{"gene":"STK17B","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2004,"finding":"DRAK2 raises the threshold for T cell activation by negatively regulating signals through the TCR. Drak2-/- T cells showed enhanced sensitivity to TCR-mediated stimulation with a reduced requirement for costimulation, but no defects in apoptosis or negative selection.","method":"Genetic knockout mouse model (Drak2-/- mice), functional T cell assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, replicated across multiple subsequent studies","pmids":["15589167"],"is_preprint":false},{"year":2003,"finding":"The calcium-binding protein CHP (calcineurin homologous protein) inhibits DRAK2 kinase activity (approximately 85% inhibition of both autophosphorylation and phosphorylation of myosin light chain substrate) in a calcium-dependent manner, while the CHP-DRAK2 physical interaction itself is not calcium-dependent.","method":"In vitro kinase assay, protein interaction studies","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay with exogenous substrate, single lab, single study","pmids":["12966074"],"is_preprint":false},{"year":2006,"finding":"Nuclear localization of DRAK2 is required for UV-induced apoptosis. DRAK2 accumulates in the nucleus following UV irradiation, and nuclear-targeted DRAK2 (NLS fusion) causes cell death, while cytoplasmic DRAK2 does not. siRNA knockdown of DRAK2 partially suppressed UV-induced apoptosis.","method":"GFP-fusion localization, NLS mutagenesis, siRNA knockdown, UV irradiation apoptosis assay","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple orthogonal methods, single lab","pmids":["16462023"],"is_preprint":false},{"year":2007,"finding":"DRAK2 contains a functional nuclear localization signal (NLS); phosphorylation of Ser350 (flanking the NLS) by PKC-gamma drives cytoplasmic localization. PMA induced cytoplasmic accumulation via PKC-gamma-mediated Ser350 phosphorylation, and the Ser350Asp mutant failed to accumulate in the nucleus upon UV irradiation.","method":"GFP-fusion NLS mutagenesis, ectopic PKC-gamma expression, PMA stimulation, site-directed mutagenesis (S350D)","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mutagenesis and localization experiments with functional readout, single lab","pmids":["18084041"],"is_preprint":false},{"year":2006,"finding":"DRAK2 autophosphorylates at Ser12, and this autophosphorylation is induced by antigen receptor stimulation in T and B cells in a calcium-dependent manner (blocked by BAPTA-AM, promoted by thapsigargin). Ser12 phosphorylation is necessary for optimal suppression of T cell activation.","method":"Mass spectrometry identification of autophosphorylation site, phospho-specific antibody, calcium chelation/mobilization experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mass spectrometry site identification, phospho-specific antibody validation, calcium perturbation experiments, single lab","pmids":["17182616"],"is_preprint":false},{"year":2005,"finding":"DRAK2 controls the threshold for calcium signaling during thymocyte selection; Drak2-deficient positively selected thymocytes displayed a reduced requirement for TCR cross-linking. DRAK2 expression in DP thymocytes is induced by TCR stimulation in a PKC- and MAP kinase-dependent manner.","method":"Drak2-/- mouse thymocyte functional assays, retroviral transduction, TCR stimulation assays","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined calcium signaling phenotype, multiple stimulation conditions, single lab","pmids":["16172133"],"is_preprint":false},{"year":2006,"finding":"Transgenic Drak2 overexpression leads to enhanced apoptosis of activated T cells in the presence of IL-2, with lower increases in anti-apoptotic factors (Bcl-2, Bcl-xL) during activation, resulting in reduced memory T cell numbers.","method":"Transgenic mouse model (human beta-actin promoter-driven Drak2), IL-2 apoptosis assays, immunophenotyping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic overexpression model with defined molecular and cellular phenotype, single lab","pmids":["16517594"],"is_preprint":false},{"year":2008,"finding":"In Drak2-/- mice, T cells require greater tonic signaling for maintenance during clonal expansion and are more sensitive to intrinsic (mitochondrial) apoptosis following stimulation, which is prevented by CD28 ligation, homeostatic cytokines, or enforced Bcl-xL expression. T cell-specific Bcl-xL