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Showing MAPK8IP3 — JIP3 is a alias.

MAPK8IP3

C-Jun-amino-terminal kinase-interacting protein 3 · UniProt Q9UPT6

Length
1336 aa
Mass
147.5 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAPK8IP3 (JIP3/JSAP1) is a neuronally enriched scaffold protein that couples JNK-pathway signaling to microtubule-based intracellular transport (PMID:10523642, PMID:21750526). As a signaling scaffold, it directly binds and assembles the JNK kinase cascade — MEKK1, SEK1/MKK4 and MKK7, and JNK3 — into an activatable complex, with phosphorylation by ASK1 and ROCK1 enhancing kinase recruitment and JNK activation in response to oxidative and stress stimuli (PMID:10523642, PMID:12189133, PMID:19036714). In parallel, JIP3 functions as a bidirectional motor adaptor: it binds kinesin-1 through both kinesin light chain and, independently, kinesin heavy chain to activate anterograde motility and engage microtubules (PMID:11106729, PMID:21750526, PMID:25944905), while its N-terminal RH1 domain binds dynein light intermediate chain to form an activating dynein-dynactin complex for retrograde transport, making RH1 a dual motor-binding hub whose kinesin and dynein sites overlap (PMID:31690808, PMID:35829703, PMID:36476638, PMID:37909920). Through these motor interactions — coordinated by GTP-bound ARF6 and RAB10 — JIP3 controls axonal transport and positioning of lysosomes, late endosomes, autophagosomes, and the TrkB receptor (PMID:21775604, PMID:23633144, PMID:35829703, PMID:37909920). JIP3 is required for neuronal development and survival, restricting axon branching via GSK3β–doublecortin signaling and driving axon elongation through kinesin- and JNK-dependent cytoskeletal remodeling (PMID:21159948, PMID:23576431), and germline loss is perinatally lethal with telencephalic commissure defects (PMID:12897243). Loss of JIP3 produces focal axonal lysosome accumulations enriched in BACE1 and presenilin-2 that amplify amyloidogenic APP processing and elevate Aβ, disrupt the axonal periodic cytoskeleton, and lead to neurodegeneration (PMID:28784610, PMID:33788575, PMID:35013510); the disease-associated R578C gain-of-function variant remodels the JIP3 interactome, impairs late-endosome transport, hyperactivates JNK-driven apoptosis, and perturbs dopamine receptor 1 signaling (PMID:40111412).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Established JIP3 as a JNK-pathway scaffold, answering how upstream and downstream JNK cascade kinases are organized into a productive signaling module.

    Evidence Yeast two-hybrid, co-IP in COS-7 cells, and deletion mutants showing direct binding to JNK3, SEK1, and MEKK1 with module-dependent JNK3 activation

    PMID:10523642

    Open questions at the time
    • Did not establish stimulus-specific or tissue-specific regulation of complex assembly
    • No structural basis for the simultaneous binding of three kinases
  2. 2000 High

    Linked the JNK scaffold to motor transport by showing JIP3 binds kinesin-1 light chain, establishing it as a candidate kinesin cargo adaptor in brain.

    Evidence Yeast two-hybrid, in vitro Kd measurement (~200 nM to KLC TPR), brain co-IP, and GFP imaging on tubulovesicular structures; neuronal expression and growth-cone localization shown in parallel

    PMID:10629060 PMID:11106729

    Open questions at the time
    • Did not determine which cargoes are transported
    • Did not distinguish adaptor role from a regulatory role on the motor
  3. 2002 High

    Resolved how scaffolding activity is controlled, showing ASK1 phosphorylation of JIP3 is required to recruit and activate JNK upon oxidative stress.

    Evidence In vitro kinase assay, co-IP, H2O2 stimulation, and mutational analysis; ROCK1 later identified as a second activating kinase via TAP and ROCK1+/- mice

    PMID:12189133 PMID:19036714

    Open questions at the time
    • Phosphosite identity and stoichiometry not fully mapped
    • Interplay between ASK1 and ROCK1 inputs not resolved
  4. 2003 High

    Defined an in vivo developmental requirement, showing JIP3 is essential for telencephalic commissure formation upstream of RhoA-ROCK signaling.

    Evidence Germline Jip3 knockout mice with perinatal lethality and corpus callosum defects; JIP1 transgenic rescue and reduced phospho-FAK/phospho-JNK shown by an independent lab

    PMID:12897243 PMID:15572149

    Open questions at the time
    • Did not separate scaffolding from transport contributions to the phenotype
    • Cell-autonomous versus non-autonomous requirement unresolved
  5. 2011 High

    Demonstrated JIP3 actively activates kinesin-1 and bridges kinesin to dynein, redefining it from passive adaptor to motor regulator and bidirectional transport coordinator.

