{"gene":"STK38","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2007,"finding":"STK38 physically interacts with MEKK1 and MEKK2 via their carboxy-terminal catalytic domains and negatively regulates MEKK1/2 activation by suppressing MEKK2 autophosphorylation and converting MEKK2 from its phosphorylated to non-phosphorylated form, without preventing MEKK1/2 binding to its substrate SEK1 and without phosphorylating MEKK1/2 itself.","method":"Co-immunoprecipitation, in vitro kinase assays, shRNA knockdown, domain mapping","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding demonstrated, in vitro autophosphorylation assay, shRNA phenotype, multiple orthogonal methods in one study","pmids":["17906693"],"is_preprint":false},{"year":2015,"finding":"STK38 constitutively associates with the E3 ubiquitin ligase Smurf1 and facilitates Smurf1-mediated K48-linked ubiquitination and proteasomal degradation of MEKK2, thereby negatively regulating TLR9/CpG-induced ERK1/2 activation and downstream TNF-α and IL-6 production in macrophages. STK38-deficient mice show increased lethality upon E. coli infection and sepsis.","method":"Co-immunoprecipitation, ubiquitination assay, STK38 knockout mice, cytokine measurement, shRNA knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo knockout model, multiple orthogonal methods, replicated mechanistic findings","pmids":["25981615"],"is_preprint":false},{"year":2015,"finding":"STK38 is a novel binding partner of Beclin1 (identified by yeast-two-hybrid), promotes autophagosome formation, supports the interaction of exocyst component Exo84 with Beclin1 and RalB, and is activated in a MOB1- and exocyst-dependent manner upon autophagy induction. STK38 depletion impairs LC3B-II conversion, ATG14L/ATG12/WIPI-1 puncta formation, and Vps34 activity (PI3P production).","method":"Yeast two-hybrid, Co-immunoprecipitation, RNAi knockdown in human cells and Drosophila, PI3P formation assay, LC3B lipidation assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus cell-biological validation, Drosophila genetic model, multiple orthogonal methods","pmids":["26387716"],"is_preprint":false},{"year":2012,"finding":"STK38 regulates MYC protein stability and turnover in a kinase activity-dependent manner in human B-cell lymphoma cells; STK38 kinase inactivation abrogates apoptosis following B-cell receptor activation, and STK38 knockdown decreases MYC protein levels and increases apoptosis.","method":"Kinase-dead mutant overexpression, siRNA knockdown, protein stability assay, in vivo xenograft, regulatory network analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant plus knockdown, in vivo validation, but mechanism of MYC stabilization not fully biochemically resolved","pmids":["23178486"],"is_preprint":false},{"year":2012,"finding":"STK38 (NDR1) potentiates TNFα-induced NF-κB activation in a kinase activity-dependent manner and interacts with multiple NF-κB signaling components; kinase-dead mutant fails to interact with TRAF2 and fails to enhance NF-κB activation induced by TRAF2 (but not RIP1).","method":"Co-immunoprecipitation, overexpression of kinase-dead mutants, siRNA knockdown, NF-κB reporter assay","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and kinase-dead mutant analysis, single lab, reporter assay","pmids":["22674419"],"is_preprint":false},{"year":2017,"finding":"SOCS2 (Cullin5 E3 ligase) interacts with STK38 (NDR1) and promotes its K48-linked ubiquitination and proteasomal degradation; SOCS2 overexpression antagonizes STK38-induced NF-κB activity upon TNFα stimulation, and NDR1 depletion rescues the effect of SOCS2 deficiency on NF-κB transactivation.","method":"Mass spectrometry proteomics, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, SOCS2-/- mouse model of colitis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS identification plus biochemical validation of ubiquitination, in vivo mouse model, multiple orthogonal methods","pmids":["28216640"],"is_preprint":false},{"year":2017,"finding":"STK38 phosphorylates Rbm24 to regulate its protein stability in cardiomyocytes; co-immunoprecipitation with mass spectrometry identified STK38 as an endogenous binding partner of Rbm24, and STK38 knockdown or kinase inhibition reduced Rbm24 protein levels and impaired sarcomere assembly.","method":"Co-immunoprecipitation/mass spectrometry, STK38 knockdown, kinase inhibitor/activator treatment, sarcomere staining","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/MS plus functional phenotype with inhibitor/activator, single lab","pmids":["28322254"],"is_preprint":false},{"year":2018,"finding":"Kir2.1 interacts with STK38 and inhibits Smurf1-mediated ubiquitination and degradation of MEKK2, thereby activating MEK1/2-ERK1/2-Snail pathway to drive EMT and invasion in gastric cancer cells, independent of ion permeation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, invasion/migration assay, mouse metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue, in vivo model; mechanistic axis consistent with prior STK38/Smurf1/MEKK2 literature","pmids":["29549164"],"is_preprint":false},{"year":2019,"finding":"STK38 phosphorylates XPO1 on serine 1055 (in XPO1's C-terminal auto-inhibitory domain), activating XPO1-dependent nuclear export; STK38 itself shuttles between the nucleus and cytoplasm and its nuclear exit requires both XPO1 and STK38 kinase activity. This mechanism also regulates nuclear export of Beclin1 and YAP1.","method":"Proximity-labeling assay, phospho-site mutagenesis, live-cell imaging, nuclear/cytoplasmic fractionation, co-immunoprecipitation, kinase-dead mutant","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — phosphorylation site identified with mutagenesis, proximity-labeling, fractionation with functional consequence, multiple orthogonal methods","pmids":["31544310"],"is_preprint":false},{"year":2019,"finding":"MEKK2 phosphorylates STK38 at Ser91, protecting STK38 from calpain-mediated cleavage at its proximal N-terminal region; calpain I directly cleaves STK38 in vitro, and deletion of the N-terminal region or phosphorylation-defective Ser91 mutant alters STK38 stability under hyperthermia.","method":"In vitro calpain cleavage assay, in vitro MEKK2 kinase assay, phosphorylation-defective mutants, calpain inhibitor (calpeptin) treatment, heat/calcium ionophore stress","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of cleavage and kinase phosphorylation, site-directed mutagenesis, multiple orthogonal approaches","pmids":["31690749"],"is_preprint":false},{"year":2019,"finding":"STK38 inhibits BAG3-mediated chaperone-assisted selective autophagy (CASA) by binding BAG3 and disrupting its functional interplay with HSPB8 and SYNPO2, independently of STK38 kinase activity.","method":"Co-immunoprecipitation, kinase-dead mutant overexpression, RNAi knockdown, autophagy flux assay","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, kinase-dead mutant, functional readout; single lab but multiple methods","pmids":["31326538"],"is_preprint":false},{"year":2016,"finding":"STK38 supports oncogenic Ras-driven transformation by promoting detachment-induced autophagy and mitophagy; STK38 knockdown impairs anoikis resistance and anchorage-independent growth, and knockdown of PINK1 or Parkin similarly impairs these, while knockdown of USP30 rescues anchorage-independent