expression restored susceptibility to EAE in Drak2-/- mice.","method":"Drak2-/- mice, Bcl-xL transgenic rescue, adoptive transfer, apoptosis assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistatic rescue with Bcl-xL, multiple orthogonal approaches, replicated phenotype across labs","pmids":["19017949"],"is_preprint":false},{"year":2009,"finding":"DRAK2 is upstream of p70S6 kinase (S6K) in beta cell apoptosis signaling; inducible NO synthase is upstream of DRAK2 and caspase-9 is downstream. Purified DRAK2 directly phosphorylates p70S6 kinase in an in vitro kinase assay. DRAK2 overexpression enhanced p70S6K phosphorylation in cells, and DRAK2 knockdown reduced it.","method":"In vitro kinase assay with purified proteins, siRNA knockdown, transgenic overexpression, epistasis analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay identifying p70S6K as direct substrate, complemented by cellular epistasis, single lab","pmids":["19342653"],"is_preprint":false},{"year":2009,"finding":"DRAK2 participates in a negative feedback loop controlling TGF-β signaling: TGF-β1 stimulation induces DRAK2 expression and promotes endogenous interaction of DRAK2 with the type I TGF-β receptor (TβRI), thereby blocking R-Smads recruitment. DRAK2 depletion markedly augmented TGF-β1 responses.","method":"Co-immunoprecipitation of DRAK2 with TβRI, siRNA knockdown, TGF-β signaling reporter assays, tumor cell line functional studies","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of endogenous proteins, knockdown with functional signaling readout, single lab","pmids":["23122956"],"is_preprint":false},{"year":2010,"finding":"Protein kinase D (PKD) is an essential upstream activator of DRAK2 following TCR ligation, requiring Ca2+ influx through Orai1 (CRAC channels). PKD physically interacts with DRAK2, phosphorylates it, and a constitutively active PKD mutant promoted DRAK2 function while kinase-dead PKD or PKD knockdown blocked DRAK2 activation. Mitochondrial reactive oxygen species generation was necessary and sufficient for DRAK2 activation in response to Ca2+ influx.","method":"PKD inhibitor (Gö6976), kinase-dead and constitutively active PKD mutants, PKD knockdown, Co-IP of DRAK2-PKD interaction, Orai1-dependent calcium influx assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including inhibitor, dominant-negative, constitutively active mutant, knockdown, and physical interaction data in single study","pmids":["21148796"],"is_preprint":false},{"year":2013,"finding":"The MYB oncogene transcriptionally represses DRAK2 expression by binding to a conserved element upstream of the DRAK2 transcription start site. MYB knockdown upregulates DRAK2, activates caspase-9, and promotes apoptosis; DRAK2 siRNA knockdown rescues cells from this apoptosis.","method":"siRNA knockdown of MYB and DRAK2, ChIP assay showing MYB binding to DRAK2 promoter, caspase-9 activity assay","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, epistatic siRNA rescue, single lab","pmids":["23398943"],"is_preprint":false},{"year":2015,"finding":"DRAK2 does NOT regulate TGF-β/Smad signaling in primary T cells. Smad2/Smad3 activation, TGF-β-mediated effects on naïve T cell proliferation, CD8+ T cell survival, Treg induction, and enhanced T cell death in Drak2-/- mice were all independent of TGF-β signaling.","method":"In vitro TGF-β signaling assays in wildtype vs Drak2-/- primary T cells, Smad phosphorylation assays, proliferation and survival assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro assays in primary cells, direct contradiction of prior report (PMID:23122956) in T cell context, single lab","pmids":["25951457"],"is_preprint":false},{"year":2020,"finding":"X-ray crystallography of STK17B with inhibitor SGC-STK17B-1 (thieno[3,2-d]pyrimidine) revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor, explaining selectivity over closely related STK17A. The compound is an ATP-competitive inhibitor.","method":"X-ray crystallography, kinase selectivity profiling, molecular dynamics simulation","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray crystal structure with functional (selectivity) validation and MD simulation, multiple orthogonal methods","pmids":["33215924"],"is_preprint":false},{"year":2021,"finding":"DRAK2 directly binds the splicing factor SRSF6 and inhibits its phosphorylation by SRPK1, thereby regulating alternative splicing of mitochondrial function-related