{"gene":"STK25","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2004,"finding":"YSK1 (STK25) targets to the Golgi apparatus via direct binding to the Golgi matrix protein GM130, and GM130 binding activates YSK1 by promoting autophosphorylation of a conserved threonine within the T-loop. A biochemical screen identified 14-3-3zeta as a specific substrate for YSK1 phosphorylation at the Golgi. Interference with YSK1 function perturbs perinuclear Golgi organization, cell migration, and invasion into type I collagen.","method":"Co-immunoprecipitation, in vitro kinase assays, biochemical substrate screen, dominant-negative interference, cell migration/invasion assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal binding demonstrated, in vitro kinase activity with substrate identification, functional loss-of-function phenotype, replicated across multiple orthogonal methods in a single rigorous study","pmids":["15037601"],"is_preprint":false},{"year":2010,"finding":"Stk25 functions as part of an LKB1-Stk25-GM130 signaling pathway that regulates Golgi morphology and neuronal polarization. Overexpression of Stk25 induces Golgi condensation and multiple axons (supernumerary axons), both of which are rescued by Reelin treatment, placing STK25 in opposition to Reelin-Dab1 signaling. Reelin-Dab1 promotes extension of the Golgi into dendrites, which is suppressed by Stk25 overexpression.","method":"Overexpression and knockdown in cultured neurons, in vivo mouse genetics (Reelin and Dab1 mutants), Golgi morphology imaging, axon/dendrite quantification","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo combined with gain/loss-of-function in culture, multiple orthogonal readouts, independently validates GM130 pathway","pmids":["21111240"],"is_preprint":false},{"year":2011,"finding":"MO25α/β isoforms directly bind to STK25/YSK1 (and MST3/MST4) and stimulate their kinase activity approximately 3- to 4-fold, in a manner analogous to how MO25 activates LKB1 via STRAD.","method":"Binding assays (surface plasmon resonance, co-immunoprecipitation), in vitro kinase activity assays with recombinant proteins, siRNA knockdown of MO25 in cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of activation, binding quantification by SPR, validated in cells, multiple orthogonal methods","pmids":["21423148"],"is_preprint":false},{"year":2008,"finding":"SOK1 (STK25) regulates apoptotic cell death after chemical anoxia via the intrinsic apoptotic pathway. A caspase-cleaved form of SOK1 translocates from the Golgi to the nucleus after anoxia, dependent on caspase activity and on amino acids 275-292 C-terminal to the kinase domain. Nuclear entry of SOK1 is required for the cell death response, as SOK1 mutants unable to enter the nucleus do not induce cell death.","method":"RNA interference (siRNA knockdown), overexpression of wild-type and nuclear-localization mutants, subcellular fractionation/imaging, apoptosis assays, caspase inhibitor experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, mutant analysis defining domain requirement, single lab","pmids":["18364353"],"is_preprint":false},{"year":1997,"finding":"YSK1 (STK25) encodes a novel mammalian Ste20-related serine/threonine kinase with intrinsic protein kinase activity detectable by immunoprecipitation kinase assay. Overexpression of YSK1 does not activate the ERK, JNK/SAPK, or p38 MAPK pathways.","method":"cDNA cloning, immunoprecipitation kinase assay, overexpression with downstream MAPK pathway reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro kinase activity demonstrated; negative MAPK results are informative; single lab","pmids":["9160885"],"is_preprint":false},{"year":2012,"finding":"PDCD10 (CCM3) physically interacts with STK25, and co-expression of both proteins accelerates cell apoptosis under oxidative stress (H2O2). PDCD10 stabilizes STK25 protein through a proteasome-dependent pathway. PDCD10/STK25 interaction modulates ERK activity under oxidative stress.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, apoptosis assays, proteasome inhibitor experiments, ERK activity measurement","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP for interaction, functional co-expression and knockdown assays, single lab with multiple readouts","pmids":["22652780"],"is_preprint":false},{"year":2012,"finding":"STK25 physically interacts with CCM2 (cerebral cavernous malformation 2 protein) and can phosphorylate CCM2. STK25 is part of the TrkA-CCM2 death-signaling pathway in medulloblastoma cells: knockdown of STK25 (but not STK24) rescues cells from NGF-induced TrkA-dependent cell death, and the kinase activity of STK25 is required for death signaling.","method":"Affinity proteomics (AP-MS), co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, cell death assays, kinase-dead mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — AP-MS for interactor identification, in vitro phosphorylation, kinase-dead mutagenesis confirming catalytic requirement, loss-of-function rescue; single lab but multiple orthogonal methods","pmids":["22782892"],"is_preprint":false},{"year":2012,"finding":"Stk25 knockdown in embryonic neurons reduces Tau phosphorylation. Stk25 regulates neuronal polarization and Golgi morphology in an antagonistic manner to Dab1 (Reelin pathway), as identified by microarray-based modifier screen in dab1-null mice and validated by knockdown.","method":"Microarray gene expression comparison between strains, siRNA knockdown in embryonic neurons, Tau phosphorylation assay, Golgi morphology imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic modifier screen combined with siRNA validation, multiple phenotypic readouts, single lab","pmids":["22355340"],"is_preprint":false},{"year":2013,"finding":"Partial depletion of STK25 in rat L6 myoblasts increases expression of Ucp3 and lipid oxidation, and enhances expression of Glut1, Glut4, and hexokinase 2, resulting in improved insulin-stimulated glucose uptake. STK25 thus negatively regulates lipid oxidation and glucose uptake in skeletal muscle cells.","method":"siRNA knockdown in L6 myoblasts, qRT-PCR, western blot, palmitate oxidation assay, glucose uptake assay","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined metabolic phenotypic readouts using multiple assays, single lab","pmids":["22391949"],"is_preprint":false},{"year":2013,"finding":"Acute loss of Stk25 function (Cre-mediated conditional knockout or siRNA knockdown) disrupts neuronal migration in the developing cortex. Knockdown of LKB1, STRAD, and GM130 — molecules in the LKB1-STRAD-Stk25-GM130 pathway — causes similar neuronal migration errors.","method":"Conditional (Cre-mediated) knockout, siRNA knockdown, in utero electroporation, neuronal migration assays in developing mouse brain","journal":"Neural development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic approach and knockdown with defined developmental phenotype, pathway placement by parallel knockdown of pathway members, single lab","pmids":["24225308"],"is_preprint":false},{"year":2015,"finding":"STK25 localizes to intrahepatic lipid droplets, colocalizing with the lipid droplet-coating protein ADFP/ATGL. STK25 overexpression reduces β-oxidation and triacylglycerol secretion in liver, promoting steatosis, while ATGL is displaced from the lipid droplet surface to the cytoplasm in STK25 transgenic livers.","method":"Transgenic mouse model (high-fat diet challenge), immunofluorescence colocalization, subcellular fractionation, β-oxidation assay, TAG secretion assay, western blot","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by