growth in STK38-depleted Ras-transformed cells, placing STK38 upstream of PINK1/Parkin-mediated mitophagy.","method":"shRNA knockdown, genetic epistasis (PINK1/Parkin/USP30), soft agar assay, xenograft model, mitochondrial ROS measurement","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between STK38 and PINK1/Parkin/USP30, multiple functional assays, single lab","pmids":["27283898"],"is_preprint":false},{"year":2020,"finding":"STK38 serves as a reader for monoufmylated histone H4 at Lys31 via a UFM1-binding motif; in a kinase-independent manner, STK38 recruits SUV39H1 to DNA double-strand breaks, leading to H3K9 trimethylation and Tip60 activation, which promotes ATM activation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, kinase-dead mutant, UFM1-binding motif mutation, H3K9me3 and Tip60 activity assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods, domain mutation, functional readout of ATM activation; single lab","pmids":["32537488"],"is_preprint":false},{"year":2021,"finding":"STK38 interacts with PPARγ (identified by Flag-PPARγ pulldown/MS), enhances PPARγ transactivation activity and protein stability (extending half-life from ~1.08 to 1.95 h), and promotes adipogenesis in a PPARγ-dependent manner, without requiring STK38 kinase activity.","method":"Flag-tag pulldown/mass spectrometry, co-immunoprecipitation, reporter assay, protein half-life assay (cycloheximide chase), STK38 overexpression/knockdown, kinase-dead mutant","journal":"Adipocyte","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown/MS identification confirmed by Co-IP, functional assays, kinase-dead mutant; single lab","pmids":["34670478"],"is_preprint":false},{"year":2023,"finding":"STK38 phosphorylates the scaffold protein DOK1, which is required for lysosomal recruitment of the AAA+ ATPase VPS4 to terminate microlysophagy (ESCRT disassembly); STK38 depletion impairs VPS4 recruitment and accelerates DNA damage-induced cellular senescence in human cells.","method":"Phosphorylation assay, RNAi knockdown, lysosomal recruitment imaging, senescence assay, genetic analysis in C. elegans","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation of DOK1 identified, functional consequence (VPS4 recruitment), senescence phenotype; single lab, moderate methods depth from abstract","pmids":["37987447"],"is_preprint":false},{"year":2023,"finding":"NLRP12 interacts with STK38 (identified by proteomics), and the NLRP12/STK38 axis inhibits phosphorylation of GSK3β, leading to β-catenin degradation and suppression of Wnt/β-catenin signaling in intestinal epithelial cells; NLRP12-deficient mice show elevated p-GSK3β and β-catenin in colorectal tumors.","method":"Proteomic interaction studies, co-immunoprecipitation, Nlrp12 conditional knockout mice, intestinal organoids, phosphorylation assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo knockout model, phosphorylation endpoint; mechanism attributed to STK38 but its precise catalytic role on GSK3β not fully resolved","pmids":["37581937"],"is_preprint":false},{"year":2023,"finding":"STK38 binds TBK1 and induces TBK1 phosphorylation to promote NF-κB nuclear translocation and proinflammatory cytokine release; STK38 also reduces AMPK-ACC signaling to enhance de novo lipogenesis, causing hepatic lipid accumulation in HFD-fed mice.","method":"Co-immunoprecipitation, siRNA/ectopic expression in mouse liver, NF-κB nuclear translocation assay, AMPK-ACC phosphorylation assay, in vivo mouse model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, in vivo mouse model, two distinct mechanistic axes described; single lab, limited kinase reconstitution detail in abstract","pmids":["37028764"],"is_preprint":false},{"year":2025,"finding":"STK38 phosphorylates GPX4 at Ser45; SCRN1 enhances the STK38-GPX4 interaction to promote this phosphorylation, which impairs HSC70 recognition and chaperone-mediated autophagy-dependent GPX4 degradation, thereby conferring ferroptosis resistance in hepatocellular carcinoma.","method":"Co-immunoprecipitation, in vitro phosphorylation assay, chaperone-mediated autophagy assay, lipid peroxidation measurement, ferroptosis assay","journal":"Nature cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site identified, CMA assay, functional ferroptosis readout; single lab, abstract-level detail","pmids":["41145774"],"is_preprint":false},{"year":2026,"finding":"STK38 and STK38L inhibit LATS kinase by competitively binding MOB1 and disrupting the LATS-MOB1 complex, independent of their kinase activity; this mechanism is evolutionarily conserved (Drosophila ortholog Tricornered similarly impairs Warts-Mats complex formation), resulting in YAP activation and tissue overgrowth.","method":"Co-immunoprecipitation, competitive binding assays, kinase-dead mutants, Drosophila genetic model (wing size phenotype), ovarian cancer xenograft","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — competitive binding demonstrated biochemically, kinase-dead mutant confirms independence of kinase activity, evolutionarily conserved in Drosophila, multiple orthogonal methods","pmids":["42128666"],"is_preprint":false},{"year":2026,"finding":"STK38 is a non-canonical YAP1 kinase that phosphorylates and deactivates YAP1 in uninjured chief cells; during paligenosis, STK38 is degraded by autophagy, leading to YAP1 dephosphorylation and activation, which is necessary and sufficient for conversion of chief cells into metaplastic proliferating progenitors. STK38 interacts with NF2/Merlin, like canonical Hippo kinases.","method":"In vivo mouse stomach model, STK38 knockdown/overexpression, YAP1 phosphorylation assay, co-immunoprecipitation with NF2, autophagy inhibition experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — kinase phosphorylation of YAP1 demonstrated, genetic rescue (YAP1 necessary and sufficient), NF2 interaction, in vivo model; multiple orthogonal methods","pmids":["41911447"],"is_preprint":false},{"year":2026,"finding":"STK38 interacts with KIF7 and GSK3β to promote Hedgehog signaling by facilitating KIF7 ciliary localization and reprogramming GSK3β substrate selectivity (leading to GLI1 stabilization and β-catenin suppression); GLI1 in turn directly enhances STK38 transcription, establishing a positive feedback loop.","method":"Co-immunoprecipitation, ciliary localization imaging, GSK3β substrate assay, GLI1 ChIP, siRNA knockdown, organoid model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, ciliary imaging, functional epistasis, single lab; abstract-level detail limits tier elevation","pmids":["41540036"],"is_preprint":false},{"year":2026,"finding":"RFC4 stabilizes STK38 and the RFC4-STK38 complex facilitates BECN1 (Beclin1) recruitment to promote autophagy and temozolomide resistance in glioblastoma; phosphorylation of STK38 at T444 stabilizes this complex, and a phospho-deficient T444 mutant impairs autophagy.","method":"Multi-omics analysis, co-immunoprecipitation, phospho-deficient mutant, autophagy flux assay, in vivo xenograft, autophagy inhibitor rescue","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site mutant, Co-IP, in vivo model, functional readout; single lab, abstract-level detail","pmids":["41872171"],"is_preprint":false},{"year":2025,"finding":"STK38 kinase activity is required for MerTK tyrosine phosphorylation and activation of Rac1 and Cdc42 downstream of