade assembly.","method":"Tetracycline-inducible IB1 expression in HEK293 cells; Western blot for JNK splice variants across tissues; protein stability assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system with protein stability assay; multiple tissues examined; single lab","pmids":["17669625"],"is_preprint":false},{"year":2018,"finding":"JIP1 mediates anterograde transport of APP by binding to both KHC and KLC of kinesin-1. Phosphorylation of KLC1 at Thr466 abolishes the JIP1b C11/KLC1-TPR interaction and the enhanced fast velocity of APP transport; this KLC1 phosphorylation increases in aged brains, suggesting age-related impairment of APP transport.","method":"In vitro binding assays (ITC, calorimetry); phosphomutant KLC1 (T466E); quantitative transport imaging in neurons; aged brain biochemistry","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphomutant biochemistry plus transport imaging plus brain aging data; single lab","pmids":["29093025"],"is_preprint":false},{"year":2018,"finding":"Biochemical characterization of the JIP1/KLC1-TPR interaction identified seven KLC1 residues critical for JIP1 binding. The autoinhibitory LFP-acidic motif of KLC1 only marginally inhibits JIP1 binding. JIP1 competes with alcadein-α (a W-acidic motif cargo) for the same KLC1-TPR footprint.","method":"Isothermal titration calorimetry (ITC); truncation mapping; competitive binding assays; structural footprinting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — quantitative biophysical binding assay (ITC) with extensive domain mapping and competition assays; single lab","pmids":["30026235"],"is_preprint":false},{"year":2018,"finding":"JIP1-mediated JNK activation negatively regulates synaptic plasticity and spatial memory: Jip1 knock-in mice with a point mutation that blocks JIP1-mediated JNK activation show increased NMDAR currents, lower threshold for hippocampal LTP induction, and improved hippocampus-dependent spatial memory and fear conditioning.","method":"Jip1 knock-in mice (point mutation blocking JNK activation); electrophysiology (NMDAR currents, LTP); behavioral tests (Morris water maze, fear conditioning); second independent Jip1 mutant mouse line","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent knock-in mouse models, electrophysiology, and behavioral readouts; multiple orthogonal methods","pmids":["29540552"],"is_preprint":false},{"year":2022,"finding":"Cdk5 phosphorylates JIP1 at Thr205, enhancing axonal outgrowth. Phospho-JIP1(Thr205) amplifies phosphorylation of Itch (E3 ubiquitin ligase), increasing Notch1 ubiquitination and degradation, thereby reducing Notch1-IC levels that would otherwise inhibit axonal outgrowth. A phosphomimic JIP1(T205E) rescues axonal outgrowth defects in JIP1−/− and p35−/− neurons.","method":"Interactome screen; in vitro and in vivo phosphorylation assays; phosphomimic/phosphodeficient mutants; rescue experiments in knockout neurons; Notch1 ubiquitination assay","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site mutagenesis with rescue in KO neurons plus downstream ubiquitination assay; single lab, multiple methods","pmids":["35581583"],"is_preprint":false},{"year":2025,"finding":"NMR spectroscopy revealed that JNK1 engages the intrinsically disordered JIP1 tail at not only the canonical D-motif but also a non-canonical F-motif, establishing a bipartite binding mode. Crystal structure of JIP1–JNK1 complex at 2.35 Å confirmed this bipartite interaction.","method":"NMR spectroscopy of the JIP1 disordered tail; X-ray crystallography of JIP1–JNK1 complex at 2.35 Å","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structure plus NMR; two orthogonal structural methods in a single study identifying new binding motif","pmids":["39999166"],"is_preprint":false},{"year":2024,"finding":"JIP1 and JIP2 heterodimerize via their SH3 domains with affinity comparable to homodimerization. Crystal structure of JIP1–JIP2 SH3 heterodimer revealed how structural features from each homodimer are used to stabilize the heterodimer. Targeted mutations disrupting dimerization impaired JNK pathway activation in cellulo.","method":"NMR spectroscopy; X-ray crystallography of JIP2 SH3 homodimer and JIP1–JIP2 SH3 heterodimer; mutagenesis and JNK activity assay in cells","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus NMR plus mutagenesis with functional JNK assay; multiple orthogonal methods in one study","pmids":["39013462"],"is_preprint":false},{"year":2013,"finding":"In Drosophila muscles, Aplip1 (JIP1 ortholog) localizes to the myotendinous junction. Aplip1 mutations cause myonuclear mispositioning and muscle instability. Aplip1 genetically interacts with Raps/Pins and kinesin for nuclear positioning, and both Dynein and Kinesin localization are disrupted in Aplip1 mutants, indicating JIP1 regulates Dynein- and Kinesin-mediated nuclear pulling.","method":"Aplip1 mutant Drosophila; genetic interaction with Raps/Pins and Kinesin; immunofluorescence of motor localization; live imaging of nuclear dynamics","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus motor localization data in Drosophila ortholog; single lab, multiple complementary approaches","pmids":["29487176"],"is_preprint":false},{"year":2017,"finding":"DUSP1 (dual-specificity phosphatase 1) interaction with the JIP1 scaffold protein prevents DUSP1-mediated dephosphorylation of JNK, protecting AP-1 activation and cytokine production from DUSP1 inhibition during viral infection.","method":"Co-immunoprecipitation; JNK phosphorylation assays; AP-1 reporter assay; siRNA knockdown of DUSP1 and JIP1","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating physical interaction, phosphatase protection assay, reporter assay; single lab","pmids":["29234123"],"is_preprint":false},{"year":2022,"finding":"JNK3, JIP1, and β-arrestin2 co-localize and form complexes with PSD95 at postsynaptic densities in hippocampal neurons, as demonstrated by super-resolution microscopy and co-immunoprecipitation.","method":"Super-resolution microscopy (STED/STORM); co-immunoprecipitation from primary hippocampal neurons","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — super-resolution localization plus Co-IP establishing synaptic complex; single lab","pmids":["35456931"],"is_preprint":false},{"year":2013,"finding":"JIP1 PTB domain (specifically residue F687) is required for JIP1–kinesin-1 binding and neurite tip localization. JIP3 is a major JIP1-binding protein identified by proteomics; JIP1–JIP3 association is F687-dependent and forms a stable ternary complex with kinesin-1. Other PTB-binding proteins can disrupt this ternary complex.","method":"Co-immunoprecipitation; site-directed mutagenesis (F687); proteomic analysis; subcellular localization imaging in Neuro2a cells","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with proteomics and localization data; single lab","pmids":["23496950"],"is_preprint":false},{"year":2017,"finding":"Class I HDAC inhibitors induce JIP1 expression in cardiomyocytes, leading to elevated KIF5A expression and formation of JIP1:KIF5A:microtubule complexes that regulate intracellular cargo (autophagosome) transport, without significantly altering JNK signaling in this context.","method":"HDAC inhibitor treatment; JIP1 knockdown; KIF5A expression analysis; co-immunoprecipitation of JIP1:KIF5A:microtubule complex; autophagosome transport imaging","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — JIP1 knockdown confirms dependence, complex formation by Co-IP, transport imaging; single lab","pmids":["28886967"],"is_preprint":false},{"year":2013,"finding":"JIP1 and POSH form a multiprotein scaffold network for TCR-mediated JNK1 activation in CD8+ T cells. Disruption of the POSH/JIP1 complex impairs JNK1 activation, reduces c-Jun, T-bet, and Eomesodermin induction, and results in impaired T cell proliferation, cytokine production, and anti-tumor responses.","method":"Co-immunoprecipitation; dominant-negative disruption of POSH/JIP1 complex; JNK1 kinase assay; transcription factor assays; tumor clearance assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional disruption of complex with defined biochemical and cellular readouts; single lab","pmids":["23963642"],"is_preprint":false}],"current_model":"MAPK8IP1/JIP1 is an intrinsically disordered scaffold protein that assembles MLK3–MKK7–JNK into a macromolecular signaling complex via its D-motif and a newly identified F-motif (bipartite binding to JNK1), uses SH3-domain homodimerization (and heterodimerization with JIP2) to regulate JNK pathway activation, controls the direction of axonal transport of APP, autophagosomes, TrkB, and other cargoes by switching between kinesin-1 activation (relieving KHC autoinhibition, regulated by JNK-dependent S421 phosphorylation) and dynein/dynactin engagement, acts downstream of upstream kinases (Cdk5, c-Abl, Src family kinases, JNK2) that phosphorylate JIP1 at specific residues to modulate its protein–protein interactions, and serves as an anti-apoptotic regulator in neurons and pancreatic beta-cells by sequestering JNK in the cytoplasm and limiting stress-induced c-Jun phosphorylation."},"narrative":{"mechanistic_narrative":"MAPK8IP1 (JIP1/IB1) is an intrinsically disordered scaffold protein that organizes the JNK MAP kinase cascade and, independently, governs the direction of microtubule-based axonal cargo transport [PMID:12640031, PMID:23897889]. It assembles the MLK3/DLK–MKK7–JNK module on a single platform: JNK docking is mediated by a canonical D-motif together with a non-canonical F-motif that together form a bipartite binding mode resolved by crystallography and NMR [PMID:15141161, PMID:39999166], while regulated SH3-domain homodimerization—and heterodimerization with JIP2—is structurally required for efficient pathway activation [PMID:16456539, PMID:39013462]. Activation of the assembled module is gated by phosphorylation of JIP1 itself: JNK phosphorylation of Thr103 triggers DLK dissociation and module firing [PMID:12756254], whereas tonic Src-family tyrosine phosphorylation maintains the complex in an inactive, DLK-bound state [PMID:17242197]. Genetically, JIP1 is essential for stress-induced JNK activation in vivo, and a knock-in mutation that selectively blocks JIP1-scaffolded JNK signaling protects mice from obesity-induced insulin resistance and lowers the threshold for hippocampal LTP and spatial memory [PMID:11562351, PMID:20679483, PMID:29540552]. In its second major role JIP1 links cargo to motors, binding kinesin heavy and light chains to relieve kinesin-1 autoinhibition while dynactin p150Glued competes for binding; JNK-dependent phosphorylation of Ser421 acts as a directional switch between anterograde kinesin and retrograde dynein transport of APP, autophagosomes, and TrkB [PMID:23897889, PMID:24914561, PMID:28638935]. JIP1 connects this transport machinery to specific cargoes including the APP intracellular domain, LC3-marked autophagosomes, and Rab10 vesicles [PMID:11724784, PMID:24914561, PMID:24478353]. As an anti-apoptotic regulator in pancreatic beta-cells and neurons, JIP1 sequesters and limits JNK-driven c-Jun phosphorylation, and its loss or caspase-3 cleavage de-represses JNK activation and apoptosis [PMID:10700186, PMID:12640031, PMID:21237154]. JIP1 also functions in the nucleus as a DNA-binding transactivator of the GLUT2 gene, with its tissue-restricted expression set by REST-mediated repression [PMID:9442013, PMID:11585908].","teleology":[{"year":1998,"claim":"Established that the rat ortholog IB1 is not only a cytoplasmic protein but a nuclear DNA-binding transactivator, revealing a transcriptional role in beta-cells before its scaffold function was known.","evidence":"expression cloning, in vitro DNA binding, transactivation reporter and GAL4 domain mapping in insulin-secreting cells","pmids":["9442013"],"confidence":"High","gaps":["Direct DNA binding by the human protein in a physiological chromatin context not shown","Relationship between nuclear transcriptional and cytoplasmic scaffold functions unresolved"]},{"year":2000,"claim":"Defined JIP1/IB1 as an anti-apoptotic regulator that buffers JNK signaling in beta-cells, linking its abundance to control of c-Jun/ATF2 phosphorylation and survival.","evidence":"antisense knockdown and viral overexpression in beta-cell lines, kinase and apoptosis assays, functional 559N