{"gene":"STK38L","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2004,"finding":"Human NDR2 is excluded from the nucleus and exhibits a punctate cytoplasmic distribution, distinct from NDR1's nuclear localization. NDR2 forms stable complexes with human Mob2 (homologous to S. cerevisiae Mob1/Mob2), and this association dramatically stimulates NDR2 catalytic activity.","method":"Immunoprecipitation from Jurkat T-cells, co-localization in HeLa cells, kinase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, co-localization, and direct kinase activity measurement in a single focused study","pmids":["15067004"],"is_preprint":false},{"year":2004,"finding":"NDR2 is activated by multi-site phosphorylation: Ser-282 is autophosphorylated in vivo (activation segment), while Thr-442 (hydrophobic motif) is targeted by an upstream kinase. S100B, an EF-hand Ca2+-binding protein, stimulates NDR2 autophosphorylation in vitro. NDR2 exhibits predominantly cytoplasmic localization.","method":"In vitro kinase assay, phospho-site mutagenesis, okadaic acid treatment, subcellular fractionation/immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, phospho-site mapping, multiple orthogonal methods in one study","pmids":["15037617"],"is_preprint":false},{"year":2004,"finding":"NDR2 associates with the actin cytoskeleton in somata, neurites, filopodia, spines, and cell contacts in PC12 cells and cortical neurons. Overexpression of NDR2 causes decreased cell spreading and changes in neurite outgrowth associated with protein serine phosphorylation.","method":"EGFP fusion protein expression, co-precipitation, pull-down assay, transfection in PC12 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-precipitation and pull-down supporting cytoskeletal association, with functional phenotype readout","pmids":["15308672"],"is_preprint":false},{"year":2005,"finding":"NDR2 is incorporated into HIV-1 virions and cleaved by HIV-1 protease both within virions and producer cells. Truncation at the protease cleavage site inhibited NDR2 enzymatic activity and altered its subcellular localization.","method":"Virion incorporation assay, in vitro/in cell HIV-1 protease cleavage, kinase activity assay, subcellular localization imaging","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct kinase activity assay and localization change shown, single study","pmids":["15582665"],"is_preprint":false},{"year":2006,"finding":"NDR2 directly phosphorylates ARK5 at conserved Thr-211 on its activation T-loop during IGF-1 signaling, thereby activating ARK5 to promote cell survival and invasion. NDR2 activation itself requires phosphorylation at Thr-75 (S100B binding, Ca2+- and PLC-γ-dependent), Ser-282 (autophosphorylation, most critical), and Thr-442 (PDK-1 dependent).","method":"In vitro kinase assay, phospho-site mutagenesis, co-immunoprecipitation, IGF-1 stimulation in colorectal cancer cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation assay with mutagenesis of both kinase and substrate, multiple phospho-sites mapped","pmids":["16488889"],"is_preprint":false},{"year":2013,"finding":"NDR2 phosphorylates Rabin8 (a Rab8 GEF) at Ser-272, which switches Rabin8's binding specificity from phosphatidylserine (on pericentrosomal vesicles) to Sec15 (exocyst component), promoting Rab8 activation and ciliary membrane formation. Loss of this phosphorylation impairs preciliary membrane assembly and ciliogenesis.","method":"In vitro kinase assay, phospho-mimetic and phospho-null Rabin8 mutants, binding assays, ciliogenesis assay, immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation, mutagenesis (S272E/S272A), binding specificity assay, and ciliogenesis functional readout in one study","pmids":["23435566"],"is_preprint":false},{"year":2014,"finding":"NDR2 controls integrin-dependent dendritic and axonal growth in hippocampal neurons by inducing phosphorylation of β1-integrin at Thr788/789, stimulating PKC- and CaMKII-dependent activation of β1-integrins, and promoting their exocytosis. NDR2 associates with integrin-positive early and recycling endosomes in primary hippocampal neurons.","method":"Kinase assay, phospho-β1-integrin detection, exocytosis assay, endosomal co-localization, Ndr2-null mutant mice analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (phosphorylation assay, exocytosis assay, subcellular localization, in vivo KO phenotype)","pmids":["24719112"],"is_preprint":false},{"year":2017,"finding":"NDR2 localizes to peroxisomes via a C-terminal PTS1-like sequence (Gly-Lys-Leu), binds the PTS1 receptor Pex5p, and is exposed on the cytosolic surface of peroxisomes. This peroxisomal localization is required for NDR2's function in promoting primary cilium formation, as an NDR2 mutant lacking the C-terminal Leu (NDR2-ΔL) fails to rescue ciliogenesis after NDR2 knockdown.","method":"Co-localization with peroxisome markers, Pex5p binding assay, topology analysis, ciliogenesis rescue assay, PEX gene knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including binding assay, co-localization, and functional rescue with deletion mutant","pmids":["28122914"],"is_preprint":false},{"year":2018,"finding":"NDR2 phosphorylates Filamin A (FLNa) at Ser-2152 upon TCR stimulation in T cells, promoting dissociation of FLNa from LFA-1 and enabling subsequent Talin and Kindlin-3 association that stabilizes the open (active) conformation of LFA-1. Ndr2-deficient T cells show impaired TCR-mediated LFA-1 activation.","method":"Kinase assay, phospho-specific antibody detection, co-immunoprecipitation, LFA-1 conformation assay, Ndr2 KO T cell analysis","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay, downstream binding changes, and KO functional phenotype","pmids":["30568657"],"is_preprint":false},{"year":2018,"finding":"NDR2 interacts directly with GEF-H1 (which contains the NDR phosphorylation consensus motif HXRXXS/T), leading to GEF-H1 phosphorylation, RhoB inactivation, YAP activation, and cytokinesis defects. This pathway operates downstream of RASSF1A loss in human bronchial epithelial cells.","method":"siRNA/shRNA depletion, co-immunoprecipitation, phosphorylation assay, epistasis (RASSF1A/NDR2/GEF-H1/RhoB/YAP), cytokinesis assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, phosphorylation assay, genetic epistasis, functional phenotype in single lab","pmids":["30979377"],"is_preprint":false},{"year":2019,"finding":"NDR2 directly associates with both RIG-I and TRIM25, facilitating formation of the RIG-I/TRIM25 complex and enhancing TRIM25-mediated K63-linked polyubiquitination of RIG-I, which is required for antiviral innate immune signaling. NDR2 conditional knockout mice (Lysm+NDR2f/f) show impaired antiviral immune response.","method":"Co-immunoprecipitation, ubiquitination assay, NDR2 KO/overexpression, kinase-inactive mutant overexpression, antiviral cytokine measurement","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, in vivo KO mouse model, multiple orthogonal methods","pmids":["30775439"],"is_preprint":false},{"year":2018,"finding":"NDR2 inhibits IL-17 signaling by interacting with Smurf1 E3 ubiquitin ligase and promoting Smurf1-mediated K48-linked ubiquitination and degradation of MEKK2, thereby suppressing IL-17-induced MAPK and NF-κB activation.