oncogenic Ras; STK38 was identified as a MerTK complex binding partner by mass spectrometry, and its kinase-dead form failed to support Ras-induced cell migration.","method":"MerTK complex purification/mass spectrometry, Co-immunoprecipitation, kinase-dead mutant, siRNA knockdown, Rac1/Cdc42 activation assay, cell migration assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — MS identification plus kinase-dead mutant, functional phenotype; single lab","pmids":["41226428"],"is_preprint":false}],"current_model":"STK38 (NDR1) is a Hippo pathway serine/threonine kinase with diverse, context-dependent mechanisms: it negatively regulates MEKK1/2 by direct interaction and suppression of autophosphorylation; it facilitates Smurf1-mediated ubiquitination and degradation of MEKK2 to dampen TLR9-ERK signaling; it promotes autophagosome formation by binding Beclin1 and supporting Exo84-RalB-Beclin1 complex assembly; it activates nuclear export by phosphorylating XPO1 at Ser1055 to regulate its own exit and that of Beclin1 and YAP1; it acts as a kinase-independent reader of ufmylated histone H4 (Lys31) to recruit SUV39H1 and activate ATM at DNA double-strand breaks; it phosphorylates YAP1 to deactivate it in quiescent cells, and is itself degraded by autophagy during tissue injury to allow YAP1-driven regenerative plasticity; it competitively binds MOB1 to disrupt the LATS-MOB1 complex and thereby inhibit Hippo signaling in a kinase-independent manner; and it phosphorylates substrates including GPX4 (Ser45), DOK1, and XPO1 in additional cellular contexts governing ferroptosis resistance, lysosomal repair, and nuclear export."},"narrative":{"mechanistic_narrative":"STK38 (NDR1) is a serine/threonine kinase that functions as a context-dependent signaling hub, acting through both catalytic and kinase-independent mechanisms across the Hippo, autophagy, MAPK, and DNA-damage response programs [PMID:17906693, PMID:26387716, PMID:42128666]. As a negative regulator of MAPK signaling, STK38 binds MEKK1/2 and suppresses MEKK2 autophosphorylation, and it constitutively associates with the E3 ligase Smurf1 to promote K48-linked ubiquitination and degradation of MEKK2, thereby restraining TLR9/ERK-driven inflammatory cytokine output [PMID:17906693, PMID:25981615]. STK38 is a core regulator of autophagy: it binds Beclin1, supports Exo84-RalB-Beclin1 complex assembly, and promotes autophagosome formation and Vps34/PI3P activity [PMID:26387716]. Within the Hippo pathway it exerts dual, opposing control of YAP1 — phosphorylating and deactivating YAP1 in quiescent cells (an activity reversed when STK38 is degraded by autophagy during tissue regeneration), while also competitively binding MOB1 to disrupt the LATS-MOB1 complex and inhibit LATS in a kinase-independent, evolutionarily conserved manner [PMID:42128666, PMID:41911447]. STK38 additionally phosphorylates XPO1 at Ser1055 to activate XPO1-dependent nuclear export, controlling its own nucleocytoplasmic shuttling as well as that of Beclin1 and YAP1 [PMID:31544310]. Beyond catalysis, STK38 acts as a reader of monoufmylated histone H4 (Lys31) that recruits SUV39H1 to DNA double-strand breaks to promote ATM activation [PMID:32537488]. Further substrates and partners place STK38 in ferroptosis resistance (GPX4 Ser45), lysosomal membrane repair (DOK1), and oncogenic Ras programs [PMID:41145774, PMID:37987447, PMID:27283898].","teleology":[{"year":2007,"claim":"Established STK38 as a negative regulator of MAPK signaling by defining its direct, non-phosphorylating action on MEKK1/2.","evidence":"Co-IP, in vitro kinase assays, shRNA, and domain mapping showing STK38 binds MEKK1/2 catalytic domains and suppresses MEKK2 autophosphorylation","pmids":["17906693"],"confidence":"High","gaps":["Mechanism by which binding suppresses autophosphorylation not resolved","Physiological contexts of this regulation untested in this study"]},{"year":2012,"claim":"Linked STK38 kinase activity to control of MYC stability and to NF-κB activation, revealing pro-survival and pro-inflammatory roles.","evidence":"Kinase-dead mutants, knockdown, protein stability assays, and NF-κB reporter/Co-IP with TRAF2 in B-cell and TNFα systems","pmids":["23178486","22674419"],"confidence":"Medium","gaps":["Direct substrate phosphorylation underlying MYC stabilization not biochemically resolved","NF-κB findings rest on reporter/Co-IP from a single lab"]},{"year":2015,"claim":"Defined two distinct STK38 functions: facilitating Smurf1-mediated MEKK2 degradation to limit innate immune signaling, and promoting autophagosome formation via Beclin1/exocyst.","evidence":"Reciprocal Co-IP, ubiquitination assays, STK38 knockout mice and sepsis model; yeast two-hybrid plus LC3B/PI3P assays and Drosophila genetics","pmids":["25981615","26387716"],"confidence":"High","gaps":["Whether STK38 kinase activity is required for Smurf1/MEKK2 degradation not fully defined","Direct STK38 substrate in the autophagy machinery not identified"]},{"year":2016,"claim":"Placed STK38 upstream of PINK1/Parkin mitophagy to support oncogenic Ras transformation.","evidence":"shRNA, genetic epistasis with PINK1/Parkin/USP30, soft agar and xenograft assays in Ras-transformed cells","pmids":["27283898"],"confidence":"Medium","gaps":["Molecular connection between STK38 and PINK1/Parkin not biochemically defined","Single lab"]},{"year":2017,"claim":"Identified STK38 as a degradation target (SOCS2-Cullin5) and as a kinase acting on Rbm24, expanding its regulatory inputs and substrate repertoire.","evidence":"MS, Co-IP, ubiquitination assays, SOCS2-/- colitis model; Co-IP/MS and inhibitor/activator effects on Rbm24 and sarcomere assembly","pmids":["28216640","28322254"],"confidence":"High","gaps":["Rbm24 phospho-sites not mapped","How SOCS2-driven turnover integrates with STK38 signaling outputs unclear"]},{"year":2018,"claim":"Showed Kir2.1 antagonizes the STK38/Smurf1/MEKK2 axis to drive cancer EMT, reinforcing the established degradation mechanism in a disease context.","evidence":"Co-IP, ubiquitination assay, knockdown, invasion/migration and metastasis models in gastric cancer","pmids":["29549164"],"confidence":"Medium","gaps":["Direct effect of Kir2.1 on STK38 catalytic state not defined","Single lab"]},{"year":2019,"claim":"Revealed STK38 as an activator of XPO1-dependent nuclear export and defined a reciprocal regulatory loop where MEKK2 phosphorylates STK38 to protect it from calpain cleavage; also identified kinase-independent inhibition of BAG3-mediated CASA.","evidence":"Proximity labeling, phospho-site mutagenesis, fractionation and imaging (XPO1 S1055); in vitro calpain/MEKK2 reconstitution (Ser91); Co-IP and autophagy flux (BAG3)","pmids":["31544310","31690749","31326538"],"confidence":"High","gaps":["Full set of XPO1 cargoes regulated by STK38 not enumerated","Physiological triggers of MEKK2-STK38 phospho-protection beyond hyperthermia unclear"]},{"year":2020,"claim":"Established a kinase-independent chromatin function for STK38 as a reader of ufmylated histone H4 that drives ATM activation at DNA double-strand breaks.","evidence":"Co-IP, ChIP, UFM1-binding-motif and kinase-dead mutants, H3K9me3/Tip60 activity assays","pmids":["32537488"],"confidence":"High","gaps":["Single lab","How STK38 recruitment to breaks is temporally coordinated with repair not defined"]},{"year":2021,"claim":"Extended