mutation","pmids":["10700186"],"confidence":"High","gaps":["Whether sequestration vs. assembly explains the dose-dependent effect not distinguished","In vivo relevance addressed only later"]},{"year":2001,"claim":"Genetic knockout demonstrated JIP1 is required for stress-induced JNK activation in vivo, moving the scaffold from a biochemical concept to a physiological requirement.","evidence":"Jip1 knockout mice, neuronal live-imaging, brain JNK activation assays under excitotoxic/anoxic stress","pmids":["11562351"],"confidence":"High","gaps":["Which upstream stimuli specifically require JIP1 not fully mapped","Mechanism of neurite-to-soma redistribution unexplained"]},{"year":2001,"claim":"Connected JIP1 to APP biology and to upstream MLKs, identifying both a cargo (APP intracellular domain) and a kinase input (LZK) for the scaffold.","evidence":"yeast two-hybrid, in vitro binding, FRET, brain Co-IP for APP; Co-IP and kinase assay for LZK/MKK7","pmids":["11724784","11726277"],"confidence":"High","gaps":["Functional consequence of APP–JIP1 binding for APP processing not established here","LZK study Medium-confidence, single lab"]},{"year":2001,"claim":"Explained the tissue-restricted expression of MAPK8IP1 through REST-mediated, HDAC-dependent repression at an NRSE element.","evidence":"luciferase reporter, EMSA, NRSE mutagenesis and trichostatin A treatment","pmids":["11585908"],"confidence":"High","gaps":["Other transcriptional inputs to the IB1 promoter unaddressed"]},{"year":2003,"claim":"Identified Thr103 phosphorylation by JNK as the specific switch driving DLK dissociation and module activation, and confirmed the beta-cell anti-apoptotic scaffold function via caspase-3.","evidence":"site-specific mutagenesis, in vitro kinase and DLK oligomerization assays; adenoviral over/under-expression and haploinsufficient mice with caspase-3 readout","pmids":["12756254","12640031"],"confidence":"High","gaps":["How Thr103 phosphorylation structurally weakens DLK affinity not resolved","Other phosphosite contributions not excluded"]},{"year":2004,"claim":"Provided the atomic basis of JIP1's selectivity for JNK1 and revealed an allosteric inhibition mechanism whereby peptide binding distorts the ATP cleft.","evidence":"X-ray crystallography of JNK1–pepJIP1 binary and ternary complexes","pmids":["15141161"],"confidence":"High","gaps":["Captures only the D-motif; bipartite engagement defined only later","Full-length disordered context not in the structure"]},{"year":2004,"claim":"Extended the JIP1-dependent JNK requirement to metabolic disease, showing JIP1 is needed for obesity-induced JNK activation and IRS-1 Ser307 phosphorylation underlying insulin resistance.","evidence":"Jip1 knockout mice on high-fat diet, adipose JNK and IRS-1 phosphorylation assays","pmids":["15314024"],"confidence":"High","gaps":["Tissue-specific contribution (adipose vs. liver vs. muscle) not dissected here"]},{"year":2005,"claim":"Uncovered regulatory crosstalk in which JIP1 sequesters and inhibits Akt1, with JNK2 phosphorylation releasing Akt1 to form a negative feedback loop.","evidence":"Co-IP, kinase assays, siRNA of JIP1/SEK1/Akt1 during glucose deprivation","pmids":["15998799"],"confidence":"Medium","gaps":["Single lab; reciprocal validation limited","Physiological setting beyond glucose deprivation unclear"]},{"year":2006,"claim":"Defined SH3–SH3 homodimerization as a functional requirement, structurally explaining how dimerization occludes the PxxP ligand site and tunes basal JNK activity and beta-cell function.","evidence":"X-ray crystallography, dimer-disrupting mutagenesis, JNK/GLUT2/insulin-secretion readouts; plus viral B1R kinase binding study","pmids":["16456539","16840345"],"confidence":"High","gaps":["How dimerization status is dynamically regulated in cells not established","B1R study Medium-confidence, viral context"]},{"year":2007,"claim":"Established tonic inhibitory control of the module: Src-family tyrosine phosphorylation increases JIP1 affinity for DLK and locks the complex inactive, and IB1 stabilizes short JNK splice variants against degradation.","evidence":"Co-IP, in vitro kinase and tyrosine-phosphorylation assays; inducible IB1 expression and JNK protein stability assays","pmids":["17242197","17669625"],"confidence":"Medium","gaps":["Specific Src-family member and target tyrosines partially defined","Single lab for each finding"]},{"year":2008,"claim":"Linked JIP1 to axon specification and growth, identifying c-Abl as a kinase whose phosphorylation of JIP1 is required for kinesin-dependent axonal outgrowth.","evidence":"live imaging, knockdown/rescue, c-Abl Co-IP and phosphosite mutagenesis in cortical neurons; plus VRK2 signalosome study","pmids":["18261906","18286207"],"confidence":"High","gaps":["c-Abl phosphosite identity and its effect on motor binding incompletely mapped","VRK2 study Medium-confidence"]},{"year":2010,"claim":"A knock-in mouse isolating JIP1 scaffold function (T103A) proved that JIP1-mediated JNK activation is causally required for obesity-induced insulin resistance.","evidence":"germ-line Jip1 T103A knock-in mice, high-fat diet, JNK and metabolic phenotyping","pmids":["20679483"],"confidence":"High","gaps":["Cell-type origin of the protective metabolic effect not localized"]},{"year":2013,"claim":"Resolved JIP1 as a bidirectional transport switch, showing it relieves kinesin-1 autoinhibition while p150Glued competes for binding and Ser421 phosphorylation sets transport direction for APP.","evidence":"single-molecule motility, competitive binding, live APP imaging, S421A/S421D phosphomutants in neurons","pmids":["23897889"],"confidence":"High","gaps":["Kinase/phosphatase that toggle S421 in distinct compartments only partly identified"]},{"year":2013,"claim":"Broadened the JIP1 scaffold and motor roles across pathways and cargoes: RALA/RLF-driven ROS-induced FOXO activation, POSH-dependent TCR/JNK1 signaling in CD8 T cells, and PTB-domain (F687)-mediated JIP3/kinesin-1 ternary complex assembly.","evidence":"Co-IP, RNAi, FOXO/transcription-factor reporters, C. elegans genetics; proteomics and F687 mutagenesis","pmids":["23770673","23963642","23496950"],"confidence":"Medium","gaps":["Each pathway shown by single labs","Direct vs. indirect assembly within these networks not fully separated"]},{"year":2014,"claim":"Defined cargo-specific transport mechanisms: a LIR motif binds LC3 to drive retrograde autophagosome transport (with MKP1 keeping S421 dephosphorylated), and JIP1 links GTP-Rab10 to KLC for anterograde precursor-vesicle transport; central KLC1-binding regions tune APP transport frequency and velocity.","evidence":"direct binding/competition assays, phosphomutant rescue, live imaging of autophagosomes, PPVs and APP; domain mapping and KLC1 phosphomutants","pmids":["24914561","24478353","25165140"],"confidence":"High","gaps":["How a single scaffold coordinates competing cargo signals in one axon not integrated","Rab10 and KLC1 findings Medium-confidence single-lab"]},{"year":2017,"claim":"Showed JIP1 cooperation and abundance control of transport: JIP1/JIP3 jointly relieve kinesin-1 autoinhibition for TrkB/BDNF retrograde signaling, and HDAC-inhibitor-induced JIP1 drives KIF5A-dependent cargo transport independent of JNK.","evidence":"JIP1 knockout, nerve ligation, motor-binding and live imaging; HDAC inhibition, knockdown and JIP1:KIF5A complex Co-IP in cardiomyocytes","pmids":["28638935","28886967"],"confidence":"Medium","gaps":["Quantitative contribution of JIP1 vs JIP3 not separated","Single labs"]},{"year":2018,"claim":"Provided biophysical and physiological resolution of transport regulation: KLC1-TPR binding residues and competition with W-acidic cargoes were mapped, KLC1 Thr466 phosphorylation (rising with brain age) impairs fast APP transport, and a JNK-blocking knock-in revealed JIP1-JNK as a negative regulator of synaptic plasticity and memory.","evidence":"ITC and competition assays, KLC1 T466E phosphomutant transport imaging, aged-brain biochemistry; two independent Jip1 knock-in mouse lines with electrophysiology and behavior","pmids":["30026235","29093025","29540552"],"confidence":"High","gaps":["Causal link between age-related KLC1 phosphorylation and disease not established","Transport-defect contribution to the memory phenotype not separated from JNK signaling"]},{"year":2022,"claim":"Defined Cdk5-driven control of axon outgrowth through JIP1 Thr205 phosphorylation, which amplifies Itch-mediated Notch1 degradation, and placed JNK3/JIP1/β-arrestin2/PSD95 complexes at postsynaptic densities.","evidence":"interactome screen, phosphorylation assays, phosphomimic rescue in KO neurons, Notch1 ubiquitination assay; super-resolution microscopy and Co-IP","pmids":["35581583","35456931"],"confidence":"Medium","gaps":["Single-lab findings","Interplay between Cdk5-Thr205, c-Abl, and Src inputs on the same scaffold unresolved"]},{"year":2025,"claim":"Refined the JIP1–JNK interface, showing the disordered tail engages JNK1 bipartitely through both the canonical D-motif and a newly identified F-motif.","evidence":"NMR of the JIP1 disordered tail and 2.35 Å crystal structure of the JIP1–JNK1 complex; with JIP1–JIP2 SH3 heterodimer structure (2024)","pmids":["39999166","39013462"],"confidence":"High","gaps":["Functional consequence of F-motif loss in vivo not tested","How bipartite docking integrates with allosteric ATP-cleft distortion not resolved"]},{"year":null,"claim":"How a single intrinsically disordered scaffold integrates competing inputs—nuclear transcription, JNK module assembly/inhibition, and bidirectional motor switching for distinct cargoes—within one cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting phosphocode (Thr103, Thr205, Ser421, tyrosines) to functional output","Stoichiometry and spatial segregation of JIP1 complexes in vivo unknown","No timeline disease-gene mutation linking MAPK8IP1 to a Mendelian disorder"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[18,0,13,35]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,26,39,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5,17]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[7,28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,6,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,40,26]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[38]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,18,23]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,3,26,12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,12,40]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,18,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,33,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,40]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,19]}],"complexes":["MLK3/DLK–MKK7–JNK signaling module","JIP1–kinesin-1 (KHC/KLC) motor complex","JIP1–JIP2 SH3 heterodimer","POSH/JIP1 scaffold complex"],"partners":["MAPK8 (JNK1)","MAP3K12 (DLK)","MAP2K7 (MKK7)","KIF5 (KINESIN HEAVY CHAIN)","KLC1","APP","MAP1LC3 (LC3)","RAB10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UQF2","full_name":"C-Jun-amino-terminal kinase-interacting protein 1","aliases":["Islet-brain 1","IB-1","JNK MAP kinase scaffold protein 1","Mitogen-activated protein kinase 8-interacting protein 1"],"length_aa":711,"mass_kda":77.5,"function":"The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins. Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response. Acts as a scaffold protein that coordinates with SH3RF1 in organizing different components of the JNK pathway, including RAC1 or RAC2, MAP3K11/MLK3 or MAP3K7/TAK1, MAP2K7/MKK7, MAPK8/JNK1 and/or MAPK9/JNK2 into a functional multiprotein complex to ensure the effective activation of the JNK signaling pathway. Regulates the activation of MAPK8/JNK1 and differentiation of CD8(+) T-cells","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Nucleus; Endoplasmic reticulum membrane; Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q9UQF2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAPK8IP1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAPK8IP1","total_profiled":1310},"omim":[{"mim_id":"607755","title":"MITOGEN-ACTIVATED PROTEIN KINASE 8-INTERACTING PROTEIN 2; MAPK8IP2","url":"https://www.omim.org/entry/607755"},{"mim_id":"605755","title":"DOUBLECORTIN DOMAIN-CONTAINING PROTEIN 2; DCDC2","url":"https://www.omim.org/entry/605755"},{"mim_id":"604641","title":"MITOGEN-ACTIVATED PROTEIN KINASE 8-INTERACTING PROTEIN 1; MAPK8IP1","url":"https://www.omim.org/entry/604641"},{"mim_id":"600571","title":"RE1-SILENCING TRANSCRIPTION FACTOR; REST","url":"https://www.omim.org/entry/600571"},{"mim_id":"125853","title":"TYPE 2 DIABETES MELLITUS; T2D","url":"https://www.omim.org/entry/125853"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":255.8},{"tissue":"pituitary gland","ntpm":113.0}],"url":"https://www.proteinatlas.org/search/MAPK8IP1"},"hgnc":{"alias_symbol":["IB1","JIP-1","JIP1"],"prev_symbol":["PRKM8IP"]},"alphafold":{"accession":"Q9UQF2","domains":[{"cath_id":"2.30.30.40","chopping":"482-549","consensus_level":"medium","plddt":87.3118,"start":482,"end":549},{"cath_id":"2.30.29.30","chopping":"559-703","consensus_level":"high","plddt":80.1497,"start":559,"end":703}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQF2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQF2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQF2-F1-predicted_aligned_error_v6.png","plddt_mean":54.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAPK8IP1","jax_strain_url":"https://www.jax.org/strain/search?query=MAPK8IP1"},"sequence":{"accession":"Q9UQF2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQF2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQF2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQF2"}},"corpus_meta":[{"pmid":"15141161","id":"PMC_15141161","title":"Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15141161","citation_count":228,"is_preprint":false},{"pmid":"11562351","id":"PMC_11562351","title":"Requirement of the JIP1 scaffold protein for stress-induced JNK activation.","date":"2001","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/11562351","citation_count":210,"is_preprint":false},{"pmid":"23897889","id":"PMC_23897889","title":"JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors.","date":"2013","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23897889","citation_count":209,"is_preprint":false},{"pmid":"24914561","id":"PMC_24914561","title":"LC3 binding to the scaffolding protein JIP1 regulates processive dynein-driven transport of autophagosomes.","date":"2014","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/24914561","citation_count":164,"is_preprint":false},{"pmid":"10700186","id":"PMC_10700186","title":"The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10700186","citation_count":157,"is_preprint":false},{"pmid":"11724784","id":"PMC_11724784","title":"Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein (APP).","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11724784","citation_count":148,"is_preprint":false},{"pmid":"19491104","id":"PMC_19491104","title":"Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19491104","citation_count":135,"is_preprint":false},{"pmid":"9442013","id":"PMC_9442013","title":"IB1, a JIP-1-related nuclear protein present in insulin-secreting cells.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9442013","citation_count":129,"is_preprint":false},{"pmid":"16332540","id":"PMC_16332540","title":"APLIP1, a kinesin binding JIP-1/JNK scaffold protein, influences the axonal transport of both vesicles and mitochondria in Drosophila.","date":"2005","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/16332540","citation_count":114,"is_preprint":false},{"pmid":"10748095","id":"PMC_10748095","title":"IB1 reduces cytokine-induced apoptosis of insulin-secreting cells.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10748095","citation_count":114,"is_preprint":false},{"pmid":"11121395","id":"PMC_11121395","title":"Inhibition of JNK by overexpression of the JNL binding domain of JIP-1 prevents apoptosis in sympathetic neurons.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11121395","citation_count":103,"is_preprint":false},{"pmid":"15314024","id":"PMC_15314024","title":"An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue.","date":"2004","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/15314024","citation_count":99,"is_preprint":false},{"pmid":"18261906","id":"PMC_18261906","title":"The JIP1 scaffold protein regulates axonal development in cortical neurons.","date":"2008","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/18261906","citation_count":83,"is_preprint":false},{"pmid":"23714706","id":"PMC_23714706","title":"Expanding the indications for radical trachelectomy: a report on 29 patients with stage IB1 tumors measuring 2 to 4 centimeters.","date":"2013","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/23714706","citation_count":73,"is_preprint":false},{"pmid":"12756254","id":"PMC_12756254","title":"Recruitment of JNK to JIP1 and JNK-dependent JIP1 phosphorylation regulates JNK module dynamics and activation.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12756254","citation_count":72,"is_preprint":false},{"pmid":"15998799","id":"PMC_15998799","title":"Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15998799","citation_count":62,"is_preprint":false},{"pmid":"18286207","id":"PMC_18286207","title":"Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18286207","citation_count":58,"is_preprint":false},{"pmid":"24478353","id":"PMC_24478353","title":"JIP1 mediates anterograde transport of Rab10 cargos during neuronal polarization.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24478353","citation_count":57,"is_preprint":false},{"pmid":"12640031","id":"PMC_12640031","title":"The scaffold protein IB1/JIP-1 is a critical mediator of cytokine-induced apoptosis in pancreatic beta cells.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12640031","citation_count":52,"is_preprint":false},{"pmid":"10712642","id":"PMC_10712642","title":"Spatial, temporal and subcellular localization of islet-brain 1 (IB1), a homologue of JIP-1, in mouse brain.","date":"2000","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10712642","citation_count":52,"is_preprint":false},{"pmid":"15572149","id":"PMC_15572149","title":"The axon guidance defect of the telencephalic commissures of the JSAP1-deficient brain was partially rescued by the transgenic expression of JIP1.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15572149","citation_count":52,"is_preprint":false},{"pmid":"30013340","id":"PMC_30013340","title":"Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted PEGylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance.","date":"2018","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/30013340","citation_count":49,"is_preprint":false},{"pmid":"28912645","id":"PMC_28912645","title":"Anti-inflammatory Effect of Glucagon Like Peptide-1 Receptor Agonist, Exendin-4, through Modulation of IB1/JIP1 Expression and JNK Signaling in Stroke.","date":"2017","source":"Experimental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/28912645","citation_count":49,"is_preprint":false},{"pmid":"25165140","id":"PMC_25165140","title":"Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25165140","citation_count":46,"is_preprint":false},{"pmid":"10098834","id":"PMC_10098834","title":"Molecular cloning of multiple splicing variants of JIP-1 preferentially expressed in brain.","date":"1999","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10098834","citation_count":45,"is_preprint":false},{"pmid":"12917434","id":"PMC_12917434","title":"Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12917434","citation_count":42,"is_preprint":false},{"pmid":"11585908","id":"PMC_11585908","title":"The transcriptional repressor REST determines the cell-specific expression of the human MAPK8IP1 gene encoding IB1 (JIP-1).","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11585908","citation_count":41,"is_preprint":false},{"pmid":"21721193","id":"PMC_21721193","title":"Parametrial involvement in FIGO stage IB1 cervical carcinoma diagnostic impact of tumor diameter in preoperative magnetic resonance imaging.","date":"2011","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/21721193","citation_count":41,"is_preprint":false},{"pmid":"11726277","id":"PMC_11726277","title":"Mixed lineage kinase LZK forms a functional signaling complex with JIP-1, a scaffold protein of the c-Jun NH(2)-terminal kinase pathway.","date":"2001","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11726277","citation_count":40,"is_preprint":false},{"pmid":"16456539","id":"PMC_16456539","title":"A unique set of SH3-SH3 interactions controls IB1 homodimerization.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16456539","citation_count":40,"is_preprint":false},{"pmid":"3521730","id":"PMC_3521730","title":"Basic proline-rich proteins from human parotid saliva: complete covalent structures of proteins IB-1 and IB-6.","date":"1986","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3521730","citation_count":39,"is_preprint":false},{"pmid":"23045411","id":"PMC_23045411","title":"Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin.","date":"2012","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/23045411","citation_count":33,"is_preprint":false},{"pmid":"12740599","id":"PMC_12740599","title":"Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease.","date":"2003","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/12740599","citation_count":33,"is_preprint":false},{"pmid":"15911620","id":"PMC_15911620","title":"Cross-talk between JIP3 and JIP1 during glucose deprivation: SEK1-JNK2 and Akt1 act as mediators.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15911620","citation_count":33,"is_preprint":false},{"pmid":"25483967","id":"PMC_25483967","title":"MAPK8IP1/JIP1 regulates the trafficking of autophagosomes in neurons.","date":"2014","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25483967","citation_count":32,"is_preprint":false},{"pmid":"31744889","id":"PMC_31744889","title":"Fertility-sparing surgery of cervical cancer >2 cm (International Federation of Gynecology and Obstetrics 2009 stage IB1-IIA) after neoadjuvant chemotherapy.","date":"2019","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/31744889","citation_count":32,"is_preprint":false},{"pmid":"23770673","id":"PMC_23770673","title":"The small GTPase RALA controls c-Jun N-terminal kinase-mediated FOXO activation by regulation of a JIP1 scaffold complex.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23770673","citation_count":31,"is_preprint":false},{"pmid":"17242197","id":"PMC_17242197","title":"Src family kinases directly regulate JIP1 module dynamics and activation.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17242197","citation_count":30,"is_preprint":false},{"pmid":"14515362","id":"PMC_14515362","title":"Repression of phospho-JNK and infarct volume in ischemic brain of JIP1-deficient mice.","date":"2003","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/14515362","citation_count":30,"is_preprint":false},{"pmid":"9933567","id":"PMC_9933567","title":"Genomic organization, fine-mapping, and expression of the human islet-brain 1 (IB1)/c-Jun-amino-terminal kinase interacting protein-1 (JIP-1) gene.