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, cytokine expression measurement","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay with functional cytokine readout, single lab","pmids":["30504095"],"is_preprint":false},{"year":2019,"finding":"NDR2 can be acetylated at K463 in cells; SIRT1 acts as the major deacetylase for NDR2, while p300 and CBP function as acetyltransferases. In SIRT1-deficient cells, HDAC6 and HDAC1/2 can deacetylate NDR2.","method":"Mass spectrometry identification of acetylation site, co-immunoprecipitation with deacetylases/acetyltransferases, acetylation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — acetylation site identified, writer/eraser enzymes identified by Co-IP, single lab","pmids":["31427083"],"is_preprint":false},{"year":2022,"finding":"TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of STK38L/NDR2 during starvation-induced autophagy. This ubiquitination activates STK38L, which then phosphorylates ULK1 at Ser495, rendering ULK1 permissive for TRIM27-mediated K48-linked hyper-ubiquitination and degradation of ULK1, thereby restraining autophagy amplitude.","method":"Co-immunoprecipitation, ubiquitination assay (K6/K11/K48 linkage-specific), phosphorylation assay (ULK1-Ser495), STK38L KO/overexpression, autophagy flux assay, Trim27 KO mice","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (Co-IP, specific ubiquitin linkage assays, phosphorylation assay, in vivo KO mouse), replicated across cell and animal models","pmids":["35670107"],"is_preprint":false},{"year":2022,"finding":"STK38L, induced by serum response factor (SRF) downstream of lysophosphatidic acid (LPA) signaling, phosphorylates IRF3 at Ser303, preventing IRF3 proteasomal degradation in the resting (non-infected) state and ensuring sufficient IRF3 for antiviral response upon infection. STK38L-deficient mice exhibit compromised innate antiviral responses.","method":"Phosphorylation assay (IRF3-Ser303), STK38L KO mice, serum deprivation/LPA treatment, antiviral response measurement","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assay, in vivo KO mouse, and functional antiviral phenotype","pmids":["36417850"],"is_preprint":false},{"year":2024,"finding":"NDR2 promotes SENP2-mediated de-SUMOylation, which improves NDR2 kinase activity, leading to instability of p21 and acceleration of G1/S cell cycle transition in lung cancer cells.","method":"SUMOylation assay, SENP2 co-immunoprecipitation, NDR2 kinase activity assay, p21 protein stability assay, siRNA knockdown","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — SUMOylation/de-SUMOylation assay and downstream functional readout, single lab","pmids":["38908669"],"is_preprint":false},{"year":2024,"finding":"NDR2 negatively regulates osteoclastogenesis through a mechanism involving enhancement of autophagy and mitophagy via ULK1 instability. Myeloid-specific NDR2-deficient mice show lower bone mass and exacerbated bone loss, and this phenotype is rescued by a ULK1 inhibitor.","method":"NDR2 KO/overexpression, myeloid-specific conditional KO mice, mitophagy/autophagy assays, ULK1 stability assay, in vivo bone phenotyping, ULK1 inhibitor rescue","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO mice with epistasis rescue by ULK1 inhibitor, multiple cellular assays, single lab","pmids":["39561008"],"is_preprint":false},{"year":2025,"finding":"NDR2 phosphorylates Rabin8 at S272 at the trans-Golgi/Golgi exit sites (GESs), where NDR2 co-localizes with Rabin8 and the RTC-associated R-SNARE VAMP7. Phospho-mimetic Rabin8-S272E integrates into rhodopsin transport carriers (RTCs) and supports Rab8 GEF activity for ciliary trafficking; non-phosphorylatable S272A causes GES enlargement and impairs rhodopsin Golgi-to-cilia trafficking.","method":"Xenopus laevis transgenic rod photoreceptors expressing GFP-Rabin8 mutants, co-immunoprecipitation with VAMP7, live/confocal imaging, phospho-mimetic/null mutagenesis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo transgenic model with phospho-mimetic and phospho-null mutants, co-IP with SNARE component, direct imaging of trafficking","pmids":["39774853"],"is_preprint":false},{"year":2025,"finding":"STK38L (NDR2) inhibits the Hippo pathway by competitively binding to MOB1 and disrupting the LATS-MOB1 complex, in a manner independent of STK38L kinase activity. This mechanism is conserved in Drosophila, where the ortholog Tricornered similarly impairs Warts-Mats complex formation. STK38L is required for ovarian tumor growth, and its amplification correlates with YAP activation.","method":"Co-immunoprecipitation (MOB1/LATS/STK38L), kinase-dead mutant analysis, Drosophila wing size assay (Tricornered), ovarian cancer cell viability assay, TEAD inhibitor sensitivity assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, kinase-dead mutant, evolutionarily conserved mechanism validated in Drosophila, tumor functional assay","pmids":["42128666"],"is_preprint":false},{"year":2025,"finding":"NDR2 participates in autophagosome biogenesis in NSCLC cells in an ATG9A-dependent manner, as shown by increased LC3-II expression. NDR2 is also required for lysosomal trafficking/fusion with autophagosomes. NDR2 silencing disrupts Golgi repositioning to the leading edge during cell migration under serum deprivation, impairing filopodia formation and cell polarization.","method":"siRNA/shRNA NDR2 depletion, LC3-II Western blot, chloroquine autophagosome-lysosome fusion inhibition assay, Golgi repositioning imaging, filopodia quantification","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional assays in cell lines, single lab, no in vitro reconstitution","pmids":["41390758"],"is_preprint":false},{"year":2025,"finding":"NDR2 deficiency in hippocampal neurons reduces phosphorylated β1-integrin (Thr788/789) at synaptic sites, leading to decreased synaptic density and reduced long-term potentiation (LTP) in CA1; this LTP deficit can be rescued by RGD peptide-mediated integrin activation, suggesting NDR2 regulates synapse formation and plasticity via integrin-dependent mechanisms.","method":"NDR2 null mutant mice, phospho-β1-integrin immunostaining, synaptic density quantification, electrophysiology (LTP), RGD peptide rescue, primary hippocampal neuron cultures","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with electrophysiology and molecular rescue, but single lab","pmids":["40439020"],"is_preprint":false},{"year":2017,"finding":"STK38L depletion in KRAS-dependent PDAC cell lines induces apoptosis and inhibits proliferation, accompanied by increased LATS2 expression and p21 upregulation. LATS2 depletion partially rescues the cytostatic and cytotoxic effects of STK38L depletion, placing STK38L upstream of LATS2 in this context.","method":"RNAi knockdown, apoptosis assay, proliferation assay, LATS2/p21 protein expression, epistasis rescue (double KD)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double KD rescue and multiple functional readouts, single lab","pmids":["29108249"],"is_preprint":false}],"current_model":"STK38L/NDR2 is a cytoplasmic AGC-family serine/threonine kinase that is activated by multi-site phosphorylation (autophosphorylation at Ser-282, upstream kinase-mediated Thr-442 phosphorylation) stimulated