STK38's kinase-independent scaffold roles to metabolism via PPARγ stabilization and adipogenesis.","evidence":"Pulldown/MS, Co-IP, reporter and cycloheximide-chase half-life assays, kinase-dead mutant","pmids":["34670478"],"confidence":"Medium","gaps":["Mechanism of PPARγ stabilization not resolved","Single lab"]},{"year":2023,"claim":"Expanded the substrate/partner network to DOK1 (lysosomal repair and senescence), NLRP12/GSK3β (Wnt suppression), and TBK1/AMPK (hepatic inflammation and lipogenesis).","evidence":"Phosphorylation and recruitment imaging with C. elegans genetics (DOK1); Co-IP and Nlrp12 knockout mice; Co-IP and in vivo HFD liver model (TBK1/AMPK)","pmids":["37987447","37581937","37028764"],"confidence":"Medium","gaps":["Precise catalytic role of STK38 on GSK3β not resolved","TBK1 axis rests on abstract-level kinase detail","Each axis from a single lab"]},{"year":2025,"claim":"Defined STK38 as a GPX4 Ser45 kinase conferring ferroptosis resistance and as a MerTK-complex kinase supporting Ras-driven migration.","evidence":"Co-IP, in vitro phosphorylation, CMA and lipid peroxidation assays (GPX4/SCRN1); MS, kinase-dead mutant, Rac1/Cdc42 and migration assays (MerTK)","pmids":["41145774","41226428"],"confidence":"Medium","gaps":["How SCRN1 selectively enhances STK38-GPX4 interaction unclear","Direct MerTK phosphorylation by STK38 not established","Single lab each"]},{"year":2026,"claim":"Resolved STK38's dual relationship with the Hippo/YAP1 axis — kinase-independent disruption of LATS-MOB1 versus direct YAP1-deactivating phosphorylation degraded during regeneration — and added Hedgehog/KIF7 and RFC4/BECN1 autophagy roles.","evidence":"Competitive binding and Drosophila genetics (MOB1/LATS); in vivo stomach paligenosis model and NF2 Co-IP (YAP1); Co-IP/ciliary imaging (KIF7); phospho-mutant and xenograft (RFC4/BECN1 T444)","pmids":["42128666","41911447","41540036","41872171"],"confidence":"High","gaps":["How the opposing kinase-dependent (YAP1-inhibiting) and kinase-independent (LATS-inhibiting) activities are balanced in a given cell is unresolved","Trigger determining autophagic degradation of STK38 during paligenosis not fully defined"]},{"year":null,"claim":"How a single kinase reconciles its many opposing, catalytic and non-catalytic activities into context-specific outcomes remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying framework for choosing between kinase-dependent and scaffold modes","Structural basis for distinct partner engagement unmapped","Tissue-specific substrate repertoire incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,8,17,19]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[8,17,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,12,18]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,11,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,18,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,16]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[8]}],"complexes":["Exo84-RalB-Beclin1 complex","MerTK complex"],"partners":["MEKK2","SMURF1","BECN1","XPO1","MOB1","YAP1","NF2","SUV39H1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15208","full_name":"Serine/threonine-protein kinase 38","aliases":["NDR1 protein kinase","Nuclear Dbf2-related kinase 1"],"length_aa":465,"mass_kda":54.2,"function":"Serine/threonine-protein kinase that acts as a negative regulator of MAP3K1/2 signaling (PubMed:12493777, PubMed:15197186, PubMed:17906693, PubMed:7761441). Converts MAP3K2 from its phosphorylated form to its non-phosphorylated form and inhibits autophosphorylation of MAP3K2 (PubMed:12493777, PubMed:15197186, PubMed:17906693, PubMed:7761441). Acts as an ufmylation 'reader' in a kinase-independent manner: specifically recognizes and binds mono-ufmylated histone H4 in response to DNA damage, promoting the recruitment of SUV39H1 to the double-strand breaks, resulting in ATM activation (PubMed:32537488)","subcellular_location":"Nucleus; Cytoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q15208/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STK38","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STK38","total_profiled":1310},"omim":[{"mim_id":"620798","title":"FRY-LIKE TRANSCRIPTION COACTIVATOR; FRYL","url":"https://www.omim.org/entry/620798"},{"mim_id":"615836","title":"SERINE/THREONINE PROTEIN KINASE 38-LIKE PROTEIN; STK38L","url":"https://www.omim.org/entry/615836"},{"mim_id":"614818","title":"FRY MICROTUBULE-BINDING PROTEIN; FRY","url":"https://www.omim.org/entry/614818"},{"mim_id":"606964","title":"SERINE/THREONINE PROTEIN KINASE 38; STK38","url":"https://www.omim.org/entry/606964"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STK38"},"hgnc":{"alias_symbol":["NDR","NDR1"],"prev_symbol":[]},"alphafold":{"accession":"Q15208","domains":[{"cath_id":"-","chopping":"16-80","consensus_level":"medium","plddt":86.6968,"start":16,"end":80},{"cath_id":"3.30.200.20","chopping":"85-168_404-462","consensus_level":"medium","plddt":76.5348,"start":85,"end":462},{"cath_id":"1.10.510.10","chopping":"173-381","consensus_level":"high","plddt":90.8624,"start":173,"end":381}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15208","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15208-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15208-F1-predicted_aligned_error_v6.png","plddt_mean":84.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STK38","jax_strain_url":"https://www.jax.org/strain/search?query=STK38"},"sequence":{"accession":"Q15208","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15208.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15208/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15208"}},"corpus_meta":[{"pmid":"29549164","id":"PMC_29549164","title":"Kir2.1 Interaction with Stk38 Promotes Invasion and Metastasis of Human Gastric Cancer by Enhancing MEKK2-MEK1/2-ERK1/2 Signaling.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29549164","citation_count":56,"is_preprint":false},{"pmid":"25981615","id":"PMC_25981615","title":"Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25981615","citation_count":52,"is_preprint":false},{"pmid":"26387716","id":"PMC_26387716","title":"The Pro-apoptotic STK38 Kinase Is a New Beclin1 Partner Positively Regulating Autophagy.","date":"2015","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/26387716","citation_count":51,"is_preprint":false},{"pmid":"32537488","id":"PMC_32537488","title":"STK38 promotes ATM activation by acting as a reader of histone H4 ufmylation.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32537488","citation_count":51,"is_preprint":false},{"pmid":"23178486","id":"PMC_23178486","title":"STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23178486","citation_count":48,"is_preprint":false},{"pmid":"31544310","id":"PMC_31544310","title":"STK38 kinase acts as XPO1 gatekeeper regulating the nuclear export of autophagy proteins and other cargoes.","date":"2019","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/31544310","citation_count":45,"is_preprint":false},{"pmid":"28216640","id":"PMC_28216640","title":"The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28216640","citation_count":35,"is_preprint":false},{"pmid":"37987447","id":"PMC_37987447","title":"Microautophagy regulated by STK38 and GABARAPs is essential to repair lysosomes and prevent aging.