    Evidence In vitro single-molecule motility assays showing KHC-dependent activation, separation-of-function mutants, plus C. elegans co-IP and genetics showing UNC-16 links kinesin-1 to dynein DLIC for retrograde cargo transport

    PMID:21307258 PMID:21750526

    Open questions at the time
    • Structural basis of KHC activation not defined at this stage
    • How directionality is switched between motors unresolved
  6. 2013 High

    Established JIP3 as an organelle gatekeeper and a positive driver of process outgrowth, clarifying its dual roles in restricting organelle escape and promoting axon elongation.

    Evidence C. elegans EM and quantitative live imaging showing AIS-localized UNC-16 inhibits organelle escape; hippocampal neuron deletion mutants showing kinesin- and JNK-dependent axon elongation via cofilin/actin

    PMID:23576431 PMID:23633144

    Open questions at the time
    • Mechanism distinguishing gatekeeping from transport not fully resolved
    • Did not identify the full cargo set retained at the AIS
  7. 2011 High

    Identified specific receptor cargo, showing JIP3 binds TrkB and selectively drives its axonal anterograde transport to support BDNF signaling.

    Evidence Co-IP, juxtamembrane domain mapping, live axonal transport imaging, and BDNF/Erk signaling readouts in hippocampal neurons; JIP1/JIP3 cooperativity in relieving kinesin-1 autoinhibition shown later

    PMID:21775604 PMID:28638935

    Open questions at the time
    • Selectivity for axons over dendrites mechanistically unexplained
    • Other receptor cargoes not surveyed
  8. 2017 High

    Connected JIP3 transport function to neurodegenerative pathology, showing loss causes axonal lysosome accumulation that amplifies amyloidogenic APP processing.

    Evidence JIP3 knockout primary neurons and an AD mouse model with haploinsufficiency, showing BACE1/PS2-laden focal swellings and elevated Aβ; replicated in human iPSC neurons with JIP4 overlap

    PMID:28784610 PMID:33788575

    Open questions at the time
    • Causal chain from lysosome stalling to Aβ generation not fully dissected
    • Contribution of JIP4 redundancy to disease threshold unclear
  9. 2019 High

    Provided structural identity to the dual motor hub, localizing dynein DLIC and kinesin KHC binding to an overlapping N-terminal RH1 domain.

    Evidence Homology modeling/SAXS of the RH1-LZI tandem homodimer and pull-down assays; human DLIC binding and separation-of-function RH1 point mutations with C. elegans rescue established RH1 as a dual motor-binding hub

    PMID:31690808 PMID:35829703

    Open questions at the time
    • High-resolution structure of motor-bound RH1 not determined
    • Functional significance of the in vitro myosin 5A interaction in cells unresolved
  10. 2023 High

    Defined how directional transport is regulated by small GTPases, showing JIP3 activates dynein on autophagosomes/lysosomes under ARF6 and RAB10 control.

    Evidence Lysate-based single-molecule motility assays, live neuronal imaging, and ARF6/RAB10 GTPase mutants; DCX shown by reconstitution to compete with the second dynein and slow JIP3-dynein-dynactin transport

    PMID:36476638 PMID:37909920

    Open questions at the time
    • How RAB10 toggles between opposing motors mechanistically unresolved
    • Cargo-specific GTPase code not fully mapped
  11. 2022 Medium

    Linked JIP3-dependent lysosome transport to axonal integrity, showing depletion disrupts the periodic spectrin/actin scaffold and local microtubules.

    Evidence JIP3 KO iPSC neurons with super-resolution imaging of cytoskeletal markers at lysosome-filled swellings

    PMID:35013510

    Open questions at the time
    • Whether cytoskeletal disruption is cause or consequence of lysosome accumulation unresolved
    • Single lab, single model system
  12. 2025 Medium

    Established a disease mechanism for a pathogenic variant, showing R578C is a toxic gain-of-function that remodels the interactome and dysregulates transport, JNK, and dopamine signaling.

    Evidence Patient iPSC/cell lines with interactome MS, late-endosome transport imaging, JNK and dopamine receptor signaling assays, and ASO knockdown