genes and driving NAFLD/NASH progression. Hepatic deletion of DRAK2 suppressed hepatic steatosis progression to NASH.","method":"Phosphoproteome and transcriptome analyses, Co-IP/pulldown identifying SRSF6 as direct DRAK2 binding partner, DRAK2 conditional liver knockout mice, RNA splicing analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction identified, phosphoproteomics, transcriptomics, and conditional KO with defined phenotype, multiple orthogonal methods","pmids":["34614409"],"is_preprint":false},{"year":2021,"finding":"STK17B is strongly expressed in cerebellar Purkinje cells and functions as a downstream effector of PKC. STK17B overexpression potentiates PKC-induced morphological changes in Purkinje cell dendritic trees; a phosphorylation-mimetic STK17B variant caused marked reduction in dendritic tree size; and STK17B inhibition partially rescued PKC activation-induced dendritic changes.","method":"Overexpression and pharmacological inhibition in primary Purkinje cell cultures, phospho-mimetic mutant (STK17B-S350D equivalent), morphological quantification","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and pharmacological inhibition with quantified morphological readout, multiple approaches, single lab","pmids":["34536317"],"is_preprint":false},{"year":2023,"finding":"DRAK2 regulates IL-2 signaling by inhibiting STAT5A phosphorylation, not by limiting TCR signaling as previously hypothesized. Enhanced sensitivity to IL-2 in Drak2-/- mice augments thymic regulatory T cell (Treg) development, and resistance to T1D requires Treg presence.","method":"Drak2-/- NOD mice, T cell-specific conditional approaches, adoptive transfer with/without Tregs, STAT5A phosphorylation assays, Treg development analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Treg depletion epistasis, STAT5A phosphorylation measurement, adoptive transfer, single lab","pmids":["36773294"],"is_preprint":false},{"year":2024,"finding":"DRAK2 directly phosphorylates ULK1 at Ser56, leading to ULK1 ubiquitylation and suppression of autophagy. In pancreatic β cells, this DRAK2-ULK1 axis impairs mitochondrial function and insulin secretion upon lipotoxic stress. Conditional β cell-specific DRAK2 knockout preserved autophagy and mitochondrial function under high-fat diet.","method":"Phosphoproteome analysis of primary mouse islets, ULK1-S56A point mutant rescue, DRAK2 conditional KO mice, in vitro kinase assay (direct phosphorylation), autophagy and mitochondrial function assays","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation, site-specific mutagenesis (S56A rescue), phosphoproteomics, and conditional KO with defined phenotype in one study","pmids":["38324636"],"is_preprint":false},{"year":2024,"finding":"DRAK2 phosphorylates myosin light chain 2 (MLC2) in T cells. In the absence of DRAK2, polymerized actin is decreased, and myosin-dependent T cell functions including migration, TCR microcluster accumulation, and conjugation to antigen-presenting cells are impaired.","method":"Drak2-/- T cell functional assays, actin polymerization assay, phosphorylation analysis of MLC2, T cell-APC conjugation assay, TCR microcluster imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with multiple defined functional readouts, phosphoproteomic substrate identification in companion paper (PMID:39502695), single lab","pmids":["39421891"],"is_preprint":false},{"year":2024,"finding":"Pharmacological STK17B inhibitors identify Ser19 on myosin light chain 2 (MLC2) as a STK17B substrate by mass spectrometry-based phosphoproteomics. In mouse T cell activation assays, STK17B inhibitors enhanced IL-2 production and enhanced T cell priming (CD69, IL-2, IFN-γ upregulation) in vivo.","method":"MS-based phosphoproteomics with selective kinase inhibitors, flow cytometry pharmacodynamic assay, in vivo T cell activation assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics substrate identification with pharmacological inhibitors, in vivo PD readout, single lab","pmids":["39502695"],"is_preprint":false},{"year":2026,"finding":"STK17B phosphorylates IREB2 at Ser157 and HSPB1 at Ser15, identified by proximity labeling combined with phosphoproteomic analysis. This modulates the balance between proferroptotic transferrin receptor and antiferroptotic ferritin heavy chain, suppressing ferroptosis in multiple myeloma cells. STK17B also indirectly maintains activating phosphorylation