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/37987447","citation_count":30,"is_preprint":false},{"pmid":"17906693","id":"PMC_17906693","title":"Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38).","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17906693","citation_count":28,"is_preprint":false},{"pmid":"37581937","id":"PMC_37581937","title":"NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37581937","citation_count":27,"is_preprint":false},{"pmid":"28322254","id":"PMC_28322254","title":"Stk38 Modulates Rbm24 Protein Stability to Regulate Sarcomere Assembly in Cardiomyocytes.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28322254","citation_count":27,"is_preprint":false},{"pmid":"31326538","id":"PMC_31326538","title":"The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy.","date":"2019","source":"Biochimica et biophysica acta. 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loop regulation of the hedgehog pathway governing tumor heterogeneity in renal papillary carcinoma.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41540036","citation_count":0,"is_preprint":false},{"pmid":"41911447","id":"PMC_41911447","title":"Regulation of STK38 by autophagy governs YAP1 activity during paligenosis.","date":"2026","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41911447","citation_count":0,"is_preprint":false},{"pmid":"41872171","id":"PMC_41872171","title":"RFC4 drives temozolomide resistance in glioblastoma by activating STK38-BECN1-dependent autophagy.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41872171","citation_count":0,"is_preprint":false},{"pmid":"41821474","id":"PMC_41821474","title":"CTCF/STK38 axis drives tumor progression via the Wnt/β-catenin and Hippo pathways.","date":"2026","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/41821474","citation_count":0,"is_preprint":false},{"pmid":"42089599","id":"PMC_42089599","title":"SDPR-STK38 axis controls the proliferation-differentiation balance in alveolar type II cells.","date":"2026","source":"Animal models and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42089599","citation_count":0,"is_preprint":false},{"pmid":"28753211","id":"PMC_28753211","title":"Corrigendum: Stk38 Modulates Rbm24 Protein Stability to Regulate Sarcomere Assembly in Cardiomyocytes.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28753211","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.14.648819","title":"Autophagy-Dependent Regulation of YAP1 by STK38 Governs Recruitment of Differentiated Cells as Progenitor Cells During Regeneration","date":"2025-04-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.14.648819","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.12.659313","title":"NDR2 Kinase Regulate Microglial Metabolic Adaptation and Inflammatory Response: Critical Role in Glucose-Dependent Functional Plasticity","date":"2025-06-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.12.659313","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18623,"output_tokens":6049,"usd":0.073302,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14698,"output_tokens":4537,"usd":0.093457,"stage2_stop_reason":"end_turn"},"total_usd":0.166759,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"STK38 physically interacts with MEKK1 and MEKK2 via their carboxy-terminal catalytic domains and negatively regulates MEKK1/2 activation by suppressing MEKK2 autophosphorylation and converting MEKK2 from its phosphorylated to non-phosphorylated form, without preventing MEKK1/2 binding to its substrate SEK1 and without phosphorylating MEKK1/2 itself.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assays, shRNA knockdown, domain mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding demonstrated, in vitro autophosphorylation assay, shRNA phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17906693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STK38 constitutively associates with the E3 ubiquitin ligase Smurf1 and facilitates Smurf1-mediated K48-linked ubiquitination and proteasomal degradation of MEKK2, thereby negatively regulating TLR9/CpG-induced ERK1/2 activation and downstream TNF-α and IL-6 production in macrophages. STK38-deficient mice show increased lethality upon E. coli infection and sepsis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, STK38 knockout mice, cytokine measurement, shRNA knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo knockout model, multiple orthogonal methods, replicated mechanistic findings\",\n      \"pmids\": [\"25981615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STK38 is a novel binding partner of Beclin1 (identified by yeast-two-hybrid), promotes autophagosome formation, supports the interaction of exocyst component Exo84 with Beclin1 and RalB, and is activated in a MOB1- and exocyst-dependent manner upon autophagy induction. STK38 depletion impairs LC3B-II conversion, ATG14L/ATG12/WIPI-1 puncta formation, and Vps34 activity (PI3P production).\",\n      \"method\": \"Yeast two-hybrid, Co-immunoprecipitation, RNAi knockdown in human cells and Drosophila, PI3P formation assay, LC3B lipidation assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus cell-biological validation, Drosophila genetic model, multiple orthogonal methods\",\n      \"pmids\": [\"26387716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STK38 regulates MYC protein stability and turnover in a kinase activity-dependent manner in human B-cell lymphoma cells; STK38 kinase inactivation abrogates apoptosis following B-cell receptor activation, and STK38 knockdown decreases MYC protein levels and increases apoptosis.\",\n      \"method\": \"Kinase-dead mutant overexpression, siRNA knockdown, protein stability assay, in vivo xenograft, regulatory network analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant plus knockdown, in vivo validation, but mechanism of MYC stabilization not fully biochemically resolved\",\n      \"pmids\": [\"23178486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STK38 (NDR1) potentiates TNFα-induced NF-κB activation in a kinase activity-dependent manner and interacts with multiple NF-κB signaling components; kinase-dead mutant fails to interact with TRAF2 and fails to enhance NF-κB activation induced by TRAF2 (but not RIP1).\",\n      \"method\": \"Co-immunoprecipitation, overexpression of kinase-dead mutants, siRNA knockdown, NF-κB reporter assay\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and kinase-dead mutant analysis, single lab, reporter assay\",\n      \"pmids\": [\"22674419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SOCS2 (Cullin5 E3 ligase) interacts with STK38 (NDR1) and promotes its K48-linked ubiquitination and proteasomal degradation; SOCS2 overexpression antagonizes STK38-induced NF-κB activity upon TNFα stimulation, and NDR1 depletion rescues the effect of SOCS2 deficiency on NF-κB transactivation.\",\n      \"method\": \"Mass spectrometry proteomics, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, SOCS2-/- mouse model of colitis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus biochemical validation of ubiquitination, in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"28216640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STK38 phosphorylates Rbm24 to regulate its protein stability in cardiomyocytes; co-immunoprecipitation with mass spectrometry identified STK38 as an endogenous binding partner of Rbm24, and STK38 knockdown or kinase inhibition reduced Rbm24 protein levels and impaired sarcomere assembly.