    PMID:40111412

    Open questions at the time
    • No independent replication of the gain-of-function mechanism
    • In vivo correlate of dopamine receptor 1 dysregulation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How JIP3 integrates its scaffolding (JNK), gatekeeping, and bidirectional motor functions into a single regulated switch on individual cargoes remains unresolved.
  • No structural model of a JIP3-cargo-dual-motor assembly in a defined state
  • Mechanism coordinating JNK signaling output with transport activity unknown
  • Cargo-specific rules governing anterograde vs retrograde commitment undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 7 GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 4
Localization
GO:0005764 lysosome 4 GO:0031410 cytoplasmic vesicle 4 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-9609507 Protein localization 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 1
Partners
ARF6DLICJNK3KHCKLCMKK4RAB10TRKB
Complex memberships
JNK signaling module (MEKK1-SEK1/MKK4/MKK7-JNK)dynein-dynactin transport complexkinesin-1 (KHC/KLC)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 JIP3/JSAP1 (mouse) was identified as a scaffold protein that directly binds JNK3 (and JNK1/JNK2), SEK1 MAPKK, and MEKK1 MAPKKK via distinct regions, assembles them into a signaling complex, and facilitates JNK3 activation in cultured COS-7 cells; deletion of the JNK- or MEKK1-binding regions reduced JNK3 activation. Yeast two-hybrid screen, co-immunoprecipitation in COS-7 cells, in vitro binding assay, deletion mutant analysis, kinase activation assay Molecular and cellular biology High 10523642
2000 JIP3 (mouse SYD/JSAP1) was shown to bind kinesin-I via the tetratricopeptide repeat (TPR) domain of kinesin light chain (KLC) with Kd ~200 nM, and GFP-tagged mammalian SYD localizes to tubulovesicular structures that co-stain for kinesin-I and a secretory pathway marker; co-immunoprecipitation confirmed the complex forms in vivo in mouse brain. Yeast two-hybrid, in vitro binding/affinity measurement, co-immunoprecipitation, GFP live-cell imaging Cell High 11106729
2000 JIP3 is expressed predominantly in the brain (lower levels in heart) and accumulates in growth cones of developing neurites, establishing its neuronal subcellular localization. Immunofluorescence, Northern/Western blot Molecular and cellular biology Medium 10629060
2002 ASK1 phosphorylates JIP3/JSAP1 in vitro and in vivo; this phosphorylation enhances interactions of JSAP1 with SEK1/MKK4, MKK7, and JNK3, and is required for JSAP1 to recruit and activate JNK in response to H2O2, establishing a phosphorylation-dependent scaffolding mechanism. In vitro kinase assay, co-immunoprecipitation, H2O2 stimulation assay, mutational analysis The Journal of biological chemistry High 12189133
2000 Alternative splicing of the JSAP1 gene generates four isoforms (JSAP1a–d); the JNK-binding domain maps to aa 201–217 (exon 6); isoforms JSAP1c and JSAP1d, which contain an extra 31-aa sequence, show lower binding affinity for JNKs (especially JNK3), suggesting they may attenuate scaffolding activity. cDNA cloning, exon-intron mapping, co-immunoprecipitation binding assay Gene Medium 11024282
2003 Germline Jip3 knockout mice die at birth and display severe defects in telencephalic commissure (corpus callosum) morphogenesis; the phenotype is partly attributable to reduced RhoA/ROCK signaling, placing JIP3 upstream of RhoA-ROCK in brain commissure development. Targeted gene disruption (knockout mice), histological analysis, signaling pathway assay Proceedings of the National Academy of Sciences of the United States of America High 12897243
2005 JSAP1/JIP3 forms a complex with focal adhesion kinase (FAK) and mediates FAK/p130Cas-dependent JNK activation in response to fibronectin; JSAP1 co-localizes with JNK and phospho-FAK at the leading edge and stimulates cell migration in a JNK-binding-domain-dependent manner. Co-immunoprecipitation, co-expression/transfection, immunofluorescence co-localization, migration assay, dominant-negative constructs The Journal of biological chemistry Medium 16141199
2005 Transgenic expression of JIP1 partially rescued the corpus callosum and anterior commissure axon guidance defects of jsap1-/- mice, and JIP3-null brains showed reduced phospho-FAK and phospho-JNK distribution, linking JIP3 to FAK and JNK signaling in commissure axon guidance in vivo. Transgenic rescue in knockout mice, Western blot/immunohistochemistry Developmental biology Medium 15572149
2008 ROCK1 was identified as an upstream activator of JIP3; upon UVB stress in keratinocytes, ROCK1 binds JIP3 and phosphorylates it, which is required for JNK recruitment to JIP3 and subsequent JNK activation and apoptosis. Tandem affinity purification, co-IP, phosphorylation assay, ROCK1 inhibition, ROCK1+/- mice Science signaling High 19036714
2010 JIP3 restriction of axon branching in cerebellar granule neurons is mediated by GSK3β: JIP3 knockdown reduces GSK3β levels, and GSK3β knockdown phenocopies JIP3 knockdown; GSK3β phosphorylates doublecortin (DCX) at Ser327 to restrict axon branching downstream of JIP3. shRNA knockdown, in utero electroporation, kinase assay (GSK3β phosphorylation of DCX), cerebellar slice and in vivo rat models The Journal of neuroscience : the official journal of the Society for Neuroscience High 21159948