of STAT3.","method":"Proximity labeling (BioID or similar) combined with phosphoproteomics, site-specific phosphorylation validation, ferroptosis assays (labile iron pool, lipid peroxidation), xenograft mouse model, selective STK17B inhibitor","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling plus phosphoproteomics identifying direct substrates, functional ferroptosis assays, single lab","pmids":["40953235"],"is_preprint":false}],"current_model":"STK17B/DRAK2 is a serine/threonine kinase of the DAPK family that is activated downstream of TCR/Ca2+ influx via a PKD-ROS signaling module, autophosphorylates at Ser12, and translocates between nucleus and cytoplasm under control of PKC-gamma-mediated Ser350 phosphorylation; it raises the threshold for T cell activation by inhibiting STAT5A (not TCR signaling directly) to limit IL-2 sensitivity and Treg development, phosphorylates myosin light chain 2 to control actomyosin dynamics and T cell migration, directly phosphorylates ULK1 at Ser56 to suppress autophagy in pancreatic β cells, binds and sequesters the splicing factor SRSF6 to modulate alternative splicing of mitochondrial genes in liver, and phosphorylates IREB2 (Ser157) and HSPB1 (Ser15) to suppress ferroptosis; its kinase activity is negatively regulated by the calcium-binding protein CHP, and its expression is transcriptionally repressed by MYB and induced as a negative-feedback antagonist by TGF-β."},"narrative":{"mechanistic_narrative":"STK17B (DRAK2) is a calcium-responsive serine/threonine kinase best characterized as a negative regulator that raises the threshold for lymphocyte activation and as a stress-responsive kinase controlling cell survival and metabolism across multiple tissues [PMID:15589167, PMID:21148796]. In T cells its activation is driven by TCR ligation through Orai1/CRAC-dependent Ca2+ influx, a PKD-mediated phosphorylation step, and mitochondrial ROS, and it autophosphorylates at Ser12 in a calcium-dependent manner required for optimal suppression of T cell activation [PMID:17182616, PMID:21148796]. Rather than dampening proximal TCR signaling, STK17B limits IL-2 sensitivity by inhibiting STAT5A phosphorylation, thereby restraining regulatory T cell development [PMID:36773294]; loss of the kinase sensitizes activated T cells to intrinsic mitochondrial apoptosis that is rescued by Bcl-xL [PMID:19017949]. STK17B also phosphorylates myosin light chain 2 to support actin polymerization, TCR microcluster formation, and myosin-dependent T cell migration and conjugation [PMID:39421891, PMID:39502695]. Its subcellular distribution is governed by a functional NLS whose adjacent Ser350 is phosphorylated by PKC-gamma to drive cytoplasmic accumulation, while nuclear localization is required for UV-induced apoptosis [PMID:16462023, PMID:18084041]. Beyond immunity, STK17B acts through defined substrates: it phosphorylates ULK1 at Ser56 to trigger its ubiquitylation and suppress autophagy in pancreatic beta cells [PMID:38324636], binds the splicing factor SRSF6 and blocks its phosphorylation by SRPK1 to reprogram mitochondrial-gene splicing during NASH progression [PMID:34614409], and phosphorylates IREB2 (Ser157) and HSPB1 (Ser15) to suppress ferroptosis in multiple myeloma [PMID:40953235]. Kinase activity is inhibited in a calcium-dependent manner by the calcium-binding protein CHP, and expression is transcriptionally repressed by MYB [PMID:12966074, PMID:23398943]. A crystal structure with the selective inhibitor SGC-STK17B-1 defined a distinctive P-loop conformation involving an R41 salt bridge that confers selectivity over STK17A [PMID:33215924].","teleology":[{"year":2003,"claim":"Established the first negative regulator of STK17B catalytic output, linking its kinase activity to calcium signaling at the biochemical level.","evidence":"In vitro kinase assay with CHP and MLC substrate, plus interaction studies","pmids":["12966074"],"confidence":"Medium","gaps":["Single in vitro study with exogenous substrate","Cellular relevance of CHP inhibition not tested in primary cells"]},{"year":2004,"claim":"Defined the core physiological role by showing STK17B sets the activation threshold of T cells, distinguishing it from an apoptotic or selection function.","evidence":"Drak2-/- knockout mouse with T cell functional assays","pmids":["15589167"],"confidence":"High","gaps":["Molecular target downstream of the kinase not identified","Mechanism