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry, STK38 knockdown, kinase inhibitor/activator treatment, sarcomere staining\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/MS plus functional phenotype with inhibitor/activator, single lab\",\n      \"pmids\": [\"28322254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Kir2.1 interacts with STK38 and inhibits Smurf1-mediated ubiquitination and degradation of MEKK2, thereby activating MEK1/2-ERK1/2-Snail pathway to drive EMT and invasion in gastric cancer cells, independent of ion permeation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, invasion/migration assay, mouse metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue, in vivo model; mechanistic axis consistent with prior STK38/Smurf1/MEKK2 literature\",\n      \"pmids\": [\"29549164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STK38 phosphorylates XPO1 on serine 1055 (in XPO1's C-terminal auto-inhibitory domain), activating XPO1-dependent nuclear export; STK38 itself shuttles between the nucleus and cytoplasm and its nuclear exit requires both XPO1 and STK38 kinase activity. This mechanism also regulates nuclear export of Beclin1 and YAP1.\",\n      \"method\": \"Proximity-labeling assay, phospho-site mutagenesis, live-cell imaging, nuclear/cytoplasmic fractionation, co-immunoprecipitation, kinase-dead mutant\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — phosphorylation site identified with mutagenesis, proximity-labeling, fractionation with functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"31544310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MEKK2 phosphorylates STK38 at Ser91, protecting STK38 from calpain-mediated cleavage at its proximal N-terminal region; calpain I directly cleaves STK38 in vitro, and deletion of the N-terminal region or phosphorylation-defective Ser91 mutant alters STK38 stability under hyperthermia.\",\n      \"method\": \"In vitro calpain cleavage assay, in vitro MEKK2 kinase assay, phosphorylation-defective mutants, calpain inhibitor (calpeptin) treatment, heat/calcium ionophore stress\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of cleavage and kinase phosphorylation, site-directed mutagenesis, multiple orthogonal approaches\",\n      \"pmids\": [\"31690749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STK38 inhibits BAG3-mediated chaperone-assisted selective autophagy (CASA) by binding BAG3 and disrupting its functional interplay with HSPB8 and SYNPO2, independently of STK38 kinase activity.\",\n      \"method\": \"Co-immunoprecipitation, kinase-dead mutant overexpression, RNAi knockdown, autophagy flux assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, kinase-dead mutant, functional readout; single lab but multiple methods\",\n      \"pmids\": [\"31326538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STK38 supports oncogenic Ras-driven transformation by promoting detachment-induced autophagy and mitophagy; STK38 knockdown impairs anoikis resistance and anchorage-independent growth, and knockdown of PINK1 or Parkin similarly impairs these, while knockdown of USP30 rescues anchorage-independent growth in STK38-depleted Ras-transformed cells, placing STK38 upstream of PINK1/Parkin-mediated mitophagy.\",\n      \"method\": \"shRNA knockdown, genetic epistasis (PINK1/Parkin/USP30), soft agar assay, xenograft model, mitochondrial ROS measurement\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between STK38 and PINK1/Parkin/USP30, multiple functional assays, single lab\",\n      \"pmids\": [\"27283898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STK38 serves as a reader for monoufmylated histone H4 at Lys31 via a UFM1-binding motif; in a kinase-independent manner, STK38 recruits SUV39H1 to DNA double-strand breaks, leading to H3K9 trimethylation and Tip60 activation, which promotes ATM activation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, kinase-dead mutant, UFM1-binding motif mutation, H3K9me3 and Tip60 activity assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods, domain mutation, functional readout of ATM activation; single lab\",\n      \"pmids\": [\"32537488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STK38 interacts with PPARγ (identified by Flag-PPARγ pulldown/MS), enhances PPARγ transactivation activity and protein stability (extending half-life from ~1.08 to 1.95 h), and promotes adipogenesis in a PPARγ-dependent manner, without requiring STK38 kinase activity.\",\n      \"method\": \"Flag-tag pulldown/mass spectrometry, co-immunoprecipitation, reporter assay, protein half-life assay (cycloheximide chase), STK38 overexpression/knockdown, kinase-dead mutant\",\n      \"journal\": \"Adipocyte\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown/MS identification confirmed by Co-IP, functional assays, kinase-dead mutant; single lab\",\n      \"pmids\": [\"34670478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STK38 phosphorylates the scaffold protein DOK1, which is required for lysosomal recruitment of the AAA+ ATPase VPS4 to terminate microlysophagy (ESCRT disassembly); STK38 depletion impairs VPS4 recruitment and accelerates DNA damage-induced cellular senescence in human cells.\",\n      \"method\": \"Phosphorylation assay, RNAi knockdown, lysosomal recruitment imaging, senescence assay, genetic analysis in C. elegans\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation of DOK1 identified, functional consequence (VPS4 recruitment), senescence phenotype; single lab, moderate methods depth from abstract\",\n      \"pmids\": [\"37987447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NLRP12 interacts with STK38 (identified by proteomics), and the NLRP12/STK38 axis inhibits phosphorylation of GSK3β, leading to β-catenin degradation and suppression of Wnt/β-catenin signaling in intestinal epithelial cells; NLRP12-deficient mice show elevated p-GSK3β and β-catenin in colorectal tumors.\",\n      \"method\": \"Proteomic interaction studies, co-immunoprecipitation, Nlrp12 conditional knockout mice, intestinal organoids, phosphorylation assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo knockout model, phosphorylation endpoint; mechanism attributed to STK38 but its precise catalytic role on GSK3β not fully resolved\",\n      \"pmids\": [\"37581937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STK38 binds TBK1 and induces TBK1 phosphorylation to promote NF-κB nuclear translocation and proinflammatory cytokine release; STK38 also reduces AMPK-ACC signaling to enhance de novo lipogenesis, causing hepatic lipid accumulation in HFD-fed mice.