2010 ARF6 GTP-bound form interacts with JIP3 (via the LZII region), and JIP3 acts as a downstream effector of ARF6 to regulate neurite morphogenesis in cortical neurons; overexpression of an ARF6 dominant-negative mutant unable to bind JIP3, or JIP3 knockdown, both stimulate neurite elongation and branching. Pull-down/co-IP, dominant-negative ARF6 mutant, JIP3 knockdown, neurite morphology assay FEBS letters Medium 20493856
2011 Sunday Driver (JIP3/syd) interacts directly with kinesin heavy chain (KHC) via a domain independent of KLC; syd activates KHC for transport in an in vitro motility assay, increasing both KHC velocity and run length; syd mutants that bind KHC but not KLC are still transported to axons and dendrites. In vitro binding/pull-down, in vitro single-molecule motility assay, neuronal transport assay with separation-of-function mutants The EMBO journal High 21750526
2011 C. elegans UNC-16/JIP3 binds dynein light intermediate (DLI) chain and links kinesin-1 to dynein; both kinesin-1 and UNC-16 are required for localization of DLI-1 at microtubule plus-ends; retrograde transport of APL-1 depends on kinesin-1, UNC-16, and dynein, demonstrating that kinesin-1/UNC-16 mediates anterograde transport of dynein for subsequent retrograde cargo transport. Co-IP, genetic loss-of-function, live imaging in C. elegans The Journal of neuroscience : the official journal of the Society for Neuroscience High 21307258
2011 JIP3 binds directly to TrkB via a 12 aa juxtamembrane domain and links TrkB to kinesin-1, selectively driving TrkB anterograde transport in axons (but not dendrites) of hippocampal neurons; JIP3-mediated TrkB axonal transport enhances BDNF-induced Erk activation and axonal filopodia formation. Co-IP, deletion mutant binding assay, live axonal transport imaging, BDNF signaling assay The Journal of neuroscience : the official journal of the Society for Neuroscience High 21775604
2013 C. elegans UNC-16/JIP3 acts as an organelle gatekeeper at the axon initial segment (AIS): loss of UNC-16 causes up to 10-fold accumulation of Golgi, endosomes, and lysosomes (but not ER) in axons; UNC-16 is concentrated at the AIS and inhibits organelle escape past the AIS rather than promoting anterograde transport. Electron microscopy, quantitative live imaging of tagged organelles, time-lapse microscopy in C. elegans Genetics High 23633144
2013 JIP3 promotes axon elongation in hippocampal neurons via kinesin-dependent transport to axon tips and JNK-dependent modulation of cofilin and actin dynamics; deletion mutants lacking the kinesin-binding or JNK-binding domain abolish the elongation effect. Gain/loss-of-function, deletion mutants, in utero electroporation, immunofluorescence of cofilin phosphorylation The Journal of biological chemistry Medium 23576431
2014 Drosophila Syd/JIP3 specifically regulates kinesin- and dynein-dependent cortical pulling of myonuclei without affecting motor activity near the nucleus; Syd mediates kinesin-dependent localization of dynein to muscle ends, and JNK signaling acts upstream of Syd to promote this cortical dynein localization. Drosophila genetics (loss-of-function), live imaging, epistasis analysis, rescue with mammalian JIP3 PLoS genetics Medium 25522254
2015 JIP3 binding to KHC (not KLC) activates tetrameric kinesin-1 motility and is essential for axon elongation in hippocampal neurons and axon regeneration in sensory neurons; approximately four JIP3 molecules bind per KHC dimer; JIP3 binding to KLC engages kinesin-1 with microtubules. In vitro motility assay (single-molecule), stoichiometry analysis, hippocampal/sensory neuron culture with separation-of-function mutants The Journal of biological chemistry High 25944905
2015 JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport with functional redundancy; JSAP1/JLP binding to kinesin-1 heavy chain is required for kinesin-1/microtubule interactions; defective kinesin-1 transport in Jsap1/Jlp double-KO neurons leads to intra-axonal Ca2+ rise, JNK hyperactivation, and neuronal death via calpain and c-Jun activation. Double conditional knockout mice, primary neuron culture, gene rescue, calcium imaging, JNK inhibition, calpain inhibition Cell death and differentiation High 25571974
2015 ARF6 together with JIP3 and JIP4 regulate MT1-MMP endosome positioning and exocytosis in breast cancer cells; JIP3/JIP4 are recruited by WASH on MT1-MMP endosomes where they recruit dynein-dynactin and kinesin-1; plasma membrane ARF6 coordinates dynein/dynactin-kinesin-1 tug-of-war leading to endosome tubulation and MT1-MMP exocytosis. siRNA silencing, live-cell imaging, co-IP, co-localization, invasion assay The Journal of cell biology Medium 26504170
2017 JIP3 knockout mouse neurons accumulate lysosomes within focal axonal swellings that contain high levels of BACE1 and presenilin-2, leading to elevated Aβ peptide; JIP3 haploinsufficiency worsens amyloid plaque pathology in an AD mouse model, establishing JIP3 as a critical regulator of axonal lysosome transport and amyloidogenic APP processing. JIP3 knockout primary neuron culture, mouse AD model with haploinsufficiency, immunofluorescence, Aβ ELISA, western blot The Journal of cell biology High 28784610