by S100B and Mob2-binding, and is subject to additional regulation by acetylation (via p300/CBP, reversed by SIRT1) and ubiquitination (by TRIM27); it localizes to peroxisomes via a C-terminal PTS1-like sequence (GKL) where it promotes ciliogenesis by phosphorylating Rabin8 at Ser-272 to switch its binding from phosphatidylserine to the exocyst component Sec15, enabling Rab8 activation and ciliary membrane formation; in neurons it phosphorylates β1-integrin at Thr788/789 to drive integrin activation and trafficking for dendritic growth and synaptic plasticity; in immune cells it scaffolds the RIG-I/TRIM25 complex to enhance antiviral K63-ubiquitination of RIG-I, phosphorylates IRF3 at Ser303 to stabilize it for antiviral readiness, and promotes Smurf1-mediated degradation of MEKK2 to restrain IL-17 signaling; in autophagy it is ubiquitinated by TRIM27 which activates it to phosphorylate ULK1 at Ser495 thereby enabling TRIM27-mediated ULK1 degradation to limit autophagy amplitude; and in the Hippo pathway STK38L competitively binds MOB1 to disrupt the LATS-MOB1 activating complex and promote YAP-dependent growth independently of its kinase activity."},"narrative":{"mechanistic_narrative":"STK38L (NDR2) is a cytoplasmic AGC-family serine/threonine kinase that couples upstream activating signals to substrate phosphorylation across ciliogenesis, neuronal integrin signaling, innate immunity, autophagy, and growth control [PMID:15067004, PMID:16488889, PMID:23435566]. Its catalytic output is gated by multi-site phosphorylation—autophosphorylation at the activation-segment Ser-282, hydrophobic-motif Thr-442 phosphorylation by an upstream (PDK-1) kinase, and a Thr-75 site stimulated by Ca2+-dependent S100B binding—and is further enhanced by stable association with Mob2 [PMID:15067004, PMID:15037617, PMID:16488889]. The kinase is additionally tuned by reversible acetylation at K463 (p300/CBP writers, SIRT1 eraser) and by SENP2-mediated de-SUMOylation that boosts its activity [PMID:31427083, PMID:38908669]. In ciliogenesis STK38L localizes to the cytosolic surface of peroxisomes through a C-terminal PTS1-like GKL motif recognized by Pex5p, a localization required for cilium formation, and phosphorylates the Rab8 GEF Rabin8 at Ser-272 to switch its binding from phosphatidylserine to the exocyst component Sec15, driving Rab8 activation and ciliary/rhodopsin-carrier membrane trafficking [PMID:23435566, PMID:28122914, PMID:39774853]. In neurons it phosphorylates β1-integrin at Thr788/789 to promote integrin activation, exocytosis, dendritic/axonal growth, and synaptic plasticity, with loss producing CA1 LTP deficits rescuable by RGD-mediated integrin activation [PMID:24719112, PMID:40439020]. In immune cells it scaffolds the RIG-I/TRIM25 complex to enhance K63-linked ubiquitination of RIG-I, phosphorylates IRF3 at Ser303 to stabilize it for antiviral readiness, phosphorylates Filamin A to license LFA-1 activation, and restrains IL-17 signaling by promoting Smurf1-mediated degradation of MEKK2 [PMID:30568657, PMID:30775439, PMID:30504095, PMID:36417850]. It also limits autophagy amplitude: TRIM27-catalyzed K6/K11 ubiquitination activates STK38L to phosphorylate ULK1 at Ser-495, priming ULK1 for degradation, a circuit that also negatively regulates osteoclastogenesis [PMID:35670107, PMID:39561008]. In growth control STK38L acts in the Hippo pathway by competitively binding MOB1 to disrupt the LATS-MOB1 complex and promote YAP activation independently of its kinase activity, supporting tumor growth [PMID:42128666, PMID:29108249].","teleology":[{"year":2004,"claim":"Established NDR2 as a distinct cytoplasmic kinase whose activity is controlled by Mob2 binding and multi-site phosphorylation, defining the basic activation logic.","evidence":"Co-IP, co-localization, and kinase assays in T-cell/HeLa systems plus in vitro phospho-site mapping and S100B stimulation","pmids":["15067004","15037617"],"confidence":"High","gaps":["Identity of the upstream Thr-442 kinase not defined in these studies","Physiological substrates not yet identified"]},{"year":2004,"claim":"Linked NDR2 to the actin cytoskeleton and to neurite/cell-spreading phenotypes, hinting at a role in cytoskeletal morphogenesis.","evidence":"EGFP fusion, co-precipitation and pull-down with overexpression phenotypes in PC12 cells and cortical neurons","pmids":["15308672"],"confidence":"Medium","gaps":["Direct cytoskeletal substrate not identified","Mechanism connecting kinase activity to spreading unresolved"]},{"year":2005,"claim":"Showed NDR2 is incorporated into HIV-1 virions and cleaved by HIV-1 protease, a host-pathogen modification that inactivates the kinase.","evidence":"Virion incorporation, protease cleavage, kinase activity and localization assays","pmids":["15582665"],"confidence":"Medium","gaps":["Functional consequence for viral replication not established","Single study"]},{"year":2006,"claim":"Identified the first direct substrate, ARK5, phosphorylated at its T-loop Thr-211 in IGF-1 signaling, and mapped the three activating phospho-sites of NDR2.","evidence":"In vitro kinase assay, substrate and kinase mutagenesis, IGF-1 stimulation in colorectal cancer lines","pmids":["16488889"],"confidence":"High","gaps":["In vivo relevance of ARK5 phosphorylation not tested","Tissue specificity unknown"]},{"year":2013,"claim":"Defined a ciliogenesis mechanism: NDR2 phosphorylates Rabin8 at Ser-272 to switch its lipid-to-exocyst binding and enable Rab8-driven ciliary membrane assembly.","evidence":"In vitro kinase assay, phospho-mimetic/null Rabin8 mutants, binding-specificity and ciliogenesis assays","pmids":["23435566"],"confidence":"High","gaps":["Upstream signal triggering Rabin8 phosphorylation not defined","Spatial source of active NDR2 not yet localized"]},{"year":2014,"claim":"Established NDR2 control of integrin-dependent neuronal growth via β1-integrin Thr788/789 phosphorylation and integrin exocytosis.","evidence":"Kinase and exocytosis assays, endosomal co-localization, and Ndr2-null mouse analysis","pmids":["24719112"],"confidence":"High","gaps":["Whether NDR2 phosphorylates integrin directly versus via intermediary kinases not fully resolved"]},{"year":2017,"claim":"Resolved where ciliogenic NDR2 acts: a C-terminal PTS1-like GKL motif targets it to the peroxisome surface via Pex5p, a localization required for cilium formation.","evidence":"Co-localization, Pex5p binding, topology, and ciliogenesis rescue with ΔL mutant plus PEX knockdown","pmids":["28122914"],"confidence":"High","gaps":["How peroxisomal anchoring connects spatially to Rabin8 phosphorylation unclear","Role of peroxisomal pool in non-ciliary functions untested"]},{"year":2017,"claim":"Placed STK38L upstream of LATS2 in KRAS-dependent pancreatic cancer survival, foreshadowing a Hippo-pathway connection.","evidence":"RNAi knockdown, apoptosis/proliferation assays and LATS2 epistasis rescue in PDAC lines","pmids":["29108249"],"confidence":"Medium","gaps":["Molecular link between STK38L and LATS2 regulation not defined here","Single context"]},{"year":2018,"claim":"Extended immune function: NDR2 phosphorylates Filamin A to license LFA-1 activation and promotes Smurf1-mediated MEKK2 degradation to restrain IL-17 