of threshold-raising left open"]},{"year":2005,"claim":"Connected STK17B to calcium-tuned thymocyte selection and showed its expression is induced by TCR signaling via PKC and MAP kinase.","evidence":"Drak2-/- thymocyte assays and retroviral transduction with TCR stimulation","pmids":["16172133"],"confidence":"Medium","gaps":["Direct transcriptional inducers not mapped","Substrate mediating threshold control unknown"]},{"year":2006,"claim":"Identified Ser12 autophosphorylation as a calcium-dependent activation mark required for suppressive function, providing a molecular readout of activity.","evidence":"Mass spectrometry, phospho-specific antibody, and calcium perturbation in T and B cells","pmids":["17182616"],"confidence":"Medium","gaps":["Upstream kinase/sensor coupling calcium to Ser12 not defined at this stage"]},{"year":2006,"claim":"Showed overexpression promotes apoptosis of activated T cells in the presence of IL-2, linking kinase dosage to survival and memory T cell numbers.","evidence":"Transgenic Drak2-overexpressing mice with IL-2 apoptosis assays","pmids":["16517594"],"confidence":"Medium","gaps":["Direct apoptotic substrate not identified","Overexpression may not reflect endogenous stoichiometry"]},{"year":2006,"claim":"Demonstrated nuclear localization is required for apoptotic function, establishing subcellular compartmentalization as a control point.","evidence":"GFP-fusion localization, NLS mutagenesis, siRNA, UV apoptosis assay","pmids":["16462023"],"confidence":"Medium","gaps":["Nuclear substrates driving apoptosis not identified","Single lab"]},{"year":2007,"claim":"Identified PKC-gamma phosphorylation of Ser350 flanking the NLS as the switch controlling nucleocytoplasmic shuttling.","evidence":"GFP-fusion mutagenesis, PKC-gamma expression, PMA stimulation, S350D mutant","pmids":["18084041"],"confidence":"Medium","gaps":["Physiological stimuli triggering PKC-gamma-dependent relocation in vivo not established"]},{"year":2008,"claim":"Resolved the survival phenotype by showing Drak2-/- T cells are hypersensitive to intrinsic mitochondrial apoptosis, rescuable by Bcl-xL.","evidence":"Drak2-/- mice, Bcl-xL transgenic rescue, adoptive transfer, EAE model","pmids":["19017949"],"confidence":"High","gaps":["Direct kinase link to mitochondrial apoptotic machinery not defined"]},{"year":2009,"claim":"Proposed p70S6 kinase as a direct substrate in beta cell apoptosis, situating STK17B within an iNOS-caspase-9 axis.","evidence":"In vitro kinase assay, siRNA, overexpression, epistasis","pmids":["19342653"],"confidence":"Medium","gaps":["Phosphosite on p70S6K not mapped","Single lab; not validated in vivo"]},{"year":2009,"claim":"Placed STK17B in a TGF-beta negative-feedback loop through interaction with TbRI that blocks R-Smad recruitment.","evidence":"Co-IP with TbRI, siRNA, TGF-beta reporter assays in tumor cells","pmids":["23122956"],"confidence":"Medium","gaps":["Later contradicted in primary T cells (#12)","Direct phosphorylation of receptor not shown"]},{"year":2010,"claim":"Defined the activation module by showing PKD, Orai1-dependent Ca2+ influx, and mitochondrial ROS are required and sufficient for STK17B activation downstream of TCR.","evidence":"PKD inhibitor, kinase-dead/constitutively active mutants, knockdown, Co-IP, calcium influx assays","pmids":["21148796"],"confidence":"High","gaps":["PKD phosphosite on STK17B not pinpointed","Connection to Ser12 autophosphorylation not directly bridged"]},{"year":2013,"claim":"Identified MYB as a direct transcriptional repressor of STK17B, linking its expression to apoptotic control in leukemia cells.","evidence":"siRNA of MYB and DRAK2, ChIP at the promoter, caspase-9 assay","pmids":["23398943"],"confidence":"Medium","gaps":["Whether this regulation operates in normal lymphocytes unknown"]},{"year":2015,"claim":"Corrected the TGF-beta model by showing STK17B does not regulate TGF-beta/Smad signaling in primary T cells, narrowing the receptor-interaction finding to specific contexts.","evidence":"TGF-beta signaling and Smad phosphorylation assays in WT vs Drak2-/- primary T cells","pmids":["25951457"],"confidence":"Medium","gaps":["Reconciliation with the tumor-cell TbRI finding (#9) not resolved mechanistically"]},{"year":2020,"claim":"Delivered a structural basis for selective inhibition, defining a unique P-loop conformation distinguishing STK17B from STK17A.","evidence":"X-ray