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/ectopic expression in mouse liver, NF-κB nuclear translocation assay, AMPK-ACC phosphorylation assay, in vivo mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, in vivo mouse model, two distinct mechanistic axes described; single lab, limited kinase reconstitution detail in abstract\",\n      \"pmids\": [\"37028764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STK38 phosphorylates GPX4 at Ser45; SCRN1 enhances the STK38-GPX4 interaction to promote this phosphorylation, which impairs HSC70 recognition and chaperone-mediated autophagy-dependent GPX4 degradation, thereby conferring ferroptosis resistance in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphorylation assay, chaperone-mediated autophagy assay, lipid peroxidation measurement, ferroptosis assay\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site identified, CMA assay, functional ferroptosis readout; single lab, abstract-level detail\",\n      \"pmids\": [\"41145774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STK38 and STK38L inhibit LATS kinase by competitively binding MOB1 and disrupting the LATS-MOB1 complex, independent of their kinase activity; this mechanism is evolutionarily conserved (Drosophila ortholog Tricornered similarly impairs Warts-Mats complex formation), resulting in YAP activation and tissue overgrowth.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, kinase-dead mutants, Drosophila genetic model (wing size phenotype), ovarian cancer xenograft\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — competitive binding demonstrated biochemically, kinase-dead mutant confirms independence of kinase activity, evolutionarily conserved in Drosophila, multiple orthogonal methods\",\n      \"pmids\": [\"42128666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STK38 is a non-canonical YAP1 kinase that phosphorylates and deactivates YAP1 in uninjured chief cells; during paligenosis, STK38 is degraded by autophagy, leading to YAP1 dephosphorylation and activation, which is necessary and sufficient for conversion of chief cells into metaplastic proliferating progenitors. STK38 interacts with NF2/Merlin, like canonical Hippo kinases.\",\n      \"method\": \"In vivo mouse stomach model, STK38 knockdown/overexpression, YAP1 phosphorylation assay, co-immunoprecipitation with NF2, autophagy inhibition experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase phosphorylation of YAP1 demonstrated, genetic rescue (YAP1 necessary and sufficient), NF2 interaction, in vivo model; multiple orthogonal methods\",\n      \"pmids\": [\"41911447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STK38 interacts with KIF7 and GSK3β to promote Hedgehog signaling by facilitating KIF7 ciliary localization and reprogramming GSK3β substrate selectivity (leading to GLI1 stabilization and β-catenin suppression); GLI1 in turn directly enhances STK38 transcription, establishing a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ciliary localization imaging, GSK3β substrate assay, GLI1 ChIP, siRNA knockdown, organoid model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, ciliary imaging, functional epistasis, single lab; abstract-level detail limits tier elevation\",\n      \"pmids\": [\"41540036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RFC4 stabilizes STK38 and the RFC4-STK38 complex facilitates BECN1 (Beclin1) recruitment to promote autophagy and temozolomide resistance in glioblastoma; phosphorylation of STK38 at T444 stabilizes this complex, and a phospho-deficient T444 mutant impairs autophagy.\",\n      \"method\": \"Multi-omics analysis, co-immunoprecipitation, phospho-deficient mutant, autophagy flux assay, in vivo xenograft, autophagy inhibitor rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site mutant, Co-IP, in vivo model, functional readout; single lab, abstract-level detail\",\n      \"pmids\": [\"41872171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STK38 kinase activity is required for MerTK tyrosine phosphorylation and activation of Rac1 and Cdc42 downstream of oncogenic Ras; STK38 was identified as a MerTK complex binding partner by mass spectrometry, and its kinase-dead form failed to support Ras-induced cell migration.\",\n      \"method\": \"MerTK complex purification/mass spectrometry, Co-immunoprecipitation, kinase-dead mutant, siRNA knockdown, Rac1/Cdc42 activation assay, cell migration assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MS identification plus kinase-dead mutant, functional phenotype; single lab\",\n      \"pmids\": [\"41226428\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STK38 (NDR1) is a Hippo pathway serine/threonine kinase with diverse, context-dependent mechanisms: it negatively regulates MEKK1/2 by direct interaction and suppression of autophosphorylation; it facilitates Smurf1-mediated ubiquitination and degradation of MEKK2 to dampen TLR9-ERK signaling; it promotes autophagosome formation by binding Beclin1 and supporting Exo84-RalB-Beclin1 complex assembly; it activates nuclear export by phosphorylating XPO1 at Ser1055 to regulate its own exit and that of Beclin1 and YAP1; it acts as a kinase-independent reader of ufmylated histone H4 (Lys31) to recruit SUV39H1 and activate ATM at DNA double-strand breaks; it phosphorylates YAP1 to deactivate it in quiescent cells, and is itself degraded by autophagy during tissue injury to allow YAP1-driven regenerative plasticity; it competitively binds MOB1 to disrupt the LATS-MOB1 complex and thereby inhibit Hippo signaling in a kinase-independent manner; and it phosphorylates substrates including GPX4 (Ser45), DOK1, and XPO1 in additional cellular contexts governing ferroptosis resistance, lysosomal repair, and nuclear export.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STK38 (NDR1) is a serine/threonine kinase that functions as a context-dependent signaling hub, acting through both catalytic and kinase-independent mechanisms across the Hippo, autophagy, MAPK, and DNA-damage response programs [#0, #2, #18]. As a negative regulator of MAPK signaling, STK38 binds MEKK1/2 and suppresses MEKK2 autophosphorylation, and it constitutively associates with the E3 ligase Smurf1 to promote K48-linked ubiquitination and degradation of MEKK2, thereby restraining TLR9/ERK-driven inflammatory cytokine output [#0, #1]. STK38 is a core regulator of autophagy: it binds Beclin1, supports Exo84-RalB-Beclin1 complex assembly, and promotes autophagosome formation and Vps34/PI3P activity [#2]. Within the Hippo pathway it exerts dual, opposing control of YAP1 — phosphorylating and deactivating YAP1 in quiescent cells (an activity reversed when STK38 is degraded by autophagy during tissue regeneration), while also competitively binding MOB1 to disrupt the LATS-MOB1 complex and inhibit LATS in a kinase-independent, evolutionarily conserved manner [#18, #19]. STK38 additionally phosphorylates XPO1 at Ser1055 to activate XPO1-dependent nuclear export, controlling its own nucleocytoplasmic shuttling as well as that of Beclin1 and YAP1 [#8]. Beyond catalysis, STK38 acts as a reader of monoufmylated histone H4 (Lys31) that recruits SUV39H1 to DNA double-strand breaks to promote ATM activation [#12]. Further substrates and partners place STK38 in ferroptosis resistance (GPX4 Ser45), lysosomal membrane repair (DOK1), and oncogenic Ras programs [#17, #14, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established STK38 as a negative regulator of MAPK signaling by defining its direct, non-phosphorylating action on MEKK1/2.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, shRNA, and domain mapping showing STK38 binds MEKK1/2 catalytic domains and suppresses MEKK2 autophosphorylation\",\n      \"pmids\": [\"17906693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which binding suppresses autophosphorylation not resolved\", \"Physiological contexts of this regulation untested in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked STK38 kinase activity to control of MYC stability and to NF-\\u03baB activation, revealing pro-survival and pro-inflammatory roles.