signaling.","evidence":"Kinase, Co-IP and ubiquitination assays with KO/knockdown functional readouts in T cells","pmids":["30568657","30504095"],"confidence":"Medium","gaps":["IL-17 axis based on knockdown in single lab","How NDR2 distinguishes these immune substrates contextually unclear"]},{"year":2019,"claim":"Showed NDR2 acts as a positive scaffold/kinase for antiviral signaling by promoting RIG-I/TRIM25 complex formation and K63-ubiquitination of RIG-I.","evidence":"Reciprocal Co-IP, ubiquitination assay, kinase-inactive mutant, and conditional KO mice","pmids":["30775439"],"confidence":"High","gaps":["Whether scaffolding requires kinase activity not fully separated","Direct substrate in this complex not defined"]},{"year":2019,"claim":"Connected NDR2 to RhoB/YAP control via GEF-H1 phosphorylation downstream of RASSF1A loss, and identified its regulation by acetylation.","evidence":"Depletion, Co-IP, phosphorylation and epistasis assays (GEF-H1); MS plus writer/eraser Co-IP for K463 acetylation","pmids":["30979377","31427083"],"confidence":"Medium","gaps":["Functional consequence of K463 acetylation on activity not quantified","GEF-H1 pathway in single lab/cell type"]},{"year":2022,"claim":"Defined a ubiquitin-gated autophagy-limiting circuit: TRIM27 K6/K11 ubiquitination activates STK38L to phosphorylate ULK1 Ser-495, priming ULK1 for degradation.","evidence":"Linkage-specific ubiquitination assays, ULK1-Ser495 phosphorylation, autophagy flux, STK38L and Trim27 KO mice","pmids":["35670107"],"confidence":"High","gaps":["How K6/K11 ubiquitination mechanistically activates the kinase unresolved","Generality beyond starvation autophagy untested here"]},{"year":2022,"claim":"Showed STK38L maintains antiviral readiness by phosphorylating IRF3 at Ser-303 to prevent its degradation in resting cells, induced via SRF downstream of LPA.","evidence":"Phosphorylation assay, STK38L KO mice, serum deprivation/LPA treatment, antiviral readouts","pmids":["36417850"],"confidence":"High","gaps":["Relationship between this resting-state role and the RIG-I scaffolding role not integrated"]},{"year":2024,"claim":"Extended the autophagy/ULK1 axis to bone biology: NDR2 negatively regulates osteoclastogenesis via ULK1 instability and enhanced mito/autophagy.","evidence":"Myeloid-specific KO mice, autophagy/mitophagy assays, ULK1 stability, ULK1-inhibitor rescue","pmids":["39561008"],"confidence":"Medium","gaps":["Direct molecular link to the TRIM27/ULK1 circuit not formally tested","Single lab"]},{"year":2024,"claim":"Identified de-SUMOylation by SENP2 as an activating modification that destabilizes p21 and accelerates G1/S transition.","evidence":"SUMOylation/de-SUMOylation assays, SENP2 Co-IP, kinase activity and p21 stability assays in lung cancer cells","pmids":["38908669"],"confidence":"Medium","gaps":["SUMO site on NDR2 and mechanism of activity gain not mapped","Single context"]},{"year":2025,"claim":"Refined ciliary trafficking: NDR2 phosphorylates Rabin8 Ser-272 at trans-Golgi exit sites with VAMP7 to support rhodopsin transport carrier formation in photoreceptors.","evidence":"Transgenic Xenopus rods with phospho-mimetic/null Rabin8, VAMP7 Co-IP, live/confocal imaging","pmids":["39774853"],"confidence":"High","gaps":["Reconciliation of Golgi-exit-site versus peroxisomal NDR2 pools for Rabin8 phosphorylation unresolved"]},{"year":2025,"claim":"Established a kinase-independent Hippo-inhibitory mechanism: STK38L competitively binds MOB1 to disrupt the LATS-MOB1 complex and activate YAP, conserved to Drosophila and required for ovarian tumor growth.","evidence":"Reciprocal Co-IP, kinase-dead mutant, Drosophila Tricornered wing assay, ovarian cancer viability and TEAD-inhibitor assays","pmids":["42128666"],"confidence":"High","gaps":["How the kinase-dependent and kinase-independent functions are balanced in a cell unresolved"]},{"year":2025,"claim":"Linked NDR2 to autophagosome biogenesis (ATG9A-dependent), lysosomal fusion, and Golgi repositioning during migration, broadening its vesicular-trafficking role.","evidence":"siRNA/shRNA depletion, LC3-II Western, chloroquine fusion assay, Golgi/filopodia imaging in NSCLC cells","pmids":["41390758"],"confidence":"Medium","gaps":["No in vitro reconstitution","Direct substrates in autophagosome/Golgi steps unidentified"]},{"year":2025,"claim":"Confirmed the neuronal integrin role at the synapse: NDR2 maintains phospho-β1-integrin to support synaptic density and CA1 LTP.","evidence":"Ndr2-null mice, phospho-β1-integrin immunostaining, synaptic density, LTP electrophysiology with RGD rescue","pmids":["40439020"],"confidence":"Medium","gaps":["Direct synaptic integrin substrate phosphorylation by NDR2 not biochemically isolated","Single lab"]},{"year":null,"claim":"How the diverse post-translational inputs (phosphorylation, acetylation, SUMOylation, ubiquitination) and distinct subcellular pools (peroxisome, Golgi exit sites, endosomes) are integrated to select among NDR2's many substrates and its kinase-independent MOB1 function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking modification state to substrate choice","Spatial coordination of multiple localized pools undefined","Kinase-dependent versus kinase-independent function switching uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,5,6,8,13,14,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[17,19]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13,16,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,10,11,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,18]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,7,17]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[15,21]}],"complexes":["RIG-I/TRIM25 complex"],"partners":["MOB2","MOB1","RABIN8","RIG-I","TRIM25","TRIM27","ULK1","SMURF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2H1","full_name":"Serine/threonine-protein kinase 38-like","aliases":["NDR2 protein kinase","Nuclear Dbf2-related kinase 2"],"length_aa":464,"mass_kda":54.0,"function":"Involved in the regulation of structural processes in differentiating and mature neuronal cells","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y2H1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STK38L","classification":"Not 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vessel","ntpm":80.0}],"url":"https://www.proteinatlas.org/search/STK38L"},"hgnc":{"alias_symbol":["KIAA0965","NDR2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2H1","domains":[{"cath_id":"-","chopping":"19-81","consensus_level":"medium","plddt":87.7695,"start":19,"end":81},{"cath_id":"3.30.200.20","chopping":"86-169_405-460","consensus_level":"medium","plddt":79.5954,"start":86,"end":460},{"cath_id":"1.10.510.10","chopping":"174-382","consensus_level":"high","plddt":89.9545,"start":174,"end":382}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2H1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2H1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2H1-F1-predicted_aligned_error_v6.png","plddt_mean":84.