crystallography with SGC-STK17B-1, selectivity profiling, MD simulation","pmids":["33215924"],"confidence":"High","gaps":["No substrate-bound or active-state structure","Apo conformational dynamics not fully resolved"]},{"year":2021,"claim":"Identified SRSF6 as a direct binding partner whose SRPK1-mediated phosphorylation STK17B blocks, linking the kinase to mitochondrial-gene splicing and NASH.","evidence":"Co-IP/pulldown, phosphoproteomics, transcriptomics, conditional liver KO","pmids":["34614409"],"confidence":"High","gaps":["Whether STK17B phosphorylates SRSF6 directly versus only sequestering it not fully resolved"]},{"year":2021,"claim":"Extended the PKC-effector role to neurons, showing STK17B mediates PKC-driven Purkinje cell dendritic remodeling.","evidence":"Overexpression, pharmacological inhibition, phospho-mimetic mutant in primary Purkinje cultures","pmids":["34536317"],"confidence":"Medium","gaps":["Neuronal substrates not identified","In vivo dendritic phenotype not shown"]},{"year":2023,"claim":"Reframed the immune mechanism: STK17B limits IL-2 sensitivity by inhibiting STAT5A rather than dampening TCR signaling, controlling Treg development and autoimmunity.","evidence":"Drak2-/- NOD mice, STAT5A phosphorylation assays, Treg-depletion adoptive transfer","pmids":["36773294"],"confidence":"Medium","gaps":["Direct phosphorylation target linking STK17B to STAT5A inhibition not defined"]},{"year":2024,"claim":"Established a direct ULK1 Ser56 phosphorylation-ubiquitylation axis through which STK17B suppresses autophagy and impairs beta cell mitochondrial function.","evidence":"Islet phosphoproteomics, in vitro kinase assay, ULK1-S56A rescue, conditional beta cell KO","pmids":["38324636"],"confidence":"High","gaps":["E3 ligase coupling Ser56 phosphorylation to ULK1 ubiquitylation not identified"]},{"year":2024,"claim":"Identified MLC2 as a cytoskeletal substrate, explaining STK17B control of actomyosin dynamics, T cell migration, and immune synapse formation.","evidence":"Drak2-/- T cell functional assays, actin and MLC2 phosphorylation analysis, conjugation and microcluster imaging; phosphosite mapped by companion phosphoproteomics","pmids":["39421891","39502695"],"confidence":"Medium","gaps":["Direct in vitro phosphorylation of MLC2 by purified STK17B not shown in these reports"]},{"year":2026,"claim":"Identified IREB2 (Ser157) and HSPB1 (Ser15) as direct substrates through which STK17B suppresses ferroptosis in multiple myeloma, linking it to iron handling and STAT3.","evidence":"Proximity labeling plus phosphoproteomics, site-specific validation, ferroptosis assays, xenografts, selective inhibitor","pmids":["40953235"],"confidence":"Medium","gaps":["Mechanism by which STK17B maintains STAT3 phosphorylation indirect/unmapped","Single lab"]},{"year":null,"claim":"How STK17B selects among its diverse substrates (STAT5A pathway, ULK1, SRSF6, MLC2, IREB2/HSPB1) in different tissues, and how upstream calcium/PKD/PKC-gamma inputs are integrated to direct context-specific outputs, remains unresolved.","evidence":"No single study reconciles the tissue-specific substrate repertoire","pmids":[],"confidence":"Medium","gaps":["No unifying determinant of substrate choice identified","Cross-tissue regulatory logic uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,14,17,18,19,20]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[4,8,17,18,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,7,16,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,7,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,16]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[14]}],"complexes":[],"partners":["CHP","PKD","TGFBR1","SRSF6","ULK1","MYB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94768","full_name":"Serine/threonine-protein kinase 17B","aliases":["DAP kinase-related apoptosis-inducing protein kinase 2"],"length_aa":372,"mass_kda":42.3,"function":"Phosphorylates myosin light chains (By similarity). Acts as a positive regulator of apoptosis","subcellular_location":"Nucleus; Cell membrane; Endoplasmic reticulum-Golgi intermediate compartment","url":"https://www.uniprot.org/uniprotkb/O94768/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STK17B","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STK17B","total_profiled":1310},"omim":[{"mim_id":"604727","title":"SERINE/THREONINE PROTEIN KINASE 