colocalization plus functional consequence demonstrated in vivo, single lab","pmids":["25609431"],"is_preprint":false},{"year":2015,"finding":"STK25 deficiency in knockout mice suppresses development of hyperglycemia, reduces hepatic gluconeogenesis, and increases insulin sensitivity. Stk25-/- mice show decreased protein levels of acetyl-CoA carboxylase (ACC), implicating ACC regulation as a mechanism underlying altered lipid oxidation and synthesis.","method":"Stk25 knockout mice on high-fat diet, glucose/insulin tolerance tests, euglycemic-hyperinsulinemic clamp, hepatic gene/protein expression analysis, western blot","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined metabolic phenotype and protein-level mechanism (ACC), reciprocal to transgenic results from same lab","pmids":["25845663"],"is_preprint":false},{"year":2019,"finding":"STK25 activates LATS kinase by promoting LATS activation loop phosphorylation independently of prior hydrophobic motif phosphorylation, thereby activating Hippo signaling and suppressing YAP/TAZ transcriptional co-activators. Loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation under growth-suppressive conditions.","method":"siRNA/CRISPR loss-of-function, phospho-specific antibody assays for LATS activation loop vs. hydrophobic motif, YAP/TAZ reporter assays, in vitro and in vivo proliferation assays, cancer genomics analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic phosphorylation site distinction demonstrated, loss-of-function in vitro and in vivo, multiple orthogonal readouts, published in high-tier journal","pmids":["30948712"],"is_preprint":false},{"year":2020,"finding":"STK25 promotes STRIPAK-mediated inhibition of MST2 (Hippo pathway) by directly phosphorylating the scaffolding protein SAV1, which diminishes SAV1's ability to inhibit the STRIPAK phosphatase complex. Thus STK25, as the kinase component of STRIPAK, antagonizes SAV1 to suppress Hippo signaling initiation.","method":"siRNA depletion of STK25 in human cells, in vitro kinase assay (STK25 phosphorylating SAV1), co-immunoprecipitation assessing STRIPAK integrity, MST2 activation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay with defined substrate (SAV1), epistasis analysis placing STK25 within STRIPAK, multiple orthogonal methods, peer-reviewed","pmids":["32292165"],"is_preprint":false},{"year":2018,"finding":"STK25 interacts with GOLPH3 (Golgi phosphoprotein 3) and suppresses aerobic glycolysis in colorectal cancer cells through GOLPH3-regulated mTOR signaling, thereby inhibiting cell proliferation.","method":"Co-immunoprecipitation, GST pull-down, His-tag pull-down, western blot for mTOR pathway, glucose uptake and lactate production assays, xenograft mouse model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — interaction confirmed by three pull-down methods, pathway activity measured, in vivo validation, single lab","pmids":["29996891"],"is_preprint":false},{"year":2021,"finding":"STK25 regulates neuronal migration and polarization by controlling Rho GTPase activities: STK25 promotes Rac1 activation and reduces RhoA levels in the developing brain through forming complexes with α-PIX and β-PIX (GTPase regulatory enzymes) and with Cullin3-Bacurd1/Kctd13 (a RhoA ubiquitination complex), in a kinase activity-independent manner.","method":"Stk25 conditional knockout, in utero electroporation, rescue experiments with MST3 overexpression, co-immunoprecipitation for complex formation, RhoA/Rac1 activity assays, overexpression of Bacurd1/Cul3","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for complex identification, Rho GTPase activity assays, rescue genetics, single lab with multiple orthogonal approaches","pmids":["34518307"],"is_preprint":false},{"year":2022,"finding":"STK25 phosphorylates the type Iα regulatory subunit of PKA (PRKAR1A), which leads to inhibition of PKA catalytic activity and increased binding of the regulatory subunit to the catalytic subunit in the presence of cAMP. In Stk25 knockout mice, PRKAR1A phosphorylation is diminished, PKA activity is increased, and contractile response to beta-adrenergic stimulation is augmented.","method":"iPSC-derived cardiomyocytes, in vitro kinase assay, co-immunoprecipitation (regulatory-catalytic subunit binding), Stk25 knockout mouse model, PKA activity assay, cardiac contractility measurements","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay identifying substrate and phosphorylation consequence, validated in genetic KO mouse with physiological readout, multiple orthogonal methods","pmids":["35977512"],"is_preprint":false},{"year":2022,"finding":"STK25 deficiency in mice and human endothelial cells causes KLF2 expression, Golgi dispersion, altered β-catenin distribution, and stress fiber appearance. Combined deficiency of STK24 and STK25 (but not either alone) in mice causes aggressive cavernoma-like vascular lesions, and STK25 deficiency alone induces these phenotypes in the context of STK24 heterozygosity.","method":"Double Stk24/Stk25 knockout mice, siRNA in human endothelial cells, histology, immunofluorescence for KLF2/β-catenin/stress fibers/Golgi morphology","journal":"Stroke","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model plus in vitro validation, multiple cellular readouts, single lab","pmids":["35130716"],"is_preprint":false},{"year":2022,"finding":"STK25 deficiency increases PD-L1 protein stability by regulating K48-linked ubiquitination of PD-L1 in a NEDD4-dependent manner, thereby increasing PD-L1 surface levels and modulating tumor immune evasion in colorectal cancer.","method":"STK25 knockout cell lines and mice, co-immunoprecipitation, ubiquitination assays (K48-linkage specific), western blot for PD-L1 protein levels, in vivo tumor models with anti-PD-1 treatment","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic ubiquitination assay with defined linkage and E3 ligase (NEDD4), in vivo validation, single lab","pmids":["40729594"],"is_preprint":false},{"year":2025,"finding":"STK25 undergoes autophosphorylation in response to multiple TLR triggers and phosphorylates IRF5 at Thr265, leading to IRF5 transcriptional activation and pro-inflammatory cytokine production. Loss of STK25 in primary immune cells attenuates R848-induced IRF5 nuclear translocation and pro-inflammatory cytokine production.","method":"Kinome-wide siRNA screen in THP-1 cells, in vitro kinase assay (STK25 phosphorylating IRF5-Thr265), Stk25-deficient primary immune cells, IRF5 nuclear translocation assay, cytokine ELISA","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay identifying substrate site, validated in primary KO cells; single lab","pmids":["40639948"],"is_preprint":false},{"year":2019,"finding":"STK25 coats intrahepatic lipid droplets and regulates their associated phosphoproteome; STK25 deficiency in the liver alters proteins involved in peroxisomal biogenesis, ubiquitination-mediated proteolysis, and antioxidant defense. STK25 silencing in human liver cells attenuates peroxisomal biogenesis and protects against oxidative and ER stress in a hepatocyte-autonomous manner.","method":"Stk25 knockout mice (high-fat diet), quantitative lipid droplet-associated phosphoproteomics, peroxisomal biogenesis assays, oxidative/ER stress markers in human liver cells with STK25 siRNA","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics with defined organelle fraction, validated in human cells; single lab, single study","pmids":["31857389"],"is_preprint":false},{"year":2026,"finding":"STK25 deficiency in colorectal cancer