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STK38L","jax_strain_url":"https://www.jax.org/strain/search?query=STK38L"},"sequence":{"accession":"Q9Y2H1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2H1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2H1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2H1"}},"corpus_meta":[{"pmid":"10581191","id":"PMC_10581191","title":"Identification 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and exhibits a punctate cytoplasmic distribution, distinct from NDR1's nuclear localization. NDR2 forms stable complexes with human Mob2 (homologous to S. cerevisiae Mob1/Mob2), and this association dramatically stimulates NDR2 catalytic activity.\",\n      \"method\": \"Immunoprecipitation from Jurkat T-cells, co-localization in HeLa cells, kinase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, co-localization, and direct kinase activity measurement in a single focused study\",\n      \"pmids\": [\"15067004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NDR2 is activated by multi-site phosphorylation: Ser-282 is autophosphorylated in vivo (activation segment), while Thr-442 (hydrophobic motif) is targeted by an upstream kinase. S100B, an EF-hand Ca2+-binding protein, stimulates NDR2 autophosphorylation in vitro. NDR2 exhibits predominantly cytoplasmic localization.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis, okadaic acid treatment, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, phospho-site mapping, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15037617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NDR2 associates with the actin cytoskeleton in somata, neurites, filopodia, spines, and cell contacts in PC12 cells and cortical neurons. Overexpression of NDR2 causes decreased cell spreading and changes in neurite outgrowth associated with protein serine phosphorylation.\",\n      \"method\": \"EGFP fusion protein expression, co-precipitation, pull-down assay, transfection in PC12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-precipitation and pull-down supporting cytoskeletal association, with functional phenotype readout\",\n      \"pmids\": [\"15308672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NDR2 is incorporated into HIV-1 virions and cleaved by HIV-1 protease both within virions and producer cells. Truncation at the protease cleavage site inhibited NDR2 enzymatic activity and altered its subcellular localization.\",\n      \"method\": \"Virion incorporation assay, in vitro/in cell HIV-1 protease cleavage, kinase activity assay, subcellular localization imaging\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct kinase activity assay and localization change shown, single study\",\n      \"pmids\": [\"15582665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NDR2 directly phosphorylates ARK5 at conserved Thr-211 on its activation T-loop during IGF-1 signaling, thereby activating ARK5 to promote cell survival and invasion. NDR2 activation itself requires phosphorylation at Thr-75 (S100B binding, Ca2+- and PLC-γ-dependent), Ser-282 (autophosphorylation, most critical), and Thr-442 (PDK-1 dependent).\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis, co-immunoprecipitation, IGF-1 stimulation in colorectal cancer cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation assay with mutagenesis of both kinase and substrate, multiple phospho-sites mapped\",\n      \"pmids\": [\"16488889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NDR2 phosphorylates Rabin8 (a Rab8 GEF) at Ser-272, which switches Rabin8's binding specificity from phosphatidylserine (on pericentrosomal vesicles) to Sec15 (exocyst component), promoting Rab8 activation and ciliary membrane formation. Loss of this phosphorylation impairs preciliary membrane assembly and ciliogenesis.\",\n      \"method\": \"In vitro kinase assay, phospho-mimetic and phospho-null Rabin8 mutants, binding assays, ciliogenesis assay, immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation, mutagenesis (S272E/S272A), binding specificity assay, and ciliogenesis functional readout in one study\",\n      \"pmids\": [\"23435566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NDR2 controls integrin-dependent dendritic and axonal growth in hippocampal neurons by inducing phosphorylation of β1-integrin at Thr788/789, stimulating PKC- and CaMKII-dependent activation of β1-integrins, and promoting their exocytosis. NDR2 associates with integrin-positive early and recycling endosomes in primary hippocampal neurons.\",\n      \"method\": \"Kinase assay, phospho-β1-integrin detection, exocytosis assay, endosomal co-localization, Ndr2-null mutant mice analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (phosphorylation assay, exocytosis assay, subcellular localization, in vivo KO phenotype)\",\n      \"pmids\": [\"24719112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NDR2 localizes to peroxisomes via a C-terminal PTS1-like sequence (Gly-Lys-Leu), binds the PTS1 receptor Pex5p, and is exposed on the cytosolic surface of peroxisomes. This peroxisomal localization is required for NDR2's function in promoting primary cilium formation, as an NDR2 mutant lacking the C-terminal Leu (NDR2-ΔL) fails to rescue ciliogenesis after NDR2 knockdown.\",\n      \"method\": \"Co-localization with peroxisome markers, Pex5p binding assay, topology analysis, ciliogenesis rescue assay, PEX gene knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including binding assay, co-localization, and functional rescue with deletion mutant\",\n      \"pmids\": [\"28122914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NDR2 phosphorylates Filamin A (FLNa) at Ser-2152 upon TCR stimulation in T cells, promoting dissociation of FLNa from LFA-1 and enabling subsequent Talin and Kindlin-3 association that stabilizes the open (active) conformation of LFA-1. Ndr2-deficient T cells show impaired TCR-mediated LFA-1 activation.\",\n      \"method\": \"Kinase assay, phospho-specific antibody detection, co-immunoprecipitation, LFA-1 conformation assay, Ndr2 KO T cell analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay, downstream binding changes, and KO functional phenotype\",\n      \"pmids\": [\"30568657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NDR2 interacts directly with GEF-H1 (which contains the NDR phosphorylation consensus motif HXRXXS/T), leading to GEF-H1 phosphorylation, RhoB inactivation, YAP activation, and cytokinesis defects. This pathway operates downstream of RASSF1A loss in human bronchial epithelial cells.\",\n      \"method\": \"siRNA/shRNA depletion, co-immunoprecipitation, phosphorylation assay, epistasis (RASSF1A/NDR2/GEF-H1/RhoB/YAP), cytokinesis assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, phosphorylation assay, genetic epistasis, functional phenotype in single lab\",\n      \"pmids\": [\"30979377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NDR2 directly associates with both RIG-I and TRIM25, facilitating formation of the RIG-I/TRIM25 complex and enhancing TRIM25-mediated K63-linked polyubiquitination of RIG-I, which is required for antiviral innate immune signaling. NDR2 conditional knockout mice (Lysm+NDR2f/f) show impaired antiviral immune response.