2017 JIP1 and JIP3 cooperate to relieve kinesin-1 autoinhibition for TrkB anterograde axonal transport: JIP1 binds KHC and KLC while JIP3 binds KLC; their combined binding is essential for TrkB transport and BDNF-induced retrograde signaling. JIP1 knockout mice, sciatic nerve ligation, live imaging in microfluidic chambers, microtubule-binding assay Cellular and molecular life sciences : CMLS Medium 28638935
2017 UNC-16/JIP3 is present on Golgi and is required for polarized distribution of synaptic vesicle proteins (SVPs) in neurons; UNC-16 acts through LRK-1/LRRK2, which regulates Golgi localization of AP-1 μ-subunit; UNC-16 and LRK-1 together via AP-3 regulate SVP transport carrier composition at the Golgi. C. elegans genetics, immunofluorescence, co-IP, fluorescent reporter imaging PLoS genetics Medium 29145394
2019 JSAP1/JIP3 and JLP are required for ARF6 localization to the midbody during cytokinesis; they form a tripartite complex with active ARF6 and kinesin-1 heavy chain; JSAP1/JLP mutants unable to bind active ARF6 or KHC fail to rescue ARF6 midbody localization, and double-KO delays cytokinesis. Knockout mouse embryonic fibroblasts, co-IP, rescue with mutants, live imaging Genes to cells : devoted to molecular & cellular mechanisms Medium 25130574
2019 JIP3 (together with dynein) is required for macropinosome formation and inward movement in HT1080 cells; microtubule depolymerization or JIP3 depletion blocks commitment to macropinosome formation, and ARF6 (a JIP3-interacting protein) is also required. siRNA silencing, live-cell imaging, microtubule depolymerization, co-IP Molecular biology of the cell Medium 30969891
2019 The N-terminal RH1 domain of JIP3 binds dynein light intermediate chain (DLIC); the RH1-LZI tandem forms a high-affinity homodimer with elongated alpha-helical structure; kinesin-1 KHC binding site overlaps with the RH1 domain; the RH1 domain of JIP3 also interacts with myosin 5A in vitro, suggesting JIP3 is a potential myosin 5A adaptor. Biophysical/structural (homology modelling, SAXS), pull-down assay for myosin 5A interaction, bioinformatic analysis Scientific reports Medium 31690808
2021 Loss of JIP3 in human iPSC-derived neurons causes axonal lysosome accumulation and elevated Aβ42; JIP4 has an overlapping role with JIP3 in axonal lysosome transport, shown by double knockdown experiments. iPSC-derived neuron model, JIP3/JIP4 KO, lysosome imaging, Aβ42 measurement Molecular biology of the cell Medium 33788575
2022 Human dynein light intermediate chain (DLIC) binds the N-terminal RH1 domain of JIP3 (and JIP4 and RILP); a point mutation in RH1 abrogates DLIC binding without disrupting KHC binding; in C. elegans, JIP3 that cannot bind DLIC causes prominent endo-lysosomal organelle accumulation at neurite tips; rescuing kinesin light chain binding (leucine zipper mutation) rescues this phenotype, establishing that JIP3-bound dynein is required for organelle clearance and that RH1 is a dual motor-binding hub. Co-IP/pull-down (human proteins), separation-of-function point mutations, C. elegans in vivo imaging, genetic rescue The Journal of cell biology High 35829703
2022 JIP3 depletion in human neurons causes dynamic focal lysosome accumulations accompanied by disruption of the axonal periodic scaffold (spectrin, F-actin, myosin II) throughout affected axons and local microtubule disorganization at lysosome-filled swellings, linking JIP3-dependent lysosome transport to axonal cytoskeleton maintenance. JIP3 KO iPSC neurons, super-resolution/structured illumination microscopy, cytoskeletal marker imaging Communications biology Medium 35013510
2022 DCX negatively regulates dynein-mediated retrograde transport by reducing dynein association with microtubules and disrupting dynein motor complex composition; JIP3 binds dynein and dynactin to form an active motor complex with two dyneins per complex; DCX competes with the second dynein binding, reducing velocity. Purified component reconstitution, single-molecule motility assay, Dcx KO mouse neurons, co-IP eLife High 36476638
2022 Loss of MAPK8IP3/JIP3 in human iPSC-derived neurons (i3Neurons) impairs bulk endocytic uptake without affecting lysosomal proteolytic activity in cell bodies, indicating JIP3 regulates endocytosis in neurons. MAPK8IP3 KO iPSC-derived neurons, endocytosis assay, lysosome activity assay Frontiers in cellular neuroscience Medium 35711470
2023 JIP3 and JIP4 are activating adaptors for dynein on autophagosomes and lysosomes; GTP-bound ARF6 promotes formation of the JIP3/4-dynein-dynactin complex; RAB10 coordinates opposing dynein and kinesin motor activities on autophagosomes; knockdown or overexpression of RAB10 stalls transport. Lysate-based single-molecule motility assay, live-cell imaging in primary neurons, siRNA knockdown, ARF6/RAB10 GTPase mutants The Journal of cell biology High 37909920
2025 The disease-associated R578C missense mutation in JIP3 is a toxic gain-of-function that alters JIP3's interactome, disrupts axonal transport of late endosomes, increases JNK signaling leading to apoptosis, and disrupts dopamine receptor 1 (but not DR2) signaling; ~80% reduction of mutant JIP3 by antisense oligonucleotides was tolerated in vitro. Patient iPSC/cell lines, interactome MS, late endosome transport imaging, JNK activity assay, dopamine receptor signaling assay, ASO treatment JCI insight Medium 40111412