17B; STK17B","url":"https://www.omim.org/entry/604727"},{"mim_id":"604726","title":"SERINE/THREONINE PROTEIN KINASE 17A; STK17A","url":"https://www.omim.org/entry/604726"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":355.5},{"tissue":"lymphoid tissue","ntpm":105.8}],"url":"https://www.proteinatlas.org/search/STK17B"},"hgnc":{"alias_symbol":["DRAK2"],"prev_symbol":[]},"alphafold":{"accession":"O94768","domains":[{"cath_id":"3.30.200.20","chopping":"29-110","consensus_level":"high","plddt":95.2399,"start":29,"end":110},{"cath_id":"1.10.510.10","chopping":"115-292","consensus_level":"high","plddt":94.4806,"start":115,"end":292}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94768","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94768-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94768-F1-predicted_aligned_error_v6.png","plddt_mean":81.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STK17B","jax_strain_url":"https://www.jax.org/strain/search?query=STK17B"},"sequence":{"accession":"O94768","fasta_url":"https://rest.uniprot.org/uniprotkb/O94768.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94768/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94768"}},"corpus_meta":[{"pmid":"34614409","id":"PMC_34614409","title":"DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing.","date":"2021","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34614409","citation_count":79,"is_preprint":false},{"pmid":"15589167","id":"PMC_15589167","title":"A deficiency in Drak2 results in a T cell hypersensitivity and an unexpected resistance to autoimmunity.","date":"2004","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15589167","citation_count":58,"is_preprint":false},{"pmid":"18641347","id":"PMC_18641347","title":"Drak2 contributes to West Nile virus entry into the brain and lethal encephalitis.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18641347","citation_count":55,"is_preprint":false},{"pmid":"29445189","id":"PMC_29445189","title":"STK17B promotes carcinogenesis and metastasis via AKT/GSK-3β/Snail signaling in hepatocellular carcinoma.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29445189","citation_count":49,"is_preprint":false},{"pmid":"23122956","id":"PMC_23122956","title":"DRAK2 participates in a negative feedback loop to control TGF-β/Smads signaling by binding to type I TGF-β receptor.","date":"2012","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23122956","citation_count":33,"is_preprint":false},{"pmid":"28249207","id":"PMC_28249207","title":"Discovery of benzofuran-3(2H)-one derivatives as novel DRAK2 inhibitors that protect islet β-cells from apoptosis.","date":"2017","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28249207","citation_count":32,"is_preprint":false},{"pmid":"16517594","id":"PMC_16517594","title":"Transgenic drak2 overexpression in mice leads to increased T cell apoptosis and compromised memory T cell development.","date":"2006","source":"The Journal of biological 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Leukemia.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33081245","citation_count":10,"is_preprint":false},{"pmid":"25951457","id":"PMC_25951457","title":"Drak2 Does Not Regulate TGF-β Signaling in T Cells.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25951457","citation_count":10,"is_preprint":false},{"pmid":"22494341","id":"PMC_22494341","title":"Loss of DRAK2 signaling enhances allogeneic transplant survival by limiting effector and memory T cell responses.","date":"2012","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/22494341","citation_count":10,"is_preprint":false},{"pmid":"18568639","id":"PMC_18568639","title":"A role for DRAK2 in the germinal center reaction and the antibody 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Drak2-/- T cells showed enhanced sensitivity to TCR-mediated stimulation with a reduced requirement for costimulation, but no defects in apoptosis or negative selection.\",\n      \"method\": \"Genetic knockout mouse model (Drak2-/- mice), functional T cell assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, replicated across multiple subsequent studies\",\n      \"pmids\": [\"15589167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The calcium-binding protein CHP (calcineurin homologous protein) inhibits DRAK2 kinase activity (approximately 85% inhibition of both autophosphorylation and phosphorylation of myosin light chain substrate) in a calcium-dependent manner, while the CHP-DRAK2 physical interaction itself is not calcium-dependent.