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, NDR2 KO/overexpression, kinase-inactive mutant overexpression, antiviral cytokine measurement\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, in vivo KO mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"30775439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NDR2 inhibits IL-17 signaling by interacting with Smurf1 E3 ubiquitin ligase and promoting Smurf1-mediated K48-linked ubiquitination and degradation of MEKK2, thereby suppressing IL-17-induced MAPK and NF-κB activation.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, cytokine expression measurement\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay with functional cytokine readout, single lab\",\n      \"pmids\": [\"30504095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NDR2 can be acetylated at K463 in cells; SIRT1 acts as the major deacetylase for NDR2, while p300 and CBP function as acetyltransferases. In SIRT1-deficient cells, HDAC6 and HDAC1/2 can deacetylate NDR2.\",\n      \"method\": \"Mass spectrometry identification of acetylation site, co-immunoprecipitation with deacetylases/acetyltransferases, acetylation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — acetylation site identified, writer/eraser enzymes identified by Co-IP, single lab\",\n      \"pmids\": [\"31427083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of STK38L/NDR2 during starvation-induced autophagy. This ubiquitination activates STK38L, which then phosphorylates ULK1 at Ser495, rendering ULK1 permissive for TRIM27-mediated K48-linked hyper-ubiquitination and degradation of ULK1, thereby restraining autophagy amplitude.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K6/K11/K48 linkage-specific), phosphorylation assay (ULK1-Ser495), STK38L KO/overexpression, autophagy flux assay, Trim27 KO mice\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (Co-IP, specific ubiquitin linkage assays, phosphorylation assay, in vivo KO mouse), replicated across cell and animal models\",\n      \"pmids\": [\"35670107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STK38L, induced by serum response factor (SRF) downstream of lysophosphatidic acid (LPA) signaling, phosphorylates IRF3 at Ser303, preventing IRF3 proteasomal degradation in the resting (non-infected) state and ensuring sufficient IRF3 for antiviral response upon infection. STK38L-deficient mice exhibit compromised innate antiviral responses.\",\n      \"method\": \"Phosphorylation assay (IRF3-Ser303), STK38L KO mice, serum deprivation/LPA treatment, antiviral response measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assay, in vivo KO mouse, and functional antiviral phenotype\",\n      \"pmids\": [\"36417850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NDR2 promotes SENP2-mediated de-SUMOylation, which improves NDR2 kinase activity, leading to instability of p21 and acceleration of G1/S cell cycle transition in lung cancer cells.\",\n      \"method\": \"SUMOylation assay, SENP2 co-immunoprecipitation, NDR2 kinase activity assay, p21 protein stability assay, siRNA knockdown\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — SUMOylation/de-SUMOylation assay and downstream functional readout, single lab\",\n      \"pmids\": [\"38908669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NDR2 negatively regulates osteoclastogenesis through a mechanism involving enhancement of autophagy and mitophagy via ULK1 instability. Myeloid-specific NDR2-deficient mice show lower bone mass and exacerbated bone loss, and this phenotype is rescued by a ULK1 inhibitor.\",\n      \"method\": \"NDR2 KO/overexpression, myeloid-specific conditional KO mice, mitophagy/autophagy assays, ULK1 stability assay, in vivo bone phenotyping, ULK1 inhibitor rescue\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO mice with epistasis rescue by ULK1 inhibitor, multiple cellular assays, single lab\",\n      \"pmids\": [\"39561008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NDR2 phosphorylates Rabin8 at S272 at the trans-Golgi/Golgi exit sites (GESs), where NDR2 co-localizes with Rabin8 and the RTC-associated R-SNARE VAMP7. Phospho-mimetic Rabin8-S272E integrates into rhodopsin transport carriers (RTCs) and supports Rab8 GEF activity for ciliary trafficking; non-phosphorylatable S272A causes GES enlargement and impairs rhodopsin Golgi-to-cilia trafficking.\",\n      \"method\": \"Xenopus laevis transgenic rod photoreceptors expressing GFP-Rabin8 mutants, co-immunoprecipitation with VAMP7, live/confocal imaging, phospho-mimetic/null mutagenesis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo transgenic model with phospho-mimetic and phospho-null mutants, co-IP with SNARE component, direct imaging of trafficking\",\n      \"pmids\": [\"39774853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STK38L (NDR2) inhibits the Hippo pathway by competitively binding to MOB1 and disrupting the LATS-MOB1 complex, in a manner independent of STK38L kinase activity. This mechanism is conserved in Drosophila, where the ortholog Tricornered similarly impairs Warts-Mats complex formation. STK38L is required for ovarian tumor growth, and its amplification correlates with YAP activation.\",\n      \"method\": \"Co-immunoprecipitation (MOB1/LATS/STK38L), kinase-dead mutant analysis, Drosophila wing size assay (Tricornered), ovarian cancer cell viability assay, TEAD inhibitor sensitivity assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, kinase-dead mutant, evolutionarily conserved mechanism validated in Drosophila, tumor functional assay\",\n      \"pmids\": [\"42128666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NDR2 participates in autophagosome biogenesis in NSCLC cells in an ATG9A-dependent manner, as shown by increased LC3-II expression. NDR2 is also required for lysosomal trafficking/fusion with autophagosomes. NDR2 silencing disrupts Golgi repositioning to the leading edge during cell migration under serum deprivation, impairing filopodia formation and cell polarization.\",\n      \"method\": \"siRNA/shRNA NDR2 depletion, LC3-II Western blot, chloroquine autophagosome-lysosome fusion inhibition assay, Golgi repositioning imaging, filopodia quantification\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional assays in cell lines, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"41390758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NDR2 deficiency in hippocampal neurons reduces phosphorylated β1-integrin (Thr788/789) at synaptic sites, leading to decreased synaptic density and reduced long-term potentiation (LTP) in CA1; this LTP deficit can be rescued by RGD peptide-mediated integrin activation, suggesting NDR2 regulates synapse formation and plasticity via integrin-dependent mechanisms.\",\n      \"method\": \"NDR2 null mutant mice, phospho-β1-integrin immunostaining, synaptic density quantification, electrophysiology (LTP), RGD peptide rescue, primary hippocampal neuron cultures\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with electrophysiology and molecular rescue, but single lab\",\n      \"pmids\": [\"40439020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STK38L depletion in KRAS-dependent PDAC cell lines induces apoptosis and inhibits proliferation, accompanied by increased LATS2 expression and p21 upregulation. LATS2 depletion partially rescues the cytostatic and cytotoxic effects of STK38L depletion, placing STK38L upstream of LATS2 in this context.