cells activates the NF-κB pathway, leading to p50 phosphorylation that directly binds the AREG promoter and transcriptionally upregulates AREG expression; elevated AREG then activates EGFR on cancer-associated fibroblasts (CAFs), promoting CAF activation and cetuximab resistance.","method":"siRNA knockdown and overexpression in CRC cells, ChIP assay (p50 binding to AREG promoter), dual-luciferase reporter assay, CAF co-culture, in vivo xenograft models, patient-derived organoids","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assays identify transcriptional mechanism, in vivo and organoid validation, single lab","pmids":["42057436"],"is_preprint":false}],"current_model":"STK25 (also known as YSK1/SOK1) is a Golgi-localized STE20-family serine/threonine kinase that is activated by binding to the Golgi matrix protein GM130 (via autophosphorylation of its T-loop threonine) and by the scaffold protein MO25; it phosphorylates multiple substrates including 14-3-3ζ, SAV1, PRKAR1A, IRF5, and CCM2, and it regulates Golgi organization, neuronal polarization and migration (through LKB1-STRAD-GM130 and Rho GTPase pathways), Hippo signaling (activating LATS independently of hydrophobic motif phosphorylation while also phosphorylating SAV1 to promote STRIPAK-mediated MST2 inhibition), intracellular lipid droplet metabolism and ectopic lipid accumulation in liver, skeletal muscle, and other metabolic organs, PKA activity (via PRKAR1A phosphorylation), TLR-induced IRF5 inflammatory signaling, and apoptosis following oxidative/anoxic stress via nuclear translocation of a caspase-cleaved fragment."},"narrative":{"mechanistic_narrative":"STK25 (YSK1/SOK1) is a STE20-family serine/threonine kinase that integrates Golgi organization, cell polarity, Hippo signaling, and metabolic and inflammatory control [PMID:15037601, PMID:30948712]. Its catalytic activity, intrinsic to the kinase domain [PMID:9160885], is activated by direct binding to the Golgi matrix protein GM130, which promotes autophosphorylation of a conserved T-loop threonine and recruits the kinase to the Golgi where it phosphorylates 14-3-3ζ [PMID:15037601], and is further stimulated by the scaffold protein MO25α/β [PMID:21423148]. Through an LKB1-STRAD-STK25-GM130 axis and kinase-independent assembly with α/β-PIX and the Cullin3-Bacurd1 RhoA-ubiquitination complex, STK25 controls Golgi morphology, neuronal polarization, and cortical neuronal migration by balancing Rac1 and RhoA activity, acting antagonistically to Reelin-Dab1 signaling [PMID:21111240, PMID:24225308, PMID:34518307]. In Hippo signaling STK25 promotes LATS activation-loop phosphorylation independently of hydrophobic-motif phosphorylation to suppress YAP/TAZ, and as the kinase subunit of STRIPAK it phosphorylates SAV1 to relieve SAV1-mediated inhibition of the STRIPAK phosphatase and restrain MST2 [PMID:30948712, PMID:32292165]. STK25 additionally phosphorylates the PKA regulatory subunit PRKAR1A to inhibit PKA activity [PMID:35977512] and phosphorylates IRF5 at Thr265 to drive TLR-induced pro-inflammatory cytokine production [PMID:40639948]. At intrahepatic lipid droplets STK25 coats the droplet surface, displaces ATGL, and acts as a negative regulator of β-oxidation and glucose uptake, such that its loss improves insulin sensitivity and reduces ectopic lipid accumulation [PMID:25609431, PMID:25845663, PMID:22391949]. A caspase-cleaved STK25 fragment translocates from the Golgi to the nucleus to execute apoptosis after anoxic/oxidative stress [PMID:18364353].","teleology":[{"year":1997,"claim":"Establishing that STK25 is a catalytically active STE20-related kinase distinct from canonical MAPK cascades defined it as an independent signaling node rather than an upstream MAPKKK.","evidence":"cDNA cloning with immunoprecipitation kinase assay and MAPK reporter assays after overexpression","pmids":["9160885"],"confidence":"Medium","gaps":["No physiological substrate identified","No localization or activation mechanism defined"]},{"year":2004,"claim":"Identifying GM130-dependent Golgi targeting and T-loop autophosphorylation, plus 14-3-3ζ as a substrate, explained where and how STK25 is activated and linked it to Golgi organization and cell migration.","evidence":"Co-IP, in vitro kinase assays, biochemical substrate screen, and migration/invasion assays in cells","pmids":["15037601"],"confidence":"High","gaps":["Functional consequence of 14-3-3ζ phosphorylation unresolved","Mechanism linking Golgi position to migration not detailed"]},{"year":2008,"claim":"Showing that a caspase-cleaved STK25 fragment must enter the nucleus to drive apoptosis after anoxia revealed a stress-responsive pro-death function gated by proteolysis and a defined C-terminal segment.","evidence":"siRNA, nuclear-localization mutants, fractionation/imaging and caspase-inhibitor apoptosis assays","pmids":["18364353"],"confidence":"Medium","gaps":["Nuclear substrates of the cleaved fragment unknown","Single lab; connection to Golgi pool unclear"]},{"year":2010,"claim":"Placing STK25 within an LKB1-STK25-GM130 pathway opposing Reelin-Dab1 connected its Golgi function to neuronal polarization in vivo.","evidence":"Gain/loss-of-function in cultured neurons with Reelin/Dab1 mouse genetics and Golgi/axon imaging","pmids":["21111240"],"confidence":"High","gaps":["Direct kinase substrates in this pathway not defined","How Golgi condensation generates supernumerary axons unresolved"]},{"year":2011,"claim":"Demonstrating that MO25 directly binds and stimulates STK25 kinase activity identified a second activator parallel to the LKB1-STRAD-MO25 mechanism.","evidence":"SPR binding, co-IP, in vitro kinase assays with recombinant proteins, and cellular MO25 knockdown","pmids":["21423148"],"confidence":"High","gaps":["Cellular context where MO25 vs GM130 dominates not defined","Substrate selectivity changes upon MO25 binding unknown"]},{"year":2012,"claim":"Identifying CCM3/PDCD10 stabilization and CCM2 phosphorylation embedded STK25 in CCM-protein and TrkA death-signaling networks with a catalytic requirement.","evidence":"AP-MS, co-IP, in vitro kinase assays, kinase-dead mutants, proteasome inhibitors and cell-death rescue","pmids":["22652780","22782892"],"confidence":"High","gaps":["Functional consequence of CCM2 phosphorylation not defined","Reconciliation of pro-survival and pro-death roles incomplete"]},{"year":2012,"claim":"A modifier screen confirming STK25 antagonism to Dab1 and its control of Tau phosphorylation reinforced its role in neuronal polarization and Golgi morphology.","evidence":"Microarray modifier screen in dab1-null mice with siRNA validation and Tau/Golgi readouts","pmids":["22355340"],"confidence":"Medium","gaps":["Direct kinase target driving Tau phosphorylation not identified","Mechanism is correlative for some readouts"]},{"year":2013,"claim":"Loss-of-function in muscle cells and knockout mice established STK25 as a negative regulator of lipid oxidation, glucose uptake, and gluconeogenesis, with ACC as a candidate effector.","evidence":"siRNA in L6 myoblasts and Stk25 knockout mice with metabolic phenotyping and clamp studies","pmids":["22391949","25845663"],"confidence":"Medium","gaps":["Direct substrate linking STK25 to ACC unknown","Tissue-specific mechanisms not fully separated"]},{"year":2013,"claim":"Conditional knockout phenocopied by knockdown of pathway members confirmed STK25's requirement for cortical neuronal migration within the LKB1-STRAD-GM130 axis.","evidence":"Cre knockout, siRNA, in utero electroporation and migration assays in developing