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9933567","citation_count":30,"is_preprint":false},{"pmid":"29908338","id":"PMC_29908338","title":"Surgical and Oncologic Outcomes of Radical Abdominal Trachelectomy Versus Hysterectomy for Stage IA2-IB1 Cervical Cancer.","date":"2018","source":"Journal of minimally invasive gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/29908338","citation_count":29,"is_preprint":false},{"pmid":"32062731","id":"PMC_32062731","title":"Laparoscopic versus abdominal radical hysterectomy for stage IB1 cervical cancer patients with tumor size ≤ 2 cm: a case-matched control study.","date":"2020","source":"International journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32062731","citation_count":29,"is_preprint":false},{"pmid":"28638935","id":"PMC_28638935","title":"JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1.","date":"2017","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/28638935","citation_count":28,"is_preprint":false},{"pmid":"21261310","id":"PMC_21261310","title":"Understanding the specificity of a docking interaction between JNK1 and the scaffolding protein JIP1.","date":"2011","source":"The journal of physical chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/21261310","citation_count":28,"is_preprint":false},{"pmid":"29540552","id":"PMC_29540552","title":"JIP1-Mediated JNK Activation Negatively Regulates Synaptic Plasticity and Spatial Memory.","date":"2018","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29540552","citation_count":27,"is_preprint":false},{"pmid":"15894166","id":"PMC_15894166","title":"IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation.","date":"2005","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/15894166","citation_count":26,"is_preprint":false},{"pmid":"11839789","id":"PMC_11839789","title":"The scaffold protein IB1/JIP-1 controls the activation of JNK in rat stressed urothelium.","date":"2002","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11839789","citation_count":26,"is_preprint":false},{"pmid":"16840345","id":"PMC_16840345","title":"Vaccinia virus B1R kinase interacts with JIP1 and modulates c-Jun-dependent signaling.","date":"2006","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/16840345","citation_count":25,"is_preprint":false},{"pmid":"15138488","id":"PMC_15138488","title":"JNK interacting protein 1 (JIP-1) protects LNCaP prostate cancer cells from growth arrest and apoptosis mediated by 12-0-tetradecanoylphorbol-13-acetate (TPA).","date":"2004","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15138488","citation_count":25,"is_preprint":false},{"pmid":"15836924","id":"PMC_15836924","title":"JIP1 regulates neuronal apoptosis in response to stress.","date":"2005","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/15836924","citation_count":23,"is_preprint":false},{"pmid":"28454224","id":"PMC_28454224","title":"Direct targeting of MAPK8IP1 by miR-10a-5p is a major mechanism for gastric cancer metastasis.","date":"2016","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28454224","citation_count":23,"is_preprint":false},{"pmid":"27556216","id":"PMC_27556216","title":"Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles.","date":"2016","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/27556216","citation_count":23,"is_preprint":false},{"pmid":"20679483","id":"PMC_20679483","title":"Requirement of JIP1-mediated c-Jun N-terminal kinase activation for obesity-induced insulin resistance.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20679483","citation_count":22,"is_preprint":false},{"pmid":"29234123","id":"PMC_29234123","title":"DUSP1 regulates apoptosis and cell migration, but not the JIP1-protected cytokine response, during Respiratory Syncytial Virus and Sendai Virus infection.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29234123","citation_count":22,"is_preprint":false},{"pmid":"18486448","id":"PMC_18486448","title":"The docking properties of SHIP2 influence both JIP1 tyrosine phosphorylation and JNK activity.","date":"2008","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/18486448","citation_count":20,"is_preprint":false},{"pmid":"22486458","id":"PMC_22486458","title":"Surgical-pathologic risk factors of pelvic lymph node metastasis in stage Ib1-IIb cervical cancer.","date":"2012","source":"Acta obstetricia et gynecologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/22486458","citation_count":20,"is_preprint":false},{"pmid":"14514632","id":"PMC_14514632","title":"Variations in IB1/JIP1 expression regulate susceptibility of beta-cells to cytokine-induced apoptosis irrespective of C-Jun NH2-terminal kinase signaling.","date":"2003","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/14514632","citation_count":19,"is_preprint":false},{"pmid":"12823467","id":"PMC_12823467","title":"Increased vulnerability to kainic acid-induced epileptic seizures in mice underexpressing the scaffold protein Islet-Brain 1/JIP-1.","date":"2003","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12823467","citation_count":18,"is_preprint":false},{"pmid":"30412737","id":"PMC_30412737","title":"The potential role of HO-1 in regulating the MLK3-MKK7-JNK3 module scaffolded by JIP1 during cerebral ischemia/reperfusion in rats.","date":"2018","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/30412737","citation_count":18,"is_preprint":false},{"pmid":"23172226","id":"PMC_23172226","title":"Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic β cell death.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23172226","citation_count":18,"is_preprint":false},{"pmid":"24198394","id":"PMC_24198394","title":"Regulation of axon growth by the JIP1-AKT axis.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24198394","citation_count":17,"is_preprint":false},{"pmid":"21076496","id":"PMC_21076496","title":"Regulation of stress-associated scaffold proteins JIP1 and JIP3 on the c-Jun NH2-terminal kinase in ischemia-reperfusion.","date":"2010","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21076496","citation_count":17,"is_preprint":false},{"pmid":"26070225","id":"PMC_26070225","title":"The potential for less radical surgery in women with stage IA2-IB1 cervical cancer.","date":"2015","source":"International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/26070225","citation_count":17,"is_preprint":false},{"pmid":"21237154","id":"PMC_21237154","title":"Disassembly of the JIP1/JNK molecular scaffold by caspase-3-mediated cleavage of JIP1 during apoptosis.","date":"2011","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21237154","citation_count":16,"is_preprint":false},{"pmid":"33649013","id":"PMC_33649013","title":"Oncologic and obstetric outcomes after simple conization for fertility-sparing surgery in FIGO 2018 stage IB1 cervical cancer.","date":"2021","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/33649013","citation_count":16,"is_preprint":false},{"pmid":"20508646","id":"PMC_20508646","title":"JIP1 binding to RBP-Jk mediates cross-talk between the Notch1 and JIP1-JNK signaling pathway.","date":"2010","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/20508646","citation_count":15,"is_preprint":false},{"pmid":"39849453","id":"PMC_39849453","title":"Synergistic anti-oxidative/anti-inflammatory treatment for acute lung injury with selenium based chlorogenic acid nanoparticles through modulating Mapk8ip1/MAPK and Itga2b/PI3k-AKT axis.","date":"2025","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39849453","citation_count":15,"is_preprint":false},{"pmid":"29093025","id":"PMC_29093025","title":"Phosphorylation of KLC1 modifies interaction with JIP1 and abolishes the enhanced fast velocity of APP transport by kinesin-1.","date":"2017","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/29093025","citation_count":15,"is_preprint":false},{"pmid":"9514804","id":"PMC_9514804","title":"Ovarian metastasis of stage IB1 squamous cell cancer of the cervix after radical parametrectomy and oophoropexy.","date":"1998","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/9514804","citation_count":15,"is_preprint":false},{"pmid":"26425709","id":"PMC_26425709","title":"Fertility-sparing management of a stage IB1 small cell neuroendocrine cervical carcinoma with radical abdominal trachelectomy and adjuvant chemotherapy.","date":"2015","source":"Gynecologic oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/26425709","citation_count":15,"is_preprint":false},{"pmid":"17348686","id":"PMC_17348686","title":"Crosstalk between PSD-95 and JIP1-mediated signaling modules: the mechanism of MLK3 activation in cerebral ischemia.","date":"2007","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17348686","citation_count":14,"is_preprint":false},{"pmid":"23963642","id":"PMC_23963642","title":"The POSH/JIP-1 scaffold network regulates TCR-mediated JNK1 signals and effector function in CD8(+) T cells.","date":"2013","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23963642","citation_count":14,"is_preprint":false},{"pmid":"24172100","id":"PMC_24172100","title":"Current surgical principle for uterine cervical cancer of stages Ia2, Ib1, and IIa1 in Japan: a survey of the Japanese Gynecologic Oncology Group.","date":"2013","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/24172100","citation_count":14,"is_preprint":false},{"pmid":"27536545","id":"PMC_27536545","title":"Can pelvic lymphadenectomy be omitted in patients with stage IA2, IB1, and IIA1 squamous cell cervical cancer?","date":"2016","source":"SpringerPlus","url":"https://pubmed.ncbi.nlm.nih.gov/27536545","citation_count":13,"is_preprint":false},{"pmid":"26197769","id":"PMC_26197769","title":"Pretreatment risk factors for parametrial involvement in FIGO stage IB1 cervical cancer.","date":"2015","source":"Journal of gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26197769","citation_count":13,"is_preprint":false},{"pmid":"28754175","id":"PMC_28754175","title":"Case report: term birth after fertility-sparing treatments for stage IB1 small cell neuroendocrine carcinoma of the cervix.","date":"2017","source":"BMC women's health","url":"https://pubmed.ncbi.nlm.nih.gov/28754175","citation_count":13,"is_preprint":false},{"pmid":"25548694","id":"PMC_25548694","title":"Radical Abdominal Trachelectomy for IB1 Cervical Cancer at 17 Weeks of Gestation: A Case Report and Literature Review.","date":"2014","source":"Case reports in obstetrics and gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/25548694","citation_count":13,"is_preprint":false},{"pmid":"28886967","id":"PMC_28886967","title":"Class I HDACs control a JIP1-dependent pathway for kinesin-microtubule binding in cardiomyocytes.","date":"2017","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28886967","citation_count":12,"is_preprint":false},{"pmid":"29270030","id":"PMC_29270030","title":"Comparison of survival outcomes between radical hysterectomy and definitive radiochemotherapy in stage IB1 and IIA1 cervical cancer.","date":"2017","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/29270030","citation_count":12,"is_preprint":false},{"pmid":"24816971","id":"PMC_24816971","title":"Reassembly of JIP1 scaffold complex in JNK MAP kinase pathway using heterologous protein interactions.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24816971","citation_count":11,"is_preprint":false},{"pmid":"17669625","id":"PMC_17669625","title":"Splice variant-specific stabilization of JNKs by IB1/JIP1.","date":"2007","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/17669625","citation_count":10,"is_preprint":false},{"pmid":"35433446","id":"PMC_35433446","title":"Risk Factor Assessment of Lymph Node Metastasis in Patients With FIGO Stage IB1 Cervical Cancer.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35433446","citation_count":10,"is_preprint":false},{"pmid":"39065147","id":"PMC_39065147","title":"Lacticaseibacillus casei IB1 Alleviates DSS-Induced Inflammatory Bowel Disease by Regulating the Microbiota and Restoring the Intestinal Epithelial Barrier.","date":"2024","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/39065147","citation_count":9,"is_preprint":false},{"pmid":"22492093","id":"PMC_22492093","title":"Clinical significance of peritumoral lymphatic vessel density and lymphatic vessel invasion detected by D2-40 immunostaining in FIGO Ib1-IIa squamous cell cervical cancer.","date":"2012","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/22492093","citation_count":9,"is_preprint":false},{"pmid":"29804639","id":"PMC_29804639","title":"Simple trachelectomy with pelvic lymphadenectomy as a viable treatment option in pregnant patients with stage IB1 (≥2 cm) cervical cancer: Bridging the gap to fetal viability.","date":"2018","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29804639","citation_count":9,"is_preprint":false},{"pmid":"35581583","id":"PMC_35581583","title":"Cdk5-mediated JIP1 phosphorylation regulates axonal outgrowth through Notch1 inhibition.","date":"2022","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/35581583","citation_count":8,"is_preprint":false},{"pmid":"30026235","id":"PMC_30026235","title":"Characterization of the binding mode of JNK-interacting protein 1 (JIP1) to kinesin-light chain 1 (KLC1).","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30026235","citation_count":8,"is_preprint":false},{"pmid":"23496950","id":"PMC_23496950","title":"The interaction of Kinesin-1 with its adaptor protein JIP1 can be regulated via proteins binding to the JIP1-PTB domain.","date":"2013","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23496950","citation_count":8,"is_preprint":false},{"pmid":"19695559","id":"PMC_19695559","title":"Postpartum radical trachelectomy for IB1 squamous cell carcinoma of the cervix diagnosed in pregnancy.","date":"2009","source":"American journal of obstetrics and gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/19695559","citation_count":8,"is_preprint":false},{"pmid":"31681759","id":"PMC_31681759","title":"JIP1 Deficiency Protects Retinal Ganglion Cells From Apoptosis in a Rotenone-Induced Injury Model.","date":"2019","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/31681759","citation_count":7,"is_preprint":false},{"pmid":"35193525","id":"PMC_35193525","title":"Chemotherapy versus chemoradiotherapy for FIGO stages IB1 and IIA1 cervical squamous cancer patients with lymphovascular space invasion: a retrospective study.","date":"2022","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35193525","citation_count":7,"is_preprint":false},{"pmid":"25986397","id":"PMC_25986397","title":"[Surgery alone or in association with preoperative uterovaginal brachytherapy for stage IB1 cervical cancer: Toxicities profiles].","date":"2015","source":"Gynecologie, obstetrique & fertilite","url":"https://pubmed.ncbi.nlm.nih.gov/25986397","citation_count":7,"is_preprint":false},{"pmid":"26580917","id":"PMC_26580917","title":"Pretreatment Factors Associated with Recurrence for Patients with Cervical Cancer International Federation of Gynecology and Obstetrics Stage IB1 Disease.","date":"2015","source":"Gynecologic and obstetric investigation","url":"https://pubmed.ncbi.nlm.nih.gov/26580917","citation_count":7,"is_preprint":false},{"pmid":"29487176","id":"PMC_29487176","title":"Aplip1, the Drosophila homolog of JIP1, regulates myonuclear positioning and muscle stability.