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 308 10517634
2000 Kinesin-dependent axonal transport is mediated by the sunday driver (SYD) protein. Cell 275 11106729
2000 Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3. Molecular and cellular biology 251 10629060
1999 JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Molecular and cellular biology 238 10523642
2006 SYD-2 Liprin-alpha organizes presynaptic active zone formation through ELKS. Nature neuroscience 179 17115037
2010 A Syd-1 homologue regulates pre- and postsynaptic maturation in Drosophila. The Journal of cell biology 154 20176924
2015 ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion. The Journal of cell biology 110 26504170
2012 Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly. Nature neuroscience 105 22864612
2017 Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology. The Journal of cell biology 100 28784610
2002 SYD-1, a presynaptic protein with PDZ, C2 and rhoGAP-like domains, specifies axon identity in C. elegans. Nature neuroscience 93 12379863
2006 Expression and distribution of JNK/SAPK-associated scaffold protein JSAP1 in developing and adult mouse brain. Journal of neurochemistry 89 16606357
2002 Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade. The Journal of biological chemistry 88 12189133
2009 Synaptic scaffolding protein SYD-2 clusters and activates kinesin-3 UNC-104 in C. elegans. Proceedings of the National Academy of Sciences of the United States of America 83 19880746
2011 The Caenorhabditis elegans JIP3 protein UNC-16 functions as an adaptor to link kinesin-1 with cytoplasmic dynein. The Journal of neuroscience : the official journal of the Society for Neuroscience 80 21307258
2011 Sunday Driver/JIP3 binds kinesin heavy chain directly and enhances its motility. The EMBO journal 80 21750526
2011 JIP3 mediates TrkB axonal anterograde transport and enhances BDNF signaling by directly bridging TrkB with kinesin-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 74 21775604
2003 Morphogenesis of the telencephalic commissure requires scaffold protein JNK-interacting protein 3 (JIP3). Proceedings of the National Academy of Sciences of the United States of America 66 12897243
2013 Liprin-α/SYD-2 determines the size of dense projections in presynaptic active zones in C. elegans. The Journal of cell biology 64 24322429
1995 Product of a new gene, syd, functionally interacts with SecY when overproduced in Escherichia coli. The Journal of biological chemistry 58 7890670
2013 An organelle gatekeeper function for Caenorhabditis elegans UNC-16 (JIP3) at the axon initial segment. Genetics 57 23633144
2005 JSAP1/JIP3 cooperates with focal adhesion kinase to regulate c-Jun N-terminal kinase and cell migration. The Journal of biological chemistry 55 16141199
2005 The axon guidance defect of the telencephalic commissures of the JSAP1-deficient brain was partially rescued by the transgenic expression of JIP1. Developmental biology 52 15572149
2021 Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons. Molecular biology of the cell 51 33788575
2022 Exosomes derived from M2 type tumor-associated macrophages promote osimertinib resistance in non-small cell lung cancer through MSTRG.292666.16-miR-6836-5p-MAPK8IP3 axis. Cancer cell international 50 35168607
2010 A JIP3-regulated GSK3β/DCX signaling pathway restricts axon branching. The Journal of neuroscience : the official journal of the Society for Neuroscience 50 21159948
2008 Identification of ROCK1 as an upstream activator of the JIP-3 to JNK signaling axis in response to UVB damage. Science signaling 46 19036714
2022 JIP3 interacts with dynein and kinesin-1 to regulate bidirectional organelle transport. The Journal of cell biology 45 35829703
2011 The Liprin homology domain is essential for the homomeric interaction of SYD-2/Liprin-α protein in presynaptic assembly. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 22072677
2013 c-Jun NH2-terminal kinase (JNK)-interacting protein-3 (JIP3) regulates neuronal axon elongation in a kinesin- and JNK-dependent manner. The Journal of biological chemistry 41 23576431
2019 Arf6, JIP3, and dynein shape and mediate macropinocytosis. Molecular biology of the cell 40 30969891
2015 JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration. Cell death and differentiation 37 25571974
2019 Recurrent de novo MAPK8IP3 variants cause neurological phenotypes. Annals of neurology 35 30945334
2019 Plant Growth-Promoting Fungi (PGPF) Instigate Plant Growth and Induce Disease Resistance in Capsicum annuum L. upon Infection with Colletotrichum capsici (Syd.) Butler & Bisby. Biomolecules 35 31888106
2009 The JIP3 scaffold protein UNC-16 regulates RAB-5 dependent membrane trafficking at C. elegans synapses. Developmental neurobiology 35 19105215
2017 UNC-16/JIP3 regulates early events in synaptic vesicle protein trafficking via LRK-1/LRRK2 and AP complexes. PLoS genetics 34 29145394