brain","pmids":["24225308"],"confidence":"Medium","gaps":["Molecular effectors of migration downstream of STK25 not defined here"]},{"year":2015,"claim":"Localizing STK25 to hepatic lipid droplets and showing ATGL displacement gave a physical mechanism for its promotion of steatosis.","evidence":"Transgenic mice, colocalization, fractionation, β-oxidation and TAG secretion assays","pmids":["25609431"],"confidence":"Medium","gaps":["Whether ATGL displacement is kinase-dependent unresolved","Direct droplet substrates not identified"]},{"year":2018,"claim":"Linking STK25 to GOLPH3-mTOR signaling and aerobic glycolysis suppression positioned it as a tumor-suppressive metabolic regulator in colorectal cancer.","evidence":"Co-IP, GST/His pull-downs, mTOR western blots, glycolysis assays and xenografts","pmids":["29996891"],"confidence":"Medium","gaps":["Whether STK25 phosphorylates GOLPH3 not established","Single lab"]},{"year":2019,"claim":"Mechanistic dissection of LATS activation-loop phosphorylation independent of hydrophobic-motif phosphorylation defined how STK25 activates Hippo signaling and restrains YAP/TAZ-driven proliferation.","evidence":"siRNA/CRISPR, phospho-site-specific antibodies, YAP/TAZ reporters, proliferation assays and cancer genomics","pmids":["30948712"],"confidence":"High","gaps":["Direct vs indirect phosphorylation of LATS not fully resolved","Relationship to STRIPAK function not addressed here"]},{"year":2019,"claim":"Lipid-droplet phosphoproteomics tied STK25 to peroxisomal biogenesis and antioxidant/ER-stress defense in a hepatocyte-autonomous manner.","evidence":"Stk25 KO mice phosphoproteomics and human liver-cell siRNA with stress markers","pmids":["31857389"],"confidence":"Medium","gaps":["Direct droplet substrates not validated individually","Causal phosphosite for peroxisomal effects unknown"]},{"year":2020,"claim":"Demonstrating SAV1 phosphorylation by STK25 within STRIPAK clarified a second, opposing arm of STK25 Hippo control, where it relieves SAV1 inhibition of the STRIPAK phosphatase to restrain MST2.","evidence":"siRNA, in vitro kinase assay on SAV1, STRIPAK integrity co-IP and MST2 activation assays","pmids":["32292165"],"confidence":"High","gaps":["Reconciliation of LATS-activating and MST2-restraining roles incomplete","Context determining which arm dominates unknown"]},{"year":2021,"claim":"Showing kinase-independent control of Rac1/RhoA via PIX and Cullin3-Bacurd1 complexes revealed a non-catalytic scaffolding mechanism for STK25 in neuronal migration.","evidence":"Conditional KO, in utero electroporation, co-IP, Rho GTPase activity assays and MST3 rescue","pmids":["34518307"],"confidence":"Medium","gaps":["Structural basis of PIX/Cul3 complex assembly unknown","Interplay with kinase-dependent functions undefined"]},{"year":2022,"claim":"Identifying PRKAR1A as a substrate whose phosphorylation inhibits PKA connected STK25 to cAMP/PKA signaling and cardiac contractility.","evidence":"iPSC-cardiomyocytes, in vitro kinase assay, regulatory-catalytic subunit co-IP, KO mice and contractility measurements","pmids":["35977512"],"confidence":"High","gaps":["Phosphosite on PRKAR1A not specified here","Tissue breadth of PKA regulation not mapped"]},{"year":2022,"claim":"Combined STK24/STK25 deficiency producing cavernoma-like lesions with KLF2 and β-catenin/Golgi changes implicated STK25 in vascular integrity, partly redundant with STK24.","evidence":"Double KO mice and endothelial siRNA with histology and immunofluorescence","pmids":["35130716"],"confidence":"Medium","gaps":["Substrate driving endothelial phenotype not identified","Mechanistic link to CCM-protein interactions not closed"]},{"year":2022,"claim":"Linking STK25 loss to NEDD4-dependent K48-ubiquitination of PD-L1 connected the kinase to tumor immune evasion.","evidence":"KO cells/mice, co-IP, K48-linkage ubiquitination assays and anti-PD-1 tumor models","pmids":["40729594"],"confidence":"Medium","gaps":["Whether STK25 directly phosphorylates NEDD4 or PD-L1 unresolved","Single lab"]},{"year":2025,"claim":"Identifying IRF5-Thr265 as a substrate established STK25 as a TLR-responsive kinase driving IRF5-dependent inflammatory cytokine production.","evidence":"Kinome-wide siRNA screen, in vitro kinase assay, KO primary immune cells, IRF5 translocation and cytokine ELISA","pmids":["40639948"],"confidence":"Medium","gaps":["Upstream signal activating STK25 in TLR pathway not defined","Single lab"]},{"year":2026,"claim":"Linking STK25 loss to NF-κB/p50-driven AREG transcription and EGFR activation on fibroblasts explained a mechanism of cetuximab resistance in colorectal cancer.","evidence":"siRNA/overexpression, ChIP, luciferase, CAF co-culture, xenografts and patient-derived organoids","pmids":["42057436"],"confidence":"Medium","gaps":["Direct kinase substrate connecting STK25 to NF-κB unknown","Single lab"]},{"year":null,"claim":"It remains unresolved how STK25's many context-specific functions are coordinated by a single kinase, and how activation inputs select among its diverse substrates.","evidence":"No single study reconciles the Golgi, Hippo, metabolic, inflammatory and apoptotic roles","pmids":[],"confidence":"Low","gaps":["No unifying substrate-selection mechanism defined","Tissue- and stimulus-specific activator usage not mapped","Structural basis of kinase-dependent vs scaffolding functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,13,16,19]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4,13,16,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1,3,17]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[10,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,13,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,10,11,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,9,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,6]}],"complexes":["STRIPAK"],"partners":["GM130","CAB39 (MO25)","PDCD10","CCM2","SAV1","GOLPH3","ARHGEF6 (ALPHA-PIX)","CUL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00506","full_name":"Serine/threonine-protein kinase 25","aliases":["Ste20-like kinase","Sterile 20/oxidant stress-response kinase 1","SOK-1","Ste20/oxidant stress response kinase 1"],"length_aa":426,"mass_kda":48.1,"function":"Oxidant stress-activated serine/threonine kinase that may play a role in the response to environmental stress. Targets to the Golgi apparatus where it appears to regulate protein transport events, cell adhesion, and polarity complexes important for cell migration. Part of the striatin-interacting phosphatase and kinase (STRIPAK) complexes. STRIPAK complexes have critical roles in protein (de)phosphorylation and are regulators of multiple signaling pathways including Hippo, MAPK, nuclear receptor and cytoskeleton remodeling. Different types of STRIPAK complexes are involved in a variety of biological processes such as cell growth, differentiation, apoptosis, metabolism and immune regulation (PubMed:18782753)","subcellular_location":"Cytoplasm; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/O00506/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STK25","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000115694","cell_line_id":"CID001278","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"golgi","grade":1}],"interactors":[{"gene":"STK26","stoichiometry":10.0},{"gene":"PDCD10","stoichiometry":10.0},{"gene":"STRN4","stoichiometry":4.0},{"gene":"STRN3","stoichiometry":4.0},{"gene":"STRN","stoichiometry":0.2},{"gene":"CLCN7","stoichiometry":0.2},{"gene":"PPP2R1A","stoichiometry":0.2},{"gene":"STK24","stoichiometry":0.2},{"gene":"SLMAP","stoichiometry":0.2},{"gene":"MANF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001278","total_profiled":1310},"omim":[{"mim_id":"620607","title":"SPASTIC PARAPLEGIA 30B, AUTOSOMAL RECESSIVE; SPG30B","url":"https://www.omim.org/entry/620607"},{"mim_id":"618903","title":"METHYLTRANSFERASE 6, METHYLCYTIDINE; 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A biochemical screen identified 14-3-3zeta as a specific substrate for YSK1 phosphorylation at the Golgi. Interference with YSK1 function perturbs perinuclear Golgi organization, cell migration, and invasion into type I collagen.