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/29487176","citation_count":6,"is_preprint":false},{"pmid":"18979134","id":"PMC_18979134","title":"Matched-case comparison for the role of surgery in FIGO stage Ib1-IIa squamous cell carcinoma of cervix and suspicious para-aortic lymph node metastasis.","date":"2008","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18979134","citation_count":6,"is_preprint":false},{"pmid":"35456931","id":"PMC_35456931","title":"Colocalization and Interaction Study of Neuronal JNK3, JIP1, and β-Arrestin2 Together with PSD95.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35456931","citation_count":5,"is_preprint":false},{"pmid":"19596915","id":"PMC_19596915","title":"Expression of JNK-interacting protein JIP-1 and insulin-like growth factor II in Wilms tumour cell lines and primary Wilms tumours.","date":"2009","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19596915","citation_count":5,"is_preprint":false},{"pmid":"39999166","id":"PMC_39999166","title":"Bipartite binding of the intrinsically disordered scaffold protein JIP1 to the kinase JNK1.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39999166","citation_count":4,"is_preprint":false},{"pmid":"39013462","id":"PMC_39013462","title":"Structural basis of homodimerization of the JNK scaffold protein JIP2 and its heterodimerization with JIP1.","date":"2024","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/39013462","citation_count":4,"is_preprint":false},{"pmid":"12064607","id":"PMC_12064607","title":"Connexin26 is regulated in rat urothelium by the scaffold protein IB1/JIP-1.","date":"2001","source":"Cell communication & adhesion","url":"https://pubmed.ncbi.nlm.nih.gov/12064607","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51050,"output_tokens":10781,"usd":0.157433,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21444,"output_tokens":6775,"usd":0.138297,"stage2_stop_reason":"end_turn"},"total_usd":0.29573,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of human JNK1 complexed with the JIP1 peptide (pepJIP1) revealed that Pro157, Leu160, and Leu162 of pepJIP1 make van der Waals contacts and Arg156 of pepJIP1 forms a hydrogen bond with Glu329 of JNK1, conferring selectivity for JNK1 over other MAPKs. Peptide binding induces a hinge motion between N- and C-terminal domains of JNK1, distorting the ATP-binding cleft and reducing ATP affinity (allosteric inhibition mechanism).\",\n      \"method\": \"X-ray crystallography of JNK1–pepJIP1 binary complex and JNK1–pepJIP1–SP600125 ternary complex\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structures with direct identification of contact residues; mechanistic conclusions about allostery structurally validated\",\n      \"pmids\": [\"15141161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"JIP1 scaffold protein is required for stress-induced JNK activation in vivo: JIP1-knockout mice are refractory to JNK activation caused by excitotoxic and anoxic stress. Under stress, JIP1 redistributes from neurites to the soma together with activated JNK and phosphorylated c-Jun.\",\n      \"method\": \"Homologous recombination gene knockout in mice; live-imaging of JIP1 localization in primary hippocampal neurons; JNK activation assays in brain\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined biochemical readout (JNK phosphorylation) in vivo; replicated with in vitro stress models\",\n      \"pmids\": [\"11562351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JIP1 coordinates bidirectional APP axonal transport by switching between anterograde (kinesin-1) and retrograde (dynein) motor complexes. JIP1 binds kinesin heavy chain (KHC) directly and relieves KHC autoinhibition; dynactin subunit p150Glued competes with KHC for JIP1 binding and inhibits KHC activation. JNK-dependent phosphorylation of JIP1 at Ser421 acts as a molecular switch: phosphorylation promotes retrograde while dephosphorylation promotes anterograde transport.\",\n      \"method\": \"Single-molecule motility assays; co-immunoprecipitation; live imaging of APP transport in neurons; phosphomutant (S421A/S421D) analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted in single-molecule assays, competitive binding in vitro, and validated with phosphomutants in neurons; multiple orthogonal methods\",\n      \"pmids\": [\"23897889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JIP1 binds directly to the autophagosome adaptor LC3 via a conserved LIR motif. This interaction is required for retrograde autophagosome transport initiation and sustenance in axons. LC3 binding to JIP1 competitively disrupts JIP1-mediated kinesin-1 activation, and dephosphorylated JIP1-S421 (maintained by autophagosome-associated MKP1 phosphatase) favors retrograde transport, ensuring robust retrograde autophagosomal movement.\",\n      \"method\": \"Direct binding assay; live-cell imaging of autophagosome transport; JIP1 depletion and rescue with phosphomutants (S421A, S421D); competitive binding assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding established, LIR motif identified, phosphomutant rescue in neurons, MKP1 phosphatase involvement demonstrated; multiple orthogonal methods\",\n      \"pmids\": [\"24914561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"JIP1 binds the cytoplasmic intracellular domain (AID) of APP. This interaction was confirmed in vitro, in vivo by FRET, and in mouse brain lysates, linking APP processing by γ-secretase to JNK stress-kinase signaling pathways.\",\n      \"method\": \"Yeast two-hybrid; in vitro binding assay; FRET in cells; co-immunoprecipitation from mouse brain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal methods (yeast two-hybrid + in vitro + FRET + brain Co-IP); independently confirmed in subsequent studies\",\n      \"pmids\": [\"11724784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JNK binding to JIP1 is necessary for stimulus-induced dissociation of DLK from JIP1, DLK oligomerization, and JNK module activation. JNK phosphorylates JIP1 on Thr-103; this phosphorylation is specifically required for DLK dissociation and subsequent module activation, not other JNK-dependent phosphorylation sites on JIP1.\",\n      \"method\": \"Mutagenesis of JIP1 phosphorylation sites; in vitro kinase assays; co-immunoprecipitation; DLK oligomerization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of specific residue combined with multiple functional readouts; single lab but orthogonal methods\",\n      \"pmids\": [\"12756254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IB1 (rat homolog of JIP-1) is a DNA-binding nuclear protein expressed in pancreatic beta-cells that binds the GTII cis-regulatory element of the GLUT2 promoter in vitro and transactivates the GLUT2 gene. An activation domain was mapped to the first 280 amino acids. IB1 localizes to both cytoplasm and nucleus of insulin-secreting cells.\",\n      \"method\": \"Expression cloning; in vitro DNA binding assay; transactivation reporter assay; immunocytochemistry; GAL4 domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods establishing DNA binding, transactivation, and subcellular localization in a single study\",\n      \"pmids\": [\"9442013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IB1/JIP-1 overexpression in insulin-producing cells prevents JNK-mediated phosphorylation of c-Jun, ATF2, and Elk1 and decreases IL-1β- and ΔMEKK1-induced apoptosis. Reducing IB1 content (antisense RNA) increases c-Jun phosphorylation and apoptosis. A missense mutation (559N) abolishes IB1's ability to counteract JNK-pathway inhibition of insulin transcription and to prevent MEKK1-induced apoptosis.\",\n      \"method\": \"Antisense RNA knockdown in beta-cell lines; overexpression with viral gene transfer; kinase activity assays; apoptosis measurement; functional mutation analysis (559N)\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, overexpression, functional mutation), two beta-cell line systems\",\n      \"pmids\": [\"10700186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JIP1 scaffold protein is essential for JNK activation in adipose tissue during obesity. JIP1 deficiency prevents JNK-dependent phosphorylation of IRS-1 on Ser307, thereby protecting against obesity-induced insulin resistance.\",\n      \"method\": \"Jip1 gene knockout mice fed high-fat diet; JNK activity assays in adipose tissue; IRS-1 phosphorylation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with defined biochemical (kinase activity, IRS-1 phosphorylation) and physiological readouts\",\n      \"pmids\": [\"15314024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Hyperphosphorylated Tau interacts with JIP1 under pathological conditions, sequestering JIP1 in the cell body and impairing JIP1 transport into axons. Tau competes with kinesin light chain for JIP1 binding. This pathological Tau/JIP1 interaction requires Tau phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation from K3 (K369I mutant Tau) transgenic mouse brain and AD human brain; immunofluorescence; primary neuronal culture transfection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in transgenic mouse and human AD brain, localization by immunofluorescence, competition assay; single lab\",\n      \"pmids\": [\"19491104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila APLIP1 (JIP-1 homolog) genetically interacts with kinesin-1 and dynein: Aplip1 mutation causes reduced anterograde and retrograde vesicle transport and reduced retrograde mitochondria transport, with synthetic phenotypes when combined with Dynein heavy chain heterozygous mutation, indicating APLIP1 is part of motor-cargo linkage complexes for both motors.\",\n      \"method\": \"Genetic screen; Aplip1 mutant analysis (larval paralysis, axonal swelling); quantitative axonal transport assays; double-mutant epistasis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with two separate motors, quantitative transport assays, defined phenotypic readouts; Drosophila ortholog of MAPK8IP1\",\n      \"pmids\": [\"16332540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JIP1 localizes specifically to a single neurite before polarization and accumulates in the emerging axon after specification in cortical neurons. JIP1 is required for normal axonal development and promotes axonal growth dependent on kinesin-1 binding and via a newly discovered interaction with c-Abl tyrosine kinase. JIP1 is phosphorylated by c-Abl, and mutation of the c-Abl phosphorylation site on JIP1 abrogates its ability to promote axonal growth.