\",\n      \"evidence\": \"Kinase-dead mutants, knockdown, protein stability assays, and NF-\\u03baB reporter/Co-IP with TRAF2 in B-cell and TNF\\u03b1 systems\",\n      \"pmids\": [\"23178486\", \"22674419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate phosphorylation underlying MYC stabilization not biochemically resolved\", \"NF-\\u03baB findings rest on reporter/Co-IP from a single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined two distinct STK38 functions: facilitating Smurf1-mediated MEKK2 degradation to limit innate immune signaling, and promoting autophagosome formation via Beclin1/exocyst.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, STK38 knockout mice and sepsis model; yeast two-hybrid plus LC3B/PI3P assays and Drosophila genetics\",\n      \"pmids\": [\"25981615\", \"26387716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STK38 kinase activity is required for Smurf1/MEKK2 degradation not fully defined\", \"Direct STK38 substrate in the autophagy machinery not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed STK38 upstream of PINK1/Parkin mitophagy to support oncogenic Ras transformation.\",\n      \"evidence\": \"shRNA, genetic epistasis with PINK1/Parkin/USP30, soft agar and xenograft assays in Ras-transformed cells\",\n      \"pmids\": [\"27283898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular connection between STK38 and PINK1/Parkin not biochemically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified STK38 as a degradation target (SOCS2-Cullin5) and as a kinase acting on Rbm24, expanding its regulatory inputs and substrate repertoire.\",\n      \"evidence\": \"MS, Co-IP, ubiquitination assays, SOCS2-/- colitis model; Co-IP/MS and inhibitor/activator effects on Rbm24 and sarcomere assembly\",\n      \"pmids\": [\"28216640\", \"28322254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rbm24 phospho-sites not mapped\", \"How SOCS2-driven turnover integrates with STK38 signaling outputs unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed Kir2.1 antagonizes the STK38/Smurf1/MEKK2 axis to drive cancer EMT, reinforcing the established degradation mechanism in a disease context.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, knockdown, invasion/migration and metastasis models in gastric cancer\",\n      \"pmids\": [\"29549164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of Kir2.1 on STK38 catalytic state not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed STK38 as an activator of XPO1-dependent nuclear export and defined a reciprocal regulatory loop where MEKK2 phosphorylates STK38 to protect it from calpain cleavage; also identified kinase-independent inhibition of BAG3-mediated CASA.\",\n      \"evidence\": \"Proximity labeling, phospho-site mutagenesis, fractionation and imaging (XPO1 S1055); in vitro calpain/MEKK2 reconstitution (Ser91); Co-IP and autophagy flux (BAG3)\",\n      \"pmids\": [\"31544310\", \"31690749\", \"31326538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of XPO1 cargoes regulated by STK38 not enumerated\", \"Physiological triggers of MEKK2-STK38 phospho-protection beyond hyperthermia unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a kinase-independent chromatin function for STK38 as a reader of ufmylated histone H4 that drives ATM activation at DNA double-strand breaks.\",\n      \"evidence\": \"Co-IP, ChIP, UFM1-binding-motif and kinase-dead mutants, H3K9me3/Tip60 activity assays\",\n      \"pmids\": [\"32537488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"How STK38 recruitment to breaks is temporally coordinated with repair not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended STK38's kinase-independent scaffold roles to metabolism via PPAR\\u03b3 stabilization and adipogenesis.\",\n      \"evidence\": \"Pulldown/MS, Co-IP, reporter and cycloheximide-chase half-life assays, kinase-dead mutant\",\n      \"pmids\": [\"34670478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PPAR\\u03b3 stabilization not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the substrate/partner network to DOK1 (lysosomal repair and senescence), NLRP12/GSK3\\u03b2 (Wnt suppression), and TBK1/AMPK (hepatic inflammation and lipogenesis).\",\n      \"evidence\": \"Phosphorylation and recruitment imaging with C. elegans genetics (DOK1); Co-IP and Nlrp12 knockout mice; Co-IP and in vivo HFD liver model (TBK1/AMPK)\",\n      \"pmids\": [\"37987447\", \"37581937\", \"37028764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise catalytic role of STK38 on GSK3\\u03b2 not resolved\", \"TBK1 axis rests on abstract-level kinase detail\", \"Each axis from a single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined STK38 as a GPX4 Ser45 kinase conferring ferroptosis resistance and as a MerTK-complex kinase supporting Ras-driven migration.\",\n      \"evidence\": \"Co-IP, in vitro phosphorylation, CMA and lipid peroxidation assays (GPX4/SCRN1); MS, kinase-dead mutant, Rac1/Cdc42 and migration assays (MerTK)\",\n      \"pmids\": [\"41145774\", \"41226428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SCRN1 selectively enhances STK38-GPX4 interaction unclear\", \"Direct MerTK phosphorylation by STK38 not established\", \"Single lab each\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved STK38's dual relationship with the Hippo/YAP1 axis — kinase-independent disruption of LATS-MOB1 versus direct YAP1-deactivating phosphorylation degraded during regeneration — and added Hedgehog/KIF7 and RFC4/BECN1 autophagy roles.\",\n      \"evidence\": \"Competitive binding and Drosophila genetics (MOB1/LATS); in vivo stomach paligenosis model and NF2 Co-IP (YAP1); Co-IP/ciliary imaging (KIF7); phospho-mutant and xenograft (RFC4/BECN1 T444)\",\n      \"pmids\": [\"42128666\", \"41911447\", \"41540036\", \"41872171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the opposing kinase-dependent (YAP1-inhibiting) and kinase-independent (LATS-inhibiting) activities are balanced in a given cell is unresolved\", \"Trigger determining autophagic degradation of STK38 during paligenosis not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single kinase reconciles its many opposing, catalytic and non-catalytic activities into context-specific outcomes remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying framework for choosing between kinase-dependent and scaffold modes\", \"Structural basis for distinct partner engagement unmapped\", \"Tissue-specific substrate repertoire incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8, 17, 19]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [8, 17, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 12, 18]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 11, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 18, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"Exo84-RalB-Beclin1 complex\",\n      \"MerTK complex\"\n    ],\n    \"partners\": [\n      \"MEKK2\",\n      \"Smurf1\",\n      \"BECN1\",\n      \"XPO1\",\n      \"MOB1\",\n      \"YAP1\",\n      \"NF2\",\n      \"SUV39H1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}