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assays, biochemical substrate screen, dominant-negative interference, cell migration/invasion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal binding demonstrated, in vitro kinase activity with substrate identification, functional loss-of-function phenotype, replicated across multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"15037601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Stk25 functions as part of an LKB1-Stk25-GM130 signaling pathway that regulates Golgi morphology and neuronal polarization. Overexpression of Stk25 induces Golgi condensation and multiple axons (supernumerary axons), both of which are rescued by Reelin treatment, placing STK25 in opposition to Reelin-Dab1 signaling. Reelin-Dab1 promotes extension of the Golgi into dendrites, which is suppressed by Stk25 overexpression.\",\n      \"method\": \"Overexpression and knockdown in cultured neurons, in vivo mouse genetics (Reelin and Dab1 mutants), Golgi morphology imaging, axon/dendrite quantification\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo combined with gain/loss-of-function in culture, multiple orthogonal readouts, independently validates GM130 pathway\",\n      \"pmids\": [\"21111240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MO25α/β isoforms directly bind to STK25/YSK1 (and MST3/MST4) and stimulate their kinase activity approximately 3- to 4-fold, in a manner analogous to how MO25 activates LKB1 via STRAD.\",\n      \"method\": \"Binding assays (surface plasmon resonance, co-immunoprecipitation), in vitro kinase activity assays with recombinant proteins, siRNA knockdown of MO25 in cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of activation, binding quantification by SPR, validated in cells, multiple orthogonal methods\",\n      \"pmids\": [\"21423148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SOK1 (STK25) regulates apoptotic cell death after chemical anoxia via the intrinsic apoptotic pathway. A caspase-cleaved form of SOK1 translocates from the Golgi to the nucleus after anoxia, dependent on caspase activity and on amino acids 275-292 C-terminal to the kinase domain. Nuclear entry of SOK1 is required for the cell death response, as SOK1 mutants unable to enter the nucleus do not induce cell death.\",\n      \"method\": \"RNA interference (siRNA knockdown), overexpression of wild-type and nuclear-localization mutants, subcellular fractionation/imaging, apoptosis assays, caspase inhibitor experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, mutant analysis defining domain requirement, single lab\",\n      \"pmids\": [\"18364353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"YSK1 (STK25) encodes a novel mammalian Ste20-related serine/threonine kinase with intrinsic protein kinase activity detectable by immunoprecipitation kinase assay. Overexpression of YSK1 does not activate the ERK, JNK/SAPK, or p38 MAPK pathways.\",\n      \"method\": \"cDNA cloning, immunoprecipitation kinase assay, overexpression with downstream MAPK pathway reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro kinase activity demonstrated; negative MAPK results are informative; single lab\",\n      \"pmids\": [\"9160885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDCD10 (CCM3) physically interacts with STK25, and co-expression of both proteins accelerates cell apoptosis under oxidative stress (H2O2). PDCD10 stabilizes STK25 protein through a proteasome-dependent pathway. PDCD10/STK25 interaction modulates ERK activity under oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, apoptosis assays, proteasome inhibitor experiments, ERK activity measurement\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP for interaction, functional co-expression and knockdown assays, single lab with multiple readouts\",\n      \"pmids\": [\"22652780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STK25 physically interacts with CCM2 (cerebral cavernous malformation 2 protein) and can phosphorylate CCM2. STK25 is part of the TrkA-CCM2 death-signaling pathway in medulloblastoma cells: knockdown of STK25 (but not STK24) rescues cells from NGF-induced TrkA-dependent cell death, and the kinase activity of STK25 is required for death signaling.\",\n      \"method\": \"Affinity proteomics (AP-MS), co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, cell death assays, kinase-dead mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — AP-MS for interactor identification, in vitro phosphorylation, kinase-dead mutagenesis confirming catalytic requirement, loss-of-function rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22782892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Stk25 knockdown in embryonic neurons reduces Tau phosphorylation. Stk25 regulates neuronal polarization and Golgi morphology in an antagonistic manner to Dab1 (Reelin pathway), as identified by microarray-based modifier screen in dab1-null mice and validated by knockdown.\",\n      \"method\": \"Microarray gene expression comparison between strains, siRNA knockdown in embryonic neurons, Tau phosphorylation assay, Golgi morphology imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic modifier screen combined with siRNA validation, multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"22355340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Partial depletion of STK25 in rat L6 myoblasts increases expression of Ucp3 and lipid oxidation, and enhances expression of Glut1, Glut4, and hexokinase 2, resulting in improved insulin-stimulated glucose uptake. STK25 thus negatively regulates lipid oxidation and glucose uptake in skeletal muscle cells.\",\n      \"method\": \"siRNA knockdown in L6 myoblasts, qRT-PCR, western blot, palmitate oxidation assay, glucose uptake assay\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined metabolic phenotypic readouts using multiple assays, single lab\",\n      \"pmids\": [\"22391949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Acute loss of Stk25 function (Cre-mediated conditional knockout or siRNA knockdown) disrupts neuronal migration in the developing cortex. Knockdown of LKB1, STRAD, and GM130 — molecules in the LKB1-STRAD-Stk25-GM130 pathway — causes similar neuronal migration errors.\",\n      \"method\": \"Conditional (Cre-mediated) knockout, siRNA knockdown, in utero electroporation, neuronal migration assays in developing mouse brain\",\n      \"journal\": \"Neural development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic approach and knockdown with defined developmental phenotype, pathway placement by parallel knockdown of pathway members, single lab\",\n      \"pmids\": [\"24225308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STK25 localizes to intrahepatic lipid droplets, colocalizing with the lipid droplet-coating protein ADFP/ATGL. STK25 overexpression reduces β-oxidation and triacylglycerol secretion in liver, promoting steatosis, while ATGL is displaced from the lipid droplet surface to the cytoplasm in STK25 transgenic livers.