\",\n      \"method\": \"Live-cell imaging; JIP1 knockdown and rescue; co-immunoprecipitation with c-Abl; phosphorylation-site mutagenesis; axon length quantification\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, new binding partner identified by Co-IP, phosphomutant validation; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18261906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JIP1 interacts with the GTP-locked active form of Rab10 and directly connects Rab10 to kinesin-1 light chain (KLC), forming a kinesin-1/JIP1/Rab10 complex required for anterograde transport of plasmalemmal precursor vesicles (PPVs) during axonal growth and neuronal polarization in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation; JIP1 knockdown; live imaging of PPV transport; in vivo neuronal polarization assay in rat cortex\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP, in vitro knockdown and in vivo validation; single lab\",\n      \"pmids\": [\"24478353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IB1/JIP1 homodimerizes through a unique SH3–SH3 interaction. X-ray crystallography showed the dimer interface covers the region normally engaged in PxxP-mediated ligand recognition. Point mutations disrupting dimerization reduce IB1-dependent basal JNK activity and impair GLUT2 expression and glucose-dependent insulin secretion in beta-cells.\",\n      \"method\": \"X-ray crystallography; site-directed mutagenesis; JNK activity assay; GLUT2 expression; glucose-stimulated insulin secretion\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus functional cellular readouts in a single study; strong mechanistic evidence\",\n      \"pmids\": [\"16456539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"LZK (a mixed lineage kinase) binds the C-terminal region of JIP-1 through its kinase catalytic domain, and LZK-induced JNK activation is markedly enhanced when co-expressed with JIP-1. LZK directly phosphorylates and activates MKK7.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; co-transfection/overexpression JNK activity assay\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding by Co-IP, kinase assay for LZK→MKK7, functional enhancement shown; single lab\",\n      \"pmids\": [\"11726277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Akt1 interacts with JIP1 and its catalytic activity is inhibited when bound. JNK2-mediated phosphorylation of JIP1 causes dissociation of Akt1 from JIP1, restoring Akt1 activity. Dissociated Akt1 then binds SEK1 and inhibits it by phosphorylation on Ser-80, forming a negative regulatory feedback loop during glucose deprivation.\",\n      \"method\": \"Co-immunoprecipitation; kinase activity assays; siRNA knockdown of JIP1, SEK1, and Akt1; phosphorylation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus siRNA knockdowns plus kinase assays; multiple readouts but single lab\",\n      \"pmids\": [\"15998799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VRK2 stably interacts with JIP1, TAK1, and MKK7 (but not JNK), and its binding to the JIP1 signalosome prevents JNK association, reducing JNK phosphorylation and AP-1-dependent transcription in response to IL-1β. Knockdown of JIP1 eliminates the AP-1 transcriptional response to IL-1β.\",\n      \"method\": \"Co-immunoprecipitation; shRNA and siRNA knockdown; AP-1 reporter assays; JNK phosphorylation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RNAi knockdown plus transcriptional reporter; multiple methods, single lab\",\n      \"pmids\": [\"18286207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Src family kinases directly bind and tyrosine-phosphorylate JIP1 under basal conditions, increasing JIP1 affinity for DLK and maintaining the JIP-JNK module in a catalytically inactive state.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; tyrosine phosphorylation detection; multiple cell systems\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and phosphorylation shown with Co-IP and kinase assay in multiple systems; single lab\",\n      \"pmids\": [\"17242197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JIP1 serves as a scaffold for MLK3, MKK7, and JNK in beta-cells; cytokine-induced reduction of IB1/JIP-1 content increases JNK activity and apoptosis rate. Overproducing IB1/JIP-1 prevents cytokine-induced apoptosis by inhibiting caspase-3 cleavage. Haploinsufficient mice (one disrupted Jip1 allele) show increased JNK activity and basal apoptosis in isolated pancreatic islets.\",\n      \"method\": \"Adenoviral gene transfer (overexpression and knockdown); JNK activity assay; caspase-3 cleavage assay; apoptosis measurement; heterozygous knockout mice\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell models plus in vivo haploinsufficient mice; orthogonal overexpression and loss-of-function with caspase-3 mechanistic readout\",\n      \"pmids\": [\"12640031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The transcriptional repressor REST controls the tissue-specific expression of MAPK8IP1/IB1. REST binds the NRSE element in the IB1 promoter (confirmed by EMSA), represses IB1 transcription in non-beta, non-neuronal cells, and this repression requires histone deacetylase activity (abolished by trichostatin A).\",\n      \"method\": \"Luciferase reporter assay; EMSA (mobility shift assay); REST transfection; NRSE mutagenesis; trichostatin A treatment\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA demonstrating direct DNA binding, reporter assay, NRSE mutagenesis, and pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"11585908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"JIP1-mediated JNK activation (via Thr103 phosphorylation of JIP1) is required for obesity-induced insulin resistance. A Jip1 point mutation (T103A) that selectively blocks JIP1-mediated JNK activation severely impairs high-fat-diet-induced JNK activation and protects mice from obesity-induced insulin resistance.\",\n      \"method\": \"Germ-line Jip1 T103A knock-in mice; high-fat diet challenge; JNK activation assay; insulin tolerance/glucose tolerance tests\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model with specific point mutation isolating JIP1 scaffold function; defined biochemical and metabolic phenotype\",\n      \"pmids\": [\"20679483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JIP1 is cleaved by caspase-3 at two sites during TRAIL- and staurosporine-induced apoptosis, leading to disassembly of the JIP1/JNK scaffold complex and subsequent JNK inactivation. Inhibition of caspase-3-mediated JIP1 cleavage sustains JNK activation. Maximal JNK activation correlates with intact JIP1, while JIP1 cleavage correlates with JNK inactivation.\",\n      \"method\": \"Cell apoptosis assays (TRAIL, staurosporine); Western blot detection of caspase-3-mediated JIP1 cleavage; caspase-3 inhibitor (DEVD.fmk); co-immunoprecipitation of JIP1/JNK complex\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — caspase cleavage sites identified, pharmacological inhibition demonstrates mechanistic link to JNK activity; single lab\",\n      \"pmids\": [\"21237154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RALA GTPase, activated by RLF (in complex with JIP1 and JNK), promotes assembly and activation of MLK3, MKK4, and JNK onto the JIP1 scaffold following oxidative stress. This pathway mediates ROS-induced JNK-dependent FOXO activation and is conserved in C. elegans (ral-1 and jip-1 depletion both impair FOXO/DAF16 nuclear translocation).\",\n      \"method\": \"Co-immunoprecipitation; siRNA/RNAi knockdown; FOXO reporter assays; C. elegans genetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi, and cross-species genetic validation; single lab\",\n      \"pmids\": [\"23770673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-1β stimulates Lys-63-linked ubiquitination of MLK3 by TRAF6 via a conserved pentapeptide motif in the MLK3 catalytic domain. This ubiquitination is required for dissociation of monomeric MLK3 from the JIP1/IB1 scaffold, enabling MLK3 dimerization, autophosphorylation, and activation. Preventing MLK3 ubiquitination (or adding A20 deubiquitinase) blocks MLK3 activation and BAX translocation in cytokine-stimulated beta-cells.\",\n      \"method\": \"Ubiquitination assays; co-immunoprecipitation; MLK3 dimerization assays; BAX translocation assay; A20 expression; mutagenesis of TRAF6-binding motif\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical reconstitution of ubiquitination, mutagenesis of motif, deubiquitinase rescue, and functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"23172226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Vaccinia virus B1R kinase binds the central region of JIP1 (independent of B1R kinase activity), increasing the amount of MKK7 and TAK1 bound to JIP1 (more stable or higher affinity), increasing JNK phosphorylation in the complex, and thereby enhancing c-Jun transcription factor activity.\",\n      \"method\": \"Co-immunoprecipitation; kinase activity assays; reporter assays for c-Jun activity; kinase-dead B1R mutant\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with kinase-dead mutant separates binding from catalytic activity; c-Jun reporter as functional readout; single lab\",\n      \"pmids\": [\"16840345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SHIP2 interacts with JIP1 (confirmed in overexpression and native cells), positively modulates MLK3/JIP1-mediated JNK1 activation, and increases tyrosine phosphorylation of JIP1. This SHIP2 effect on JNK activity and JIP1 tyrosine phosphorylation is independent of SHIP2 phosphoinositide 5-phosphatase activity and is prevented by Src/Abl kinase inhibitors (PP2, Glivec).\",\n      \"method\": \"Co-immunoprecipitation in overexpression and endogenous systems; JNK activity assay; phosphatase-dead SHIP2 mutant; kinase inhibitor treatment\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in native cells plus catalytic-dead mutant to separate docking from enzymatic function; single lab\",\n      \"pmids\": [\"18486448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JIP1 and JIP3 cooperate to relieve kinesin-1 autoinhibition: JIP1 binds KHC (kinesin heavy chain) and KLC, while JIP3 binds KLC. Together they mediate anterograde axonal transport of TrkB. This cooperative mechanism is required for BDNF-induced TrkB retrograde signaling.\",\n      \"method\": \"JIP1 knockout mice; sciatic nerve ligation analysis; live imaging; microtubule-binding assays; microfluidic chamber assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus reconstitution-like motor assays and live imaging; single lab but multiple complementary methods\",\n      \"pmids\": [\"28638935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JIP1b has two novel regions in its central domain that interact with the coiled-coil domain of KLC1 (in addition to the conventional C-terminal 11-amino acid/C11 region that binds KLC1-TPR). The novel regions are required for high-frequency APP anterograde transport, while the C11 domain (regulated by the second novel region) is required for fast-velocity APP transport. KLC1 Thr466 phosphorylation abolishes C11/KLC1-TPR interaction and fast-velocity transport.\",\n      \"method\": \"Quantitative live-imaging of APP transport in JIP1-deficient neurons; truncation/domain mapping; co-immunoprecipitation; phosphomutant analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative transport assays plus domain mapping in neurons; single lab, multiple complementary methods\",\n      \"pmids\": [\"25165140\", \"29093025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"JIP1 binds RBP-Jκ (a Notch1 transcriptional effector) via the C-terminal SH3 domain of JIP1 interacting with the proline-rich domain of RBP-Jκ, causing cytoplasmic retention of RBP-Jκ and suppressing Notch1 activity. Conversely, RBP-Jκ inhibits JIP1-mediated JNK1 activation and cell death.\",\n      \"method\": \"Co-immunoprecipitation; subcellular fractionation; Notch1 reporter assay; domain-mapping by deletion mutants\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus reporter assay plus fractionation; single lab\",\n      \"pmids\": [\"20508646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IB1/JIP1 selectively stabilizes the short splice variants of JNK (not the long variants) against proteasomal degradation, increasing their steady-state protein levels. This represents a mechanism by which IB1 regulates the JNK pathway independent of direct kinase cascade assembly.