\",\n      \"method\": \"RNAi knockdown, apoptosis assay, proliferation assay, LATS2/p21 protein expression, epistasis rescue (double KD)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double KD rescue and multiple functional readouts, single lab\",\n      \"pmids\": [\"29108249\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STK38L/NDR2 is a cytoplasmic AGC-family serine/threonine kinase that is activated by multi-site phosphorylation (autophosphorylation at Ser-282, upstream kinase-mediated Thr-442 phosphorylation) stimulated by S100B and Mob2-binding, and is subject to additional regulation by acetylation (via p300/CBP, reversed by SIRT1) and ubiquitination (by TRIM27); it localizes to peroxisomes via a C-terminal PTS1-like sequence (GKL) where it promotes ciliogenesis by phosphorylating Rabin8 at Ser-272 to switch its binding from phosphatidylserine to the exocyst component Sec15, enabling Rab8 activation and ciliary membrane formation; in neurons it phosphorylates β1-integrin at Thr788/789 to drive integrin activation and trafficking for dendritic growth and synaptic plasticity; in immune cells it scaffolds the RIG-I/TRIM25 complex to enhance antiviral K63-ubiquitination of RIG-I, phosphorylates IRF3 at Ser303 to stabilize it for antiviral readiness, and promotes Smurf1-mediated degradation of MEKK2 to restrain IL-17 signaling; in autophagy it is ubiquitinated by TRIM27 which activates it to phosphorylate ULK1 at Ser495 thereby enabling TRIM27-mediated ULK1 degradation to limit autophagy amplitude; and in the Hippo pathway STK38L competitively binds MOB1 to disrupt the LATS-MOB1 activating complex and promote YAP-dependent growth independently of its kinase activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STK38L (NDR2) is a cytoplasmic AGC-family serine/threonine kinase that couples upstream activating signals to substrate phosphorylation across ciliogenesis, neuronal integrin signaling, innate immunity, autophagy, and growth control [#0, #4, #5]. Its catalytic output is gated by multi-site phosphorylation\\u2014autophosphorylation at the activation-segment Ser-282, hydrophobic-motif Thr-442 phosphorylation by an upstream (PDK-1) kinase, and a Thr-75 site stimulated by Ca2+-dependent S100B binding\\u2014and is further enhanced by stable association with Mob2 [#0, #1, #4]. The kinase is additionally tuned by reversible acetylation at K463 (p300/CBP writers, SIRT1 eraser) and by SENP2-mediated de-SUMOylation that boosts its activity [#12, #15]. In ciliogenesis STK38L localizes to the cytosolic surface of peroxisomes through a C-terminal PTS1-like GKL motif recognized by Pex5p, a localization required for cilium formation, and phosphorylates the Rab8 GEF Rabin8 at Ser-272 to switch its binding from phosphatidylserine to the exocyst component Sec15, driving Rab8 activation and ciliary/rhodopsin-carrier membrane trafficking [#5, #7, #17]. In neurons it phosphorylates \\u03b21-integrin at Thr788/789 to promote integrin activation, exocytosis, dendritic/axonal growth, and synaptic plasticity, with loss producing CA1 LTP deficits rescuable by RGD-mediated integrin activation [#6, #20]. In immune cells it scaffolds the RIG-I/TRIM25 complex to enhance K63-linked ubiquitination of RIG-I, phosphorylates IRF3 at Ser303 to stabilize it for antiviral readiness, phosphorylates Filamin A to license LFA-1 activation, and restrains IL-17 signaling by promoting Smurf1-mediated degradation of MEKK2 [#8, #10, #11, #14]. It also limits autophagy amplitude: TRIM27-catalyzed K6/K11 ubiquitination activates STK38L to phosphorylate ULK1 at Ser-495, priming ULK1 for degradation, a circuit that also negatively regulates osteoclastogenesis [#13, #16]. In growth control STK38L acts in the Hippo pathway by competitively binding MOB1 to disrupt the LATS-MOB1 complex and promote YAP activation independently of its kinase activity, supporting tumor growth [#18, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established NDR2 as a distinct cytoplasmic kinase whose activity is controlled by Mob2 binding and multi-site phosphorylation, defining the basic activation logic.\",\n      \"evidence\": \"Co-IP, co-localization, and kinase assays in T-cell/HeLa systems plus in vitro phospho-site mapping and S100B stimulation\",\n      \"pmids\": [\"15067004\", \"15037617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the upstream Thr-442 kinase not defined in these studies\", \"Physiological substrates not yet identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked NDR2 to the actin cytoskeleton and to neurite/cell-spreading phenotypes, hinting at a role in cytoskeletal morphogenesis.\",\n      \"evidence\": \"EGFP fusion, co-precipitation and pull-down with overexpression phenotypes in PC12 cells and cortical neurons\",\n      \"pmids\": [\"15308672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cytoskeletal substrate not identified\", \"Mechanism connecting kinase activity to spreading unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed NDR2 is incorporated into HIV-1 virions and cleaved by HIV-1 protease, a host-pathogen modification that inactivates the kinase.\",\n      \"evidence\": \"Virion incorporation, protease cleavage, kinase activity and localization assays\",\n      \"pmids\": [\"15582665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for viral replication not established\", \"Single study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the first direct substrate, ARK5, phosphorylated at its T-loop Thr-211 in IGF-1 signaling, and mapped the three activating phospho-sites of NDR2.\",\n      \"evidence\": \"In vitro kinase assay, substrate and kinase mutagenesis, IGF-1 stimulation in colorectal cancer lines\",\n      \"pmids\": [\"16488889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of ARK5 phosphorylation not tested\", \"Tissue specificity unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a ciliogenesis mechanism: NDR2 phosphorylates Rabin8 at Ser-272 to switch its lipid-to-exocyst binding and enable Rab8-driven ciliary membrane assembly.\",\n      \"evidence\": \"In vitro kinase assay, phospho-mimetic/null Rabin8 mutants, binding-specificity and ciliogenesis assays\",\n      \"pmids\": [\"23435566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal triggering Rabin8 phosphorylation not defined\", \"Spatial source of active NDR2 not yet localized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established NDR2 control of integrin-dependent neuronal growth via \\u03b21-integrin Thr788/789 phosphorylation and integrin exocytosis.\",\n      \"evidence\": \"Kinase and exocytosis assays, endosomal co-localization, and Ndr2-null mouse analysis\",\n      \"pmids\": [\"24719112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NDR2 phosphorylates integrin directly versus via intermediary kinases not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved where ciliogenic NDR2 acts: a C-terminal PTS1-like GKL motif targets it to the peroxisome surface via Pex5p, a localization required for cilium formation.