\",\n      \"method\": \"Transgenic mouse model (high-fat diet challenge), immunofluorescence colocalization, subcellular fractionation, β-oxidation assay, TAG secretion assay, western blot\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by colocalization plus functional consequence demonstrated in vivo, single lab\",\n      \"pmids\": [\"25609431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STK25 deficiency in knockout mice suppresses development of hyperglycemia, reduces hepatic gluconeogenesis, and increases insulin sensitivity. Stk25-/- mice show decreased protein levels of acetyl-CoA carboxylase (ACC), implicating ACC regulation as a mechanism underlying altered lipid oxidation and synthesis.\",\n      \"method\": \"Stk25 knockout mice on high-fat diet, glucose/insulin tolerance tests, euglycemic-hyperinsulinemic clamp, hepatic gene/protein expression analysis, western blot\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined metabolic phenotype and protein-level mechanism (ACC), reciprocal to transgenic results from same lab\",\n      \"pmids\": [\"25845663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STK25 activates LATS kinase by promoting LATS activation loop phosphorylation independently of prior hydrophobic motif phosphorylation, thereby activating Hippo signaling and suppressing YAP/TAZ transcriptional co-activators. Loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation under growth-suppressive conditions.\",\n      \"method\": \"siRNA/CRISPR loss-of-function, phospho-specific antibody assays for LATS activation loop vs. hydrophobic motif, YAP/TAZ reporter assays, in vitro and in vivo proliferation assays, cancer genomics analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic phosphorylation site distinction demonstrated, loss-of-function in vitro and in vivo, multiple orthogonal readouts, published in high-tier journal\",\n      \"pmids\": [\"30948712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STK25 promotes STRIPAK-mediated inhibition of MST2 (Hippo pathway) by directly phosphorylating the scaffolding protein SAV1, which diminishes SAV1's ability to inhibit the STRIPAK phosphatase complex. Thus STK25, as the kinase component of STRIPAK, antagonizes SAV1 to suppress Hippo signaling initiation.\",\n      \"method\": \"siRNA depletion of STK25 in human cells, in vitro kinase assay (STK25 phosphorylating SAV1), co-immunoprecipitation assessing STRIPAK integrity, MST2 activation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay with defined substrate (SAV1), epistasis analysis placing STK25 within STRIPAK, multiple orthogonal methods, peer-reviewed\",\n      \"pmids\": [\"32292165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STK25 interacts with GOLPH3 (Golgi phosphoprotein 3) and suppresses aerobic glycolysis in colorectal cancer cells through GOLPH3-regulated mTOR signaling, thereby inhibiting cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, His-tag pull-down, western blot for mTOR pathway, glucose uptake and lactate production assays, xenograft mouse model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — interaction confirmed by three pull-down methods, pathway activity measured, in vivo validation, single lab\",\n      \"pmids\": [\"29996891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STK25 regulates neuronal migration and polarization by controlling Rho GTPase activities: STK25 promotes Rac1 activation and reduces RhoA levels in the developing brain through forming complexes with α-PIX and β-PIX (GTPase regulatory enzymes) and with Cullin3-Bacurd1/Kctd13 (a RhoA ubiquitination complex), in a kinase activity-independent manner.\",\n      \"method\": \"Stk25 conditional knockout, in utero electroporation, rescue experiments with MST3 overexpression, co-immunoprecipitation for complex formation, RhoA/Rac1 activity assays, overexpression of Bacurd1/Cul3\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for complex identification, Rho GTPase activity assays, rescue genetics, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34518307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STK25 phosphorylates the type Iα regulatory subunit of PKA (PRKAR1A), which leads to inhibition of PKA catalytic activity and increased binding of the regulatory subunit to the catalytic subunit in the presence of cAMP. In Stk25 knockout mice, PRKAR1A phosphorylation is diminished, PKA activity is increased, and contractile response to beta-adrenergic stimulation is augmented.\",\n      \"method\": \"iPSC-derived cardiomyocytes, in vitro kinase assay, co-immunoprecipitation (regulatory-catalytic subunit binding), Stk25 knockout mouse model, PKA activity assay, cardiac contractility measurements\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay identifying substrate and phosphorylation consequence, validated in genetic KO mouse with physiological readout, multiple orthogonal methods\",\n      \"pmids\": [\"35977512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STK25 deficiency in mice and human endothelial cells causes KLF2 expression, Golgi dispersion, altered β-catenin distribution, and stress fiber appearance. Combined deficiency of STK24 and STK25 (but not either alone) in mice causes aggressive cavernoma-like vascular lesions, and STK25 deficiency alone induces these phenotypes in the context of STK24 heterozygosity.\",\n      \"method\": \"Double Stk24/Stk25 knockout mice, siRNA in human endothelial cells, histology, immunofluorescence for KLF2/β-catenin/stress fibers/Golgi morphology\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model plus in vitro validation, multiple cellular readouts, single lab\",\n      \"pmids\": [\"35130716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STK25 deficiency increases PD-L1 protein stability by regulating K48-linked ubiquitination of PD-L1 in a NEDD4-dependent manner, thereby increasing PD-L1 surface levels and modulating tumor immune evasion in colorectal cancer.\",\n      \"method\": \"STK25 knockout cell lines and mice, co-immunoprecipitation, ubiquitination assays (K48-linkage specific), western blot for PD-L1 protein levels, in vivo tumor models with anti-PD-1 treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic ubiquitination assay with defined linkage and E3 ligase (NEDD4), in vivo validation, single lab\",\n      \"pmids\": [\"40729594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STK25 undergoes autophosphorylation in response to multiple TLR triggers and phosphorylates IRF5 at Thr265, leading to IRF5 transcriptional activation and pro-inflammatory cytokine production. Loss of STK25 in primary immune cells attenuates R848-induced IRF5 nuclear translocation and pro-inflammatory cytokine production.\",\n      \"method\": \"Kinome-wide siRNA screen in THP-1 cells, in vitro kinase assay (STK25 phosphorylating IRF5-Thr265), Stk25-deficient primary immune cells, IRF5 nuclear translocation assay, cytokine ELISA\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay identifying substrate site, validated in primary KO cells; single lab\",\n      \"pmids\": [\"40639948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STK25 coats intrahepatic lipid droplets and regulates their associated phosphoproteome; STK25 deficiency in the liver alters proteins involved in peroxisomal biogenesis, ubiquitination-mediated proteolysis, and antioxidant defense. STK25 silencing in human liver cells attenuates peroxisomal biogenesis and protects against oxidative and ER stress in a hepatocyte-autonomous manner.