2005 Cross-talk between JIP3 and JIP1 during glucose deprivation: SEK1-JNK2 and Akt1 act as mediators. The Journal of biological chemistry 33 15911620
2023 Axonal transport of autophagosomes is regulated by dynein activators JIP3/JIP4 and ARF/RAB GTPases. The Journal of cell biology 32 37909920
2000 Isoforms of JSAP1 scaffold protein generated through alternative splicing. Gene 32 11024282
2009 Mechanical stretch decreases FAK phosphorylation and reduces cell migration through loss of JIP3-induced JNK phosphorylation in airway epithelial cells. American journal of physiology. Lung cellular and molecular physiology 30 19574423
2018 UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport. Scientific reports 29 29895958
2015 JIP3 Activates Kinesin-1 Motility to Promote Axon Elongation. The Journal of biological chemistry 29 25944905
2010 The scaffold protein JIP3 functions as a downstream effector of the small GTPase ARF6 to regulate neurite morphogenesis of cortical neurons. FEBS letters 29 20493856
2017 JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1. Cellular and molecular life sciences : CMLS 28 28638935
2014 Syd/JIP3 and JNK signaling are required for myonuclear positioning and muscle function. PLoS genetics 28 25522254
2013 Intramolecular regulation of presynaptic scaffold protein SYD-2/liprin-α. Molecular and cellular neurosciences 28 23541703
2021 UNC-2 CaV2 Channel Localization at Presynaptic Active Zones Depends on UNC-10/RIM and SYD-2/Liprin-α in Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 33975919
2009 Structure, binding, and activity of Syd, a SecY-interacting protein. The Journal of biological chemistry 27 19139097
1998 Syd, a SecY-interacting protein, excludes SecA from the SecYE complex with an altered SecY24 subunit. The Journal of biological chemistry 27 9668058
2003 In vitro development of mouse embryonic stem cells lacking JNK/stress-activated protein kinase-associated protein 1 (JSAP1) scaffold protein revealed its requirement during early embryonic neurogenesis. The Journal of biological chemistry 26 12968026
2001 Expression of JNK cascade scaffold protein JSAP1 in the mouse nervous system. Neuroscience research 26 11274738
2017 DLK silencing attenuated neuron apoptosis through JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats. Neurobiology of disease 25 28396258
2016 Tozasertib attenuates neuronal apoptosis via DLK/JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats. Neuropharmacology 25 27084696
2014 Drosophila Syd-1, liprin-α, and protein phosphatase 2A B' subunit Wrd function in a linear pathway to prevent ectopic accumulation of synaptic materials in distal axons. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 24948803
2015 UNC-16 (JIP3) Acts Through Synapse-Assembly Proteins to Inhibit the Active Transport of Cell Soma Organelles to Caenorhabditis elegans Motor Neuron Axons. Genetics 24 26354976
2004 Scaffold protein JSAP1 is transported to growth cones of neurites independent of JNK signaling pathways in PC12h cells. Gene 24 15033528
2019 Structural characterization of the RH1-LZI tandem of JIP3/4 highlights RH1 domains as a cytoskeletal motor-binding motif. Scientific reports 22 31690808
2006 The C2H2 zinc-finger protein SYD-9 is a putative posttranscriptional regulator for synaptic transmission. Proceedings of the National Academy of Sciences of the United States of America 21 16803962
2013 The scaffolding protein SYD-2/Liprin-α regulates the mobility and polarized distribution of dense-core vesicles in C. elegans motor neurons. PloS one 20 23358451
2015 SYD-1C, UNC-40 (DCC) and SAX-3 (Robo) function interdependently to promote axon guidance by regulating the MIG-2 GTPase. PLoS genetics 19 25876065
2022 JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton. Communications biology 18 35013510
2012 Loss of syd-1 from R7 neurons disrupts two distinct phases of presynaptic development. The Journal of neuroscience : the official journal of the Society for Neuroscience 18 23238725
2010 Regulation of stress-associated scaffold proteins JIP1 and JIP3 on the c-Jun NH2-terminal kinase in ischemia-reperfusion. Canadian journal of physiology and pharmacology 17 21076496
2008 The scaffold protein JSAP1 regulates proliferation and differentiation of cerebellar granule cell precursors by modulating JNK signaling. Molecular and cellular neurosciences 17 18804538
2010 Sub-cellular distribution of UNC-104(KIF1A) upon binding to adaptors as UNC-16(JIP3), DNC-1(DCTN1/Glued) and SYD-2(Liprin-α) in C. elegans neurons. Neuroscience 16 21195138
2015 Effects of JIP3 on epileptic seizures: Evidence from temporal lobe epilepsy patients, kainic-induced acute seizures and pentylenetetrazole-induced kindled seizures. Neuroscience 15 26002316
2023 SAD-1 kinase controls presynaptic phase separation by relieving SYD-2/Liprin-α autoinhibition. PLoS biology 12 38048304
2022 Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking. eLife 12 36476638