\",\n      \"evidence\": \"Co-localization, Pex5p binding, topology, and ciliogenesis rescue with \\u0394L mutant plus PEX knockdown\",\n      \"pmids\": [\"28122914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How peroxisomal anchoring connects spatially to Rabin8 phosphorylation unclear\", \"Role of peroxisomal pool in non-ciliary functions untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed STK38L upstream of LATS2 in KRAS-dependent pancreatic cancer survival, foreshadowing a Hippo-pathway connection.\",\n      \"evidence\": \"RNAi knockdown, apoptosis/proliferation assays and LATS2 epistasis rescue in PDAC lines\",\n      \"pmids\": [\"29108249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between STK38L and LATS2 regulation not defined here\", \"Single context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended immune function: NDR2 phosphorylates Filamin A to license LFA-1 activation and promotes Smurf1-mediated MEKK2 degradation to restrain IL-17 signaling.\",\n      \"evidence\": \"Kinase, Co-IP and ubiquitination assays with KO/knockdown functional readouts in T cells\",\n      \"pmids\": [\"30568657\", \"30504095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IL-17 axis based on knockdown in single lab\", \"How NDR2 distinguishes these immune substrates contextually unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed NDR2 acts as a positive scaffold/kinase for antiviral signaling by promoting RIG-I/TRIM25 complex formation and K63-ubiquitination of RIG-I.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, kinase-inactive mutant, and conditional KO mice\",\n      \"pmids\": [\"30775439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether scaffolding requires kinase activity not fully separated\", \"Direct substrate in this complex not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected NDR2 to RhoB/YAP control via GEF-H1 phosphorylation downstream of RASSF1A loss, and identified its regulation by acetylation.\",\n      \"evidence\": \"Depletion, Co-IP, phosphorylation and epistasis assays (GEF-H1); MS plus writer/eraser Co-IP for K463 acetylation\",\n      \"pmids\": [\"30979377\", \"31427083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of K463 acetylation on activity not quantified\", \"GEF-H1 pathway in single lab/cell type\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a ubiquitin-gated autophagy-limiting circuit: TRIM27 K6/K11 ubiquitination activates STK38L to phosphorylate ULK1 Ser-495, priming ULK1 for degradation.\",\n      \"evidence\": \"Linkage-specific ubiquitination assays, ULK1-Ser495 phosphorylation, autophagy flux, STK38L and Trim27 KO mice\",\n      \"pmids\": [\"35670107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How K6/K11 ubiquitination mechanistically activates the kinase unresolved\", \"Generality beyond starvation autophagy untested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed STK38L maintains antiviral readiness by phosphorylating IRF3 at Ser-303 to prevent its degradation in resting cells, induced via SRF downstream of LPA.\",\n      \"evidence\": \"Phosphorylation assay, STK38L KO mice, serum deprivation/LPA treatment, antiviral readouts\",\n      \"pmids\": [\"36417850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between this resting-state role and the RIG-I scaffolding role not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the autophagy/ULK1 axis to bone biology: NDR2 negatively regulates osteoclastogenesis via ULK1 instability and enhanced mito/autophagy.\",\n      \"evidence\": \"Myeloid-specific KO mice, autophagy/mitophagy assays, ULK1 stability, ULK1-inhibitor rescue\",\n      \"pmids\": [\"39561008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link to the TRIM27/ULK1 circuit not formally tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified de-SUMOylation by SENP2 as an activating modification that destabilizes p21 and accelerates G1/S transition.\",\n      \"evidence\": \"SUMOylation/de-SUMOylation assays, SENP2 Co-IP, kinase activity and p21 stability assays in lung cancer cells\",\n      \"pmids\": [\"38908669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO site on NDR2 and mechanism of activity gain not mapped\", \"Single context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refined ciliary trafficking: NDR2 phosphorylates Rabin8 Ser-272 at trans-Golgi exit sites with VAMP7 to support rhodopsin transport carrier formation in photoreceptors.\",\n      \"evidence\": \"Transgenic Xenopus rods with phospho-mimetic/null Rabin8, VAMP7 Co-IP, live/confocal imaging\",\n      \"pmids\": [\"39774853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of Golgi-exit-site versus peroxisomal NDR2 pools for Rabin8 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a kinase-independent Hippo-inhibitory mechanism: STK38L competitively binds MOB1 to disrupt the LATS-MOB1 complex and activate YAP, conserved to Drosophila and required for ovarian tumor growth.\",\n      \"evidence\": \"Reciprocal Co-IP, kinase-dead mutant, Drosophila Tricornered wing assay, ovarian cancer viability and TEAD-inhibitor assays\",\n      \"pmids\": [\"42128666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the kinase-dependent and kinase-independent functions are balanced in a cell unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked NDR2 to autophagosome biogenesis (ATG9A-dependent), lysosomal fusion, and Golgi repositioning during migration, broadening its vesicular-trafficking role.\",\n      \"evidence\": \"siRNA/shRNA depletion, LC3-II Western, chloroquine fusion assay, Golgi/filopodia imaging in NSCLC cells\",\n      \"pmids\": [\"41390758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution\", \"Direct substrates in autophagosome/Golgi steps unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed the neuronal integrin role at the synapse: NDR2 maintains phospho-\\u03b21-integrin to support synaptic density and CA1 LTP.\",\n      \"evidence\": \"Ndr2-null mice, phospho-\\u03b21-integrin immunostaining, synaptic density, LTP electrophysiology with RGD rescue\",\n      \"pmids\": [\"40439020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct synaptic integrin substrate phosphorylation by NDR2 not biochemically isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse post-translational inputs (phosphorylation, acetylation, SUMOylation, ubiquitination) and distinct subcellular pools (peroxisome, Golgi exit sites, endosomes) are integrated to select among NDR2's many substrates and its kinase-independent MOB1 function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking modification state to substrate choice\", \"Spatial coordination of multiple localized pools undefined\", \"Kinase-dependent versus kinase-independent function switching uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 5, 6, 8, 13, 14, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [17, 19]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 16, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 10, 11, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 18]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 7, 17]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [15, 21]}\n    ],\n    \"complexes\": [\"RIG-I/TRIM25 complex\"],\n    \"partners\": [\"MOB2\", \"MOB1\", \"Rabin8\", \"RIG-I\", \"TRIM25\", \"TRIM27\", \"ULK1\", \"Smurf1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}