\",\n      \"method\": \"Stk25 knockout mice (high-fat diet), quantitative lipid droplet-associated phosphoproteomics, peroxisomal biogenesis assays, oxidative/ER stress markers in human liver cells with STK25 siRNA\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics with defined organelle fraction, validated in human cells; single lab, single study\",\n      \"pmids\": [\"31857389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STK25 deficiency in colorectal cancer cells activates the NF-κB pathway, leading to p50 phosphorylation that directly binds the AREG promoter and transcriptionally upregulates AREG expression; elevated AREG then activates EGFR on cancer-associated fibroblasts (CAFs), promoting CAF activation and cetuximab resistance.\",\n      \"method\": \"siRNA knockdown and overexpression in CRC cells, ChIP assay (p50 binding to AREG promoter), dual-luciferase reporter assay, CAF co-culture, in vivo xenograft models, patient-derived organoids\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assays identify transcriptional mechanism, in vivo and organoid validation, single lab\",\n      \"pmids\": [\"42057436\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STK25 (also known as YSK1/SOK1) is a Golgi-localized STE20-family serine/threonine kinase that is activated by binding to the Golgi matrix protein GM130 (via autophosphorylation of its T-loop threonine) and by the scaffold protein MO25; it phosphorylates multiple substrates including 14-3-3ζ, SAV1, PRKAR1A, IRF5, and CCM2, and it regulates Golgi organization, neuronal polarization and migration (through LKB1-STRAD-GM130 and Rho GTPase pathways), Hippo signaling (activating LATS independently of hydrophobic motif phosphorylation while also phosphorylating SAV1 to promote STRIPAK-mediated MST2 inhibition), intracellular lipid droplet metabolism and ectopic lipid accumulation in liver, skeletal muscle, and other metabolic organs, PKA activity (via PRKAR1A phosphorylation), TLR-induced IRF5 inflammatory signaling, and apoptosis following oxidative/anoxic stress via nuclear translocation of a caspase-cleaved fragment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STK25 (YSK1/SOK1) is a STE20-family serine/threonine kinase that integrates Golgi organization, cell polarity, Hippo signaling, and metabolic and inflammatory control [#0, #12]. Its catalytic activity, intrinsic to the kinase domain [#4], is activated by direct binding to the Golgi matrix protein GM130, which promotes autophosphorylation of a conserved T-loop threonine and recruits the kinase to the Golgi where it phosphorylates 14-3-3\\u03b6 [#0], and is further stimulated by the scaffold protein MO25\\u03b1/\\u03b2 [#2]. Through an LKB1-STRAD-STK25-GM130 axis and kinase-independent assembly with \\u03b1/\\u03b2-PIX and the Cullin3-Bacurd1 RhoA-ubiquitination complex, STK25 controls Golgi morphology, neuronal polarization, and cortical neuronal migration by balancing Rac1 and RhoA activity, acting antagonistically to Reelin-Dab1 signaling [#1, #9, #15]. In Hippo signaling STK25 promotes LATS activation-loop phosphorylation independently of hydrophobic-motif phosphorylation to suppress YAP/TAZ, and as the kinase subunit of STRIPAK it phosphorylates SAV1 to relieve SAV1-mediated inhibition of the STRIPAK phosphatase and restrain MST2 [#12, #13]. STK25 additionally phosphorylates the PKA regulatory subunit PRKAR1A to inhibit PKA activity [#16] and phosphorylates IRF5 at Thr265 to drive TLR-induced pro-inflammatory cytokine production [#19]. At intrahepatic lipid droplets STK25 coats the droplet surface, displaces ATGL, and acts as a negative regulator of \\u03b2-oxidation and glucose uptake, such that its loss improves insulin sensitivity and reduces ectopic lipid accumulation [#10, #11, #8]. A caspase-cleaved STK25 fragment translocates from the Golgi to the nucleus to execute apoptosis after anoxic/oxidative stress [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that STK25 is a catalytically active STE20-related kinase distinct from canonical MAPK cascades defined it as an independent signaling node rather than an upstream MAPKKK.\",\n      \"evidence\": \"cDNA cloning with immunoprecipitation kinase assay and MAPK reporter assays after overexpression\",\n      \"pmids\": [\"9160885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physiological substrate identified\", \"No localization or activation mechanism defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying GM130-dependent Golgi targeting and T-loop autophosphorylation, plus 14-3-3\\u03b6 as a substrate, explained where and how STK25 is activated and linked it to Golgi organization and cell migration.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, biochemical substrate screen, and migration/invasion assays in cells\",\n      \"pmids\": [\"15037601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of 14-3-3\\u03b6 phosphorylation unresolved\", \"Mechanism linking Golgi position to migration not detailed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that a caspase-cleaved STK25 fragment must enter the nucleus to drive apoptosis after anoxia revealed a stress-responsive pro-death function gated by proteolysis and a defined C-terminal segment.\",\n      \"evidence\": \"siRNA, nuclear-localization mutants, fractionation/imaging and caspase-inhibitor apoptosis assays\",\n      \"pmids\": [\"18364353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear substrates of the cleaved fragment unknown\", \"Single lab; connection to Golgi pool unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placing STK25 within an LKB1-STK25-GM130 pathway opposing Reelin-Dab1 connected its Golgi function to neuronal polarization in vivo.\",\n      \"evidence\": \"Gain/loss-of-function in cultured neurons with Reelin/Dab1 mouse genetics and Golgi/axon imaging\",\n      \"pmids\": [\"21111240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrates in this pathway not defined\", \"How Golgi condensation generates supernumerary axons unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that MO25 directly binds and stimulates STK25 kinase activity identified a second activator parallel to the LKB1-STRAD-MO25 mechanism.\",\n      \"evidence\": \"SPR binding, co-IP, in vitro kinase assays with recombinant proteins, and cellular MO25 knockdown\",\n      \"pmids\": [\"21423148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular context where MO25 vs GM130 dominates not defined\", \"Substrate selectivity changes upon MO25 binding unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying CCM3/PDCD10 stabilization and CCM2 phosphorylation embedded STK25 in CCM-protein and TrkA death-signaling networks with a catalytic requirement.\",\n      \"evidence\": \"AP-MS, co-IP, in vitro kinase assays, kinase-dead mutants, proteasome inhibitors and cell-death rescue\",\n      \"pmids\": [\"22652780\", \"22782892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CCM2 phosphorylation not defined\", \"Reconciliation of pro-survival and pro-death roles incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A modifier screen confirming STK25 antagonism to Dab1 and its control of Tau phosphorylation reinforced its role in neuronal polarization and Golgi morphology.