2018 JIP3 deficiency attenuates cardiac hypertrophy by suppression of JNK pathway. Biochemical and biophysical research communications 12 29604277
2016 Molecular Characterization of Resistance to Soybean Rust (Phakopsora pachyrhizi Syd. & Syd.) in Soybean Cultivar DT 2000 (PI 635999). PloS one 12 27935940
2014 JSAP1 and JLP are required for ARF6 localization to the midbody in cytokinesis. Genes to cells : devoted to molecular & cellular mechanisms 11 25130574
2007 Effect of sydnone SYD-1, a mesoionic compound, on energy-linked functions of rat liver mitochondria. Chemico-biological interactions 11 17644080
2007 Neural-specific ablation of the scaffold protein JSAP1 in mice causes neonatal death. Neuroscience letters 11 17977657
2017 Drosophila Syd-1 Has RhoGAP Activity That Is Required for Presynaptic Clustering of Bruchpilot/ELKS but Not Neurexin-1. Genetics 10 29217522
2005 Impairment of cardiomyogenesis in embryonic stem cells lacking scaffold protein JSAP1. Biochemical and biophysical research communications 10 16253209
2010 Role of plasma membrane localization of the scaffold protein JSAP1 during differentiation of cerebellar granule cell precursors. Genes to cells : devoted to molecular & cellular mechanisms 9 21156008
2006 Regulation of N-cadherin-based cell-cell interaction by JSAP1 scaffold in PC12h cells. Biochemical and biophysical research communications 9 17188238
1998 Genetic analysis of an essential cytoplasmic domain of Escherichia coli SecY based on resistance to Syd, a SecY-interacting protein. Molecular & general genetics : MGG 9 9645430
2024 LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α. PLoS genetics 8 38722918
2020 PTP-3 phosphatase promotes intramolecular folding of SYD-2 to inactivate kinesin-3 UNC-104 in neurons. Molecular biology of the cell 7 33147118
2015 Up-regulation of c-Jun NH2-terminal kinase-interacting protein 3 (JIP3) contributes to BDNF-enhanced neurotransmitter release. Journal of neurochemistry 7 26303065
2013 The antioxidant effect of the mesoionic compound SYD-1 in mitochondria. Chemico-biological interactions 7 23867904
2011 Effect of sydnone SYD-1 on certain functions of LPS-stimulated macrophages. Molecular and cellular biochemistry 7 21877148
2022 Loss of MAPK8IP3 Affects Endocytosis in Neurons. Frontiers in cellular neuroscience 6 35711470
2016 Structure of a truncated form of leucine zipper II of JIP3 reveals an unexpected antiparallel coiled-coil arrangement. Acta crystallographica. Section F, Structural biology communications 6 26919523
2014 Sydnone SYD-1 affects the metabolic functions of isolated rat hepatocytes. Chemico-biological interactions 6 24836382
2008 Morphogenetic lung defects of JSAP1-deficient embryos proceeds via the disruptions of the normal expressions of cytoskeletal and chaperone proteins. Proteomics 6 18324732
2006 Selective expression of the scaffold protein JSAP1 in spermatogonia and spermatocytes. Reproduction (Cambridge, England) 6 16595722
2023 An antagonism between Spinophilin and Syd-1 operates upstream of memory-promoting presynaptic long-term plasticity. eLife 5 37767892
2022 Traditional Chinese Medicine Shen-Yuan-Dan (SYD) Improves Hypoxia-Induced Cardiomyocyte Apoptosis in Neonatal Rats by Upregulating miR-24/Bim Pathway. Evidence-based complementary and alternative medicine : eCAM 5 35154347
2018 JIP3 knockout protects mice against high fat diet-induced liver injury. Biochemical and biophysical research communications 5 29454969
2006 JSAP1 is required for the cell adhesion and spreading of mouse embryonic fibroblasts. Biochemical and biophysical research communications 5 16707108
2017 JIP3 regulates neuronal radial migration by mediating TrkB axonal anterograde transport in the developing cerebral cortex. Biochemical and biophysical research communications 4 28259553
2017 JIP3 localises to exocytic vesicles and focal adhesions in the growth cones of differentiated PC12 cells. Molecular and cellular biochemistry 4 29159770
2015 Critical role of JSAP1 and JLP in axonal transport in the cerebellar Purkinje cells of mice. FEBS letters 4 26320416
2024 UNC-10/SYD-2 links kinesin-3 to RAB-3-containing vesicles in the absence of the motor's PH domain. Neurobiology of disease 3 39662532
2023 Compound heterozygous variants in MAPK8IP3 were detected in severe congenital hypotonia mimicking lethal spinal muscular atrophy. American journal of medical genetics. Part A 3 37462082
2021 c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) attenuates curcumin-induced cell death differently from its family member, JNK-associated leucine zipper protein (JLP). Drug discoveries & therapeutics 3 33716240
2020 Syd/JIP3 controls tissue size by regulating Diap1 protein turnover downstream of Yorkie/YAP. Developmental biology 3 33022230
2015 SYD-1 Promotes Multiple Developmental Steps Leading to Neuronal Connectivity. Molecular neurobiology 3 26660112
2025 A toxic gain-of-function variant in MAPK8IP3 provides insights into JIP3 cellular roles. JCI insight 2 40111412

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