\",\n      \"method\": \"Tetracycline-inducible IB1 expression in HEK293 cells; Western blot for JNK splice variants across tissues; protein stability assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system with protein stability assay; multiple tissues examined; single lab\",\n      \"pmids\": [\"17669625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JIP1 mediates anterograde transport of APP by binding to both KHC and KLC of kinesin-1. Phosphorylation of KLC1 at Thr466 abolishes the JIP1b C11/KLC1-TPR interaction and the enhanced fast velocity of APP transport; this KLC1 phosphorylation increases in aged brains, suggesting age-related impairment of APP transport.\",\n      \"method\": \"In vitro binding assays (ITC, calorimetry); phosphomutant KLC1 (T466E); quantitative transport imaging in neurons; aged brain biochemistry\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphomutant biochemistry plus transport imaging plus brain aging data; single lab\",\n      \"pmids\": [\"29093025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biochemical characterization of the JIP1/KLC1-TPR interaction identified seven KLC1 residues critical for JIP1 binding. The autoinhibitory LFP-acidic motif of KLC1 only marginally inhibits JIP1 binding. JIP1 competes with alcadein-α (a W-acidic motif cargo) for the same KLC1-TPR footprint.\",\n      \"method\": \"Isothermal titration calorimetry (ITC); truncation mapping; competitive binding assays; structural footprinting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative biophysical binding assay (ITC) with extensive domain mapping and competition assays; single lab\",\n      \"pmids\": [\"30026235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JIP1-mediated JNK activation negatively regulates synaptic plasticity and spatial memory: Jip1 knock-in mice with a point mutation that blocks JIP1-mediated JNK activation show increased NMDAR currents, lower threshold for hippocampal LTP induction, and improved hippocampus-dependent spatial memory and fear conditioning.\",\n      \"method\": \"Jip1 knock-in mice (point mutation blocking JNK activation); electrophysiology (NMDAR currents, LTP); behavioral tests (Morris water maze, fear conditioning); second independent Jip1 mutant mouse line\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent knock-in mouse models, electrophysiology, and behavioral readouts; multiple orthogonal methods\",\n      \"pmids\": [\"29540552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cdk5 phosphorylates JIP1 at Thr205, enhancing axonal outgrowth. Phospho-JIP1(Thr205) amplifies phosphorylation of Itch (E3 ubiquitin ligase), increasing Notch1 ubiquitination and degradation, thereby reducing Notch1-IC levels that would otherwise inhibit axonal outgrowth. A phosphomimic JIP1(T205E) rescues axonal outgrowth defects in JIP1−/− and p35−/− neurons.\",\n      \"method\": \"Interactome screen; in vitro and in vivo phosphorylation assays; phosphomimic/phosphodeficient mutants; rescue experiments in knockout neurons; Notch1 ubiquitination assay\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site mutagenesis with rescue in KO neurons plus downstream ubiquitination assay; single lab, multiple methods\",\n      \"pmids\": [\"35581583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NMR spectroscopy revealed that JNK1 engages the intrinsically disordered JIP1 tail at not only the canonical D-motif but also a non-canonical F-motif, establishing a bipartite binding mode. Crystal structure of JIP1–JNK1 complex at 2.35 Å confirmed this bipartite interaction.\",\n      \"method\": \"NMR spectroscopy of the JIP1 disordered tail; X-ray crystallography of JIP1–JNK1 complex at 2.35 Å\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structure plus NMR; two orthogonal structural methods in a single study identifying new binding motif\",\n      \"pmids\": [\"39999166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JIP1 and JIP2 heterodimerize via their SH3 domains with affinity comparable to homodimerization. Crystal structure of JIP1–JIP2 SH3 heterodimer revealed how structural features from each homodimer are used to stabilize the heterodimer. Targeted mutations disrupting dimerization impaired JNK pathway activation in cellulo.\",\n      \"method\": \"NMR spectroscopy; X-ray crystallography of JIP2 SH3 homodimer and JIP1–JIP2 SH3 heterodimer; mutagenesis and JNK activity assay in cells\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus NMR plus mutagenesis with functional JNK assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"39013462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila muscles, Aplip1 (JIP1 ortholog) localizes to the myotendinous junction. Aplip1 mutations cause myonuclear mispositioning and muscle instability. Aplip1 genetically interacts with Raps/Pins and kinesin for nuclear positioning, and both Dynein and Kinesin localization are disrupted in Aplip1 mutants, indicating JIP1 regulates Dynein- and Kinesin-mediated nuclear pulling.\",\n      \"method\": \"Aplip1 mutant Drosophila; genetic interaction with Raps/Pins and Kinesin; immunofluorescence of motor localization; live imaging of nuclear dynamics\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus motor localization data in Drosophila ortholog; single lab, multiple complementary approaches\",\n      \"pmids\": [\"29487176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DUSP1 (dual-specificity phosphatase 1) interaction with the JIP1 scaffold protein prevents DUSP1-mediated dephosphorylation of JNK, protecting AP-1 activation and cytokine production from DUSP1 inhibition during viral infection.\",\n      \"method\": \"Co-immunoprecipitation; JNK phosphorylation assays; AP-1 reporter assay; siRNA knockdown of DUSP1 and JIP1\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating physical interaction, phosphatase protection assay, reporter assay; single lab\",\n      \"pmids\": [\"29234123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JNK3, JIP1, and β-arrestin2 co-localize and form complexes with PSD95 at postsynaptic densities in hippocampal neurons, as demonstrated by super-resolution microscopy and co-immunoprecipitation.\",\n      \"method\": \"Super-resolution microscopy (STED/STORM); co-immunoprecipitation from primary hippocampal neurons\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-resolution localization plus Co-IP establishing synaptic complex; single lab\",\n      \"pmids\": [\"35456931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JIP1 PTB domain (specifically residue F687) is required for JIP1–kinesin-1 binding and neurite tip localization. JIP3 is a major JIP1-binding protein identified by proteomics; JIP1–JIP3 association is F687-dependent and forms a stable ternary complex with kinesin-1. Other PTB-binding proteins can disrupt this ternary complex.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis (F687); proteomic analysis; subcellular localization imaging in Neuro2a cells\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with proteomics and localization data; single lab\",\n      \"pmids\": [\"23496950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Class I HDAC inhibitors induce JIP1 expression in cardiomyocytes, leading to elevated KIF5A expression and formation of JIP1:KIF5A:microtubule complexes that regulate intracellular cargo (autophagosome) transport, without significantly altering JNK signaling in this context.\",\n      \"method\": \"HDAC inhibitor treatment; JIP1 knockdown; KIF5A expression analysis; co-immunoprecipitation of JIP1:KIF5A:microtubule complex; autophagosome transport imaging\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — JIP1 knockdown confirms dependence, complex formation by Co-IP, transport imaging; single lab\",\n      \"pmids\": [\"28886967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JIP1 and POSH form a multiprotein scaffold network for TCR-mediated JNK1 activation in CD8+ T cells. Disruption of the POSH/JIP1 complex impairs JNK1 activation, reduces c-Jun, T-bet, and Eomesodermin induction, and results in impaired T cell proliferation, cytokine production, and anti-tumor responses.\",\n      \"method\": \"Co-immunoprecipitation; dominant-negative disruption of POSH/JIP1 complex; JNK1 kinase assay; transcription factor assays; tumor clearance assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional disruption of complex with defined biochemical and cellular readouts; single lab\",\n      \"pmids\": [\"23963642\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAPK8IP1/JIP1 is an intrinsically disordered scaffold protein that assembles MLK3–MKK7–JNK into a macromolecular signaling complex via its D-motif and a newly identified F-motif (bipartite binding to JNK1), uses SH3-domain homodimerization (and heterodimerization with JIP2) to regulate JNK pathway activation, controls the direction of axonal transport of APP, autophagosomes, TrkB, and other cargoes by switching between kinesin-1 activation (relieving KHC autoinhibition, regulated by JNK-dependent S421 phosphorylation) and dynein/dynactin engagement, acts downstream of upstream kinases (Cdk5, c-Abl, Src family kinases, JNK2) that phosphorylate JIP1 at specific residues to modulate its protein–protein interactions, and serves as an anti-apoptotic regulator in neurons and pancreatic beta-cells by sequestering JNK in the cytoplasm and limiting stress-induced c-Jun phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAPK8IP1 (JIP1/IB1) is an intrinsically disordered scaffold protein that organizes the JNK MAP kinase cascade and, independently, governs the direction of microtubule-based axonal cargo transport [#18, #2]. It assembles the MLK3/DLK–MKK7–JNK module on a single platform: JNK docking is mediated by a canonical D-motif together with a non-canonical F-motif that together form a bipartite binding mode resolved by crystallography and NMR [#0, #34], while regulated SH3-domain homodimerization—and heterodimerization with JIP2—is structurally required for efficient pathway activation [#13, #35]. Activation of the assembled module is gated by phosphorylation of JIP1 itself: JNK phosphorylation of Thr103 triggers DLK dissociation and module firing [#5], whereas tonic Src-family tyrosine phosphorylation maintains the complex in an inactive, DLK-bound state [#17]. Genetically, JIP1 is essential for stress-induced JNK activation in vivo, and a knock-in mutation that selectively blocks JIP1-scaffolded JNK signaling protects mice from obesity-induced insulin resistance and lowers the threshold for hippocampal LTP and spatial memory [#1, #20, #32]. In its second major role JIP1 links cargo to motors, binding kinesin heavy and light chains to relieve kinesin-1 autoinhibition while dynactin p150Glued competes for binding; JNK-dependent phosphorylation of Ser421 acts as a directional switch between anterograde kinesin and retrograde dynein transport of APP, autophagosomes, and TrkB [#2, #3, #26]. JIP1 connects this transport machinery to specific cargoes including the APP intracellular domain, LC3-marked autophagosomes, and Rab10 vesicles [#4, #3, #12]. As an anti-apoptotic regulator in pancreatic beta-cells and neurons, JIP1 sequesters and limits JNK-driven c-Jun phosphorylation, and its loss or caspase-3 cleavage de-represses JNK activation and apoptosis [#7, #18, #21]. JIP1 also functions in the nucleus as a DNA-binding transactivator of the GLUT2 gene, with its tissue-restricted expression set by REST-mediated repression [#6, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that the rat ortholog IB1 is not only a cytoplasmic protein but a nuclear DNA-binding transactivator, revealing a transcriptional role in beta-cells before its scaffold function was known.\",\n      \"evidence\": \"expression cloning, in vitro DNA binding, transactivation reporter and GAL4 domain mapping in insulin-secreting cells\",\n      \"pmids\": [\"9442013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA binding by the human protein in a physiological chromatin context not shown\", \"Relationship between nuclear transcriptional and cytoplasmic scaffold functions unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined JIP1/IB1 as an anti-apoptotic regulator that buffers JNK signaling in beta-cells, linking its abundance to control of c-Jun/ATF2 phosphorylation and survival.