\",\n      \"evidence\": \"Microarray modifier screen in dab1-null mice with siRNA validation and Tau/Golgi readouts\",\n      \"pmids\": [\"22355340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase target driving Tau phosphorylation not identified\", \"Mechanism is correlative for some readouts\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Loss-of-function in muscle cells and knockout mice established STK25 as a negative regulator of lipid oxidation, glucose uptake, and gluconeogenesis, with ACC as a candidate effector.\",\n      \"evidence\": \"siRNA in L6 myoblasts and Stk25 knockout mice with metabolic phenotyping and clamp studies\",\n      \"pmids\": [\"22391949\", \"25845663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate linking STK25 to ACC unknown\", \"Tissue-specific mechanisms not fully separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Conditional knockout phenocopied by knockdown of pathway members confirmed STK25's requirement for cortical neuronal migration within the LKB1-STRAD-GM130 axis.\",\n      \"evidence\": \"Cre knockout, siRNA, in utero electroporation and migration assays in developing brain\",\n      \"pmids\": [\"24225308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors of migration downstream of STK25 not defined here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Localizing STK25 to hepatic lipid droplets and showing ATGL displacement gave a physical mechanism for its promotion of steatosis.\",\n      \"evidence\": \"Transgenic mice, colocalization, fractionation, \\u03b2-oxidation and TAG secretion assays\",\n      \"pmids\": [\"25609431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATGL displacement is kinase-dependent unresolved\", \"Direct droplet substrates not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking STK25 to GOLPH3-mTOR signaling and aerobic glycolysis suppression positioned it as a tumor-suppressive metabolic regulator in colorectal cancer.\",\n      \"evidence\": \"Co-IP, GST/His pull-downs, mTOR western blots, glycolysis assays and xenografts\",\n      \"pmids\": [\"29996891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STK25 phosphorylates GOLPH3 not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistic dissection of LATS activation-loop phosphorylation independent of hydrophobic-motif phosphorylation defined how STK25 activates Hippo signaling and restrains YAP/TAZ-driven proliferation.\",\n      \"evidence\": \"siRNA/CRISPR, phospho-site-specific antibodies, YAP/TAZ reporters, proliferation assays and cancer genomics\",\n      \"pmids\": [\"30948712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect phosphorylation of LATS not fully resolved\", \"Relationship to STRIPAK function not addressed here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Lipid-droplet phosphoproteomics tied STK25 to peroxisomal biogenesis and antioxidant/ER-stress defense in a hepatocyte-autonomous manner.\",\n      \"evidence\": \"Stk25 KO mice phosphoproteomics and human liver-cell siRNA with stress markers\",\n      \"pmids\": [\"31857389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct droplet substrates not validated individually\", \"Causal phosphosite for peroxisomal effects unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating SAV1 phosphorylation by STK25 within STRIPAK clarified a second, opposing arm of STK25 Hippo control, where it relieves SAV1 inhibition of the STRIPAK phosphatase to restrain MST2.\",\n      \"evidence\": \"siRNA, in vitro kinase assay on SAV1, STRIPAK integrity co-IP and MST2 activation assays\",\n      \"pmids\": [\"32292165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of LATS-activating and MST2-restraining roles incomplete\", \"Context determining which arm dominates unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing kinase-independent control of Rac1/RhoA via PIX and Cullin3-Bacurd1 complexes revealed a non-catalytic scaffolding mechanism for STK25 in neuronal migration.\",\n      \"evidence\": \"Conditional KO, in utero electroporation, co-IP, Rho GTPase activity assays and MST3 rescue\",\n      \"pmids\": [\"34518307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of PIX/Cul3 complex assembly unknown\", \"Interplay with kinase-dependent functions undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying PRKAR1A as a substrate whose phosphorylation inhibits PKA connected STK25 to cAMP/PKA signaling and cardiac contractility.\",\n      \"evidence\": \"iPSC-cardiomyocytes, in vitro kinase assay, regulatory-catalytic subunit co-IP, KO mice and contractility measurements\",\n      \"pmids\": [\"35977512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite on PRKAR1A not specified here\", \"Tissue breadth of PKA regulation not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Combined STK24/STK25 deficiency producing cavernoma-like lesions with KLF2 and \\u03b2-catenin/Golgi changes implicated STK25 in vascular integrity, partly redundant with STK24.\",\n      \"evidence\": \"Double KO mice and endothelial siRNA with histology and immunofluorescence\",\n      \"pmids\": [\"35130716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate driving endothelial phenotype not identified\", \"Mechanistic link to CCM-protein interactions not closed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking STK25 loss to NEDD4-dependent K48-ubiquitination of PD-L1 connected the kinase to tumor immune evasion.\",\n      \"evidence\": \"KO cells/mice, co-IP, K48-linkage ubiquitination assays and anti-PD-1 tumor models\",\n      \"pmids\": [\"40729594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STK25 directly phosphorylates NEDD4 or PD-L1 unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying IRF5-Thr265 as a substrate established STK25 as a TLR-responsive kinase driving IRF5-dependent inflammatory cytokine production.\",\n      \"evidence\": \"Kinome-wide siRNA screen, in vitro kinase assay, KO primary immune cells, IRF5 translocation and cytokine ELISA\",\n      \"pmids\": [\"40639948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal activating STK25 in TLR pathway not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linking STK25 loss to NF-\\u03baB/p50-driven AREG transcription and EGFR activation on fibroblasts explained a mechanism of cetuximab resistance in colorectal cancer.\",\n      \"evidence\": \"siRNA/overexpression, ChIP, luciferase, CAF co-culture, xenografts and patient-derived organoids\",\n      \"pmids\": [\"42057436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase substrate connecting STK25 to NF-\\u03baB unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how STK25's many context-specific functions are coordinated by a single kinase, and how activation inputs select among its diverse substrates.\",\n      \"evidence\": \"No single study reconciles the Golgi, Hippo, metabolic, inflammatory and apoptotic roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying substrate-selection mechanism defined\", \"Tissue- and stimulus-specific activator usage not mapped\", \"Structural basis of kinase-dependent vs scaffolding functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 13, 16, 19]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4, 13, 16, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1, 3, 17]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [10, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 13, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 10, 11, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 9, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [\"STRIPAK\"],\n    \"partners\": [\"GM130\", \"CAB39 (MO25)\", \"PDCD10\", \"CCM2\", \"SAV1\", \"GOLPH3\", \"ARHGEF6 (alpha-PIX)\", \"CUL3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}