\",\n      \"evidence\": \"antisense knockdown and viral overexpression in beta-cell lines, kinase and apoptosis assays, functional 559N mutation\",\n      \"pmids\": [\"10700186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether sequestration vs. assembly explains the dose-dependent effect not distinguished\", \"In vivo relevance addressed only later\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic knockout demonstrated JIP1 is required for stress-induced JNK activation in vivo, moving the scaffold from a biochemical concept to a physiological requirement.\",\n      \"evidence\": \"Jip1 knockout mice, neuronal live-imaging, brain JNK activation assays under excitotoxic/anoxic stress\",\n      \"pmids\": [\"11562351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which upstream stimuli specifically require JIP1 not fully mapped\", \"Mechanism of neurite-to-soma redistribution unexplained\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected JIP1 to APP biology and to upstream MLKs, identifying both a cargo (APP intracellular domain) and a kinase input (LZK) for the scaffold.\",\n      \"evidence\": \"yeast two-hybrid, in vitro binding, FRET, brain Co-IP for APP; Co-IP and kinase assay for LZK/MKK7\",\n      \"pmids\": [\"11724784\", \"11726277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of APP–JIP1 binding for APP processing not established here\", \"LZK study Medium-confidence, single lab\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Explained the tissue-restricted expression of MAPK8IP1 through REST-mediated, HDAC-dependent repression at an NRSE element.\",\n      \"evidence\": \"luciferase reporter, EMSA, NRSE mutagenesis and trichostatin A treatment\",\n      \"pmids\": [\"11585908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcriptional inputs to the IB1 promoter unaddressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified Thr103 phosphorylation by JNK as the specific switch driving DLK dissociation and module activation, and confirmed the beta-cell anti-apoptotic scaffold function via caspase-3.\",\n      \"evidence\": \"site-specific mutagenesis, in vitro kinase and DLK oligomerization assays; adenoviral over/under-expression and haploinsufficient mice with caspase-3 readout\",\n      \"pmids\": [\"12756254\", \"12640031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Thr103 phosphorylation structurally weakens DLK affinity not resolved\", \"Other phosphosite contributions not excluded\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Provided the atomic basis of JIP1's selectivity for JNK1 and revealed an allosteric inhibition mechanism whereby peptide binding distorts the ATP cleft.\",\n      \"evidence\": \"X-ray crystallography of JNK1–pepJIP1 binary and ternary complexes\",\n      \"pmids\": [\"15141161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Captures only the D-motif; bipartite engagement defined only later\", \"Full-length disordered context not in the structure\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the JIP1-dependent JNK requirement to metabolic disease, showing JIP1 is needed for obesity-induced JNK activation and IRS-1 Ser307 phosphorylation underlying insulin resistance.\",\n      \"evidence\": \"Jip1 knockout mice on high-fat diet, adipose JNK and IRS-1 phosphorylation assays\",\n      \"pmids\": [\"15314024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contribution (adipose vs. liver vs. muscle) not dissected here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Uncovered regulatory crosstalk in which JIP1 sequesters and inhibits Akt1, with JNK2 phosphorylation releasing Akt1 to form a negative feedback loop.\",\n      \"evidence\": \"Co-IP, kinase assays, siRNA of JIP1/SEK1/Akt1 during glucose deprivation\",\n      \"pmids\": [\"15998799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation limited\", \"Physiological setting beyond glucose deprivation unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined SH3–SH3 homodimerization as a functional requirement, structurally explaining how dimerization occludes the PxxP ligand site and tunes basal JNK activity and beta-cell function.\",\n      \"evidence\": \"X-ray crystallography, dimer-disrupting mutagenesis, JNK/GLUT2/insulin-secretion readouts; plus viral B1R kinase binding study\",\n      \"pmids\": [\"16456539\", \"16840345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dimerization status is dynamically regulated in cells not established\", \"B1R study Medium-confidence, viral context\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established tonic inhibitory control of the module: Src-family tyrosine phosphorylation increases JIP1 affinity for DLK and locks the complex inactive, and IB1 stabilizes short JNK splice variants against degradation.\",\n      \"evidence\": \"Co-IP, in vitro kinase and tyrosine-phosphorylation assays; inducible IB1 expression and JNK protein stability assays\",\n      \"pmids\": [\"17242197\", \"17669625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific Src-family member and target tyrosines partially defined\", \"Single lab for each finding\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked JIP1 to axon specification and growth, identifying c-Abl as a kinase whose phosphorylation of JIP1 is required for kinesin-dependent axonal outgrowth.\",\n      \"evidence\": \"live imaging, knockdown/rescue, c-Abl Co-IP and phosphosite mutagenesis in cortical neurons; plus VRK2 signalosome study\",\n      \"pmids\": [\"18261906\", \"18286207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"c-Abl phosphosite identity and its effect on motor binding incompletely mapped\", \"VRK2 study Medium-confidence\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A knock-in mouse isolating JIP1 scaffold function (T103A) proved that JIP1-mediated JNK activation is causally required for obesity-induced insulin resistance.\",\n      \"evidence\": \"germ-line Jip1 T103A knock-in mice, high-fat diet, JNK and metabolic phenotyping\",\n      \"pmids\": [\"20679483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type origin of the protective metabolic effect not localized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved JIP1 as a bidirectional transport switch, showing it relieves kinesin-1 autoinhibition while p150Glued competes for binding and Ser421 phosphorylation sets transport direction for APP.\",\n      \"evidence\": \"single-molecule motility, competitive binding, live APP imaging, S421A/S421D phosphomutants in neurons\",\n      \"pmids\": [\"23897889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/phosphatase that toggle S421 in distinct compartments only partly identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Broadened the JIP1 scaffold and motor roles across pathways and cargoes: RALA/RLF-driven ROS-induced FOXO activation, POSH-dependent TCR/JNK1 signaling in CD8 T cells, and PTB-domain (F687)-mediated JIP3/kinesin-1 ternary complex assembly.\",\n      \"evidence\": \"Co-IP, RNAi, FOXO/transcription-factor reporters, C. elegans genetics; proteomics and F687 mutagenesis\",\n      \"pmids\": [\"23770673\", \"23963642\", \"23496950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each pathway shown by single labs\", \"Direct vs. indirect assembly within these networks not fully separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined cargo-specific transport mechanisms: a LIR motif binds LC3 to drive retrograde autophagosome transport (with MKP1 keeping S421 dephosphorylated), and JIP1 links GTP-Rab10 to KLC for anterograde precursor-vesicle transport; central KLC1-binding regions tune APP transport frequency and velocity.\",\n      \"evidence\": \"direct binding/competition assays, phosphomutant rescue, live imaging of autophagosomes, PPVs and APP; domain mapping and KLC1 phosphomutants\",\n      \"pmids\": [\"24914561\", \"24478353\", \"25165140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single scaffold coordinates competing cargo signals in one axon not integrated\", \"Rab10 and KLC1 findings Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed JIP1 cooperation and abundance control of transport: JIP1/JIP3 jointly relieve kinesin-1 autoinhibition for TrkB/BDNF retrograde signaling, and HDAC-inhibitor-induced JIP1 drives KIF5A-dependent cargo transport independent of JNK.\",\n      \"evidence\": \"JIP1 knockout, nerve ligation, motor-binding and live imaging; HDAC inhibition, knockdown and JIP1:KIF5A complex Co-IP in cardiomyocytes\",\n      \"pmids\": [\"28638935\", \"28886967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of JIP1 vs JIP3 not separated\", \"Single labs\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided biophysical and physiological resolution of transport regulation: KLC1-TPR binding residues and competition with W-acidic cargoes were mapped, KLC1 Thr466 phosphorylation (rising with brain age) impairs fast APP transport, and a JNK-blocking knock-in revealed JIP1-JNK as a negative regulator of synaptic plasticity and memory.\",\n      \"evidence\": \"ITC and competition assays, KLC1 T466E phosphomutant transport imaging, aged-brain biochemistry; two independent Jip1 knock-in mouse lines with electrophysiology and behavior\",\n      \"pmids\": [\"30026235\", \"29093025\", \"29540552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal link between age-related KLC1 phosphorylation and disease not established\", \"Transport-defect contribution to the memory phenotype not separated from JNK signaling\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined Cdk5-driven control of axon outgrowth through JIP1 Thr205 phosphorylation, which amplifies Itch-mediated Notch1 degradation, and placed JNK3/JIP1/β-arrestin2/PSD95 complexes at postsynaptic densities.\",\n      \"evidence\": \"interactome screen, phosphorylation assays, phosphomimic rescue in KO neurons, Notch1 ubiquitination assay; super-resolution microscopy and Co-IP\",\n      \"pmids\": [\"35581583\", \"35456931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"Interplay between Cdk5-Thr205, c-Abl, and Src inputs on the same scaffold unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined the JIP1–JNK interface, showing the disordered tail engages JNK1 bipartitely through both the canonical D-motif and a newly identified F-motif.\",\n      \"evidence\": \"NMR of the JIP1 disordered tail and 2.35 Å crystal structure of the JIP1–JNK1 complex; with JIP1–JIP2 SH3 heterodimer structure (2024)\",\n      \"pmids\": [\"39999166\", \"39013462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of F-motif loss in vivo not tested\", \"How bipartite docking integrates with allosteric ATP-cleft distortion not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single intrinsically disordered scaffold integrates competing inputs—nuclear transcription, JNK module assembly/inhibition, and bidirectional motor switching for distinct cargoes—within one cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting phosphocode (Thr103, Thr205, Ser421, tyrosines) to functional output\", \"Stoichiometry and spatial segregation of JIP1 complexes in vivo unknown\", \"No timeline disease-gene mutation linking MAPK8IP1 to a Mendelian disorder\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [18, 0, 13, 35]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 26, 39, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5, 17]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [7, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 40, 26]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 18, 23]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 3, 26, 12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 12, 40]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 18, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 33, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 40]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 19]}\n    ],\n    \"complexes\": [\n      \"MLK3/DLK–MKK7–JNK signaling module\",\n      \"JIP1–kinesin-1 (KHC/KLC) motor complex\",\n      \"JIP1–JIP2 SH3 heterodimer\",\n      \"POSH/JIP1 scaffold complex\"\n    ],\n    \"partners\": [\n      \"MAPK8 (JNK1)\",\n      \"MAP3K12 (DLK)\",\n      \"MAP2K7 (MKK7)\",\n      \"KIF5 (kinesin heavy chain)\",\n      \"KLC1\",\n      \"APP\",\n      \"MAP1LC3 (LC3)\",\n      \"RAB10\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}