\",\n      \"method\": \"In vitro kinase assay, protein interaction studies\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay with exogenous substrate, single lab, single study\",\n      \"pmids\": [\"12966074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nuclear localization of DRAK2 is required for UV-induced apoptosis. DRAK2 accumulates in the nucleus following UV irradiation, and nuclear-targeted DRAK2 (NLS fusion) causes cell death, while cytoplasmic DRAK2 does not. siRNA knockdown of DRAK2 partially suppressed UV-induced apoptosis.\",\n      \"method\": \"GFP-fusion localization, NLS mutagenesis, siRNA knockdown, UV irradiation apoptosis assay\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"16462023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DRAK2 contains a functional nuclear localization signal (NLS); phosphorylation of Ser350 (flanking the NLS) by PKC-gamma drives cytoplasmic localization. PMA induced cytoplasmic accumulation via PKC-gamma-mediated Ser350 phosphorylation, and the Ser350Asp mutant failed to accumulate in the nucleus upon UV irradiation.\",\n      \"method\": \"GFP-fusion NLS mutagenesis, ectopic PKC-gamma expression, PMA stimulation, site-directed mutagenesis (S350D)\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mutagenesis and localization experiments with functional readout, single lab\",\n      \"pmids\": [\"18084041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DRAK2 autophosphorylates at Ser12, and this autophosphorylation is induced by antigen receptor stimulation in T and B cells in a calcium-dependent manner (blocked by BAPTA-AM, promoted by thapsigargin). Ser12 phosphorylation is necessary for optimal suppression of T cell activation.\",\n      \"method\": \"Mass spectrometry identification of autophosphorylation site, phospho-specific antibody, calcium chelation/mobilization experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry site identification, phospho-specific antibody validation, calcium perturbation experiments, single lab\",\n      \"pmids\": [\"17182616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DRAK2 controls the threshold for calcium signaling during thymocyte selection; Drak2-deficient positively selected thymocytes displayed a reduced requirement for TCR cross-linking. DRAK2 expression in DP thymocytes is induced by TCR stimulation in a PKC- and MAP kinase-dependent manner.\",\n      \"method\": \"Drak2-/- mouse thymocyte functional assays, retroviral transduction, TCR stimulation assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined calcium signaling phenotype, multiple stimulation conditions, single lab\",\n      \"pmids\": [\"16172133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Transgenic Drak2 overexpression leads to enhanced apoptosis of activated T cells in the presence of IL-2, with lower increases in anti-apoptotic factors (Bcl-2, Bcl-xL) during activation, resulting in reduced memory T cell numbers.\",\n      \"method\": \"Transgenic mouse model (human beta-actin promoter-driven Drak2), IL-2 apoptosis assays, immunophenotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic overexpression model with defined molecular and cellular phenotype, single lab\",\n      \"pmids\": [\"16517594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Drak2-/- mice, T cells require greater tonic signaling for maintenance during clonal expansion and are more sensitive to intrinsic (mitochondrial) apoptosis following stimulation, which is prevented by CD28 ligation, homeostatic cytokines, or enforced Bcl-xL expression. T cell-specific Bcl-xL expression restored susceptibility to EAE in Drak2-/- mice.\",\n      \"method\": \"Drak2-/- mice, Bcl-xL transgenic rescue, adoptive transfer, apoptosis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistatic rescue with Bcl-xL, multiple orthogonal approaches, replicated phenotype across labs\",\n      \"pmids\": [\"19017949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DRAK2 is upstream of p70S6 kinase (S6K) in beta cell apoptosis signaling; inducible NO synthase is upstream of DRAK2 and caspase-9 is downstream. Purified DRAK2 directly phosphorylates p70S6 kinase in an in vitro kinase assay. DRAK2 overexpression enhanced p70S6K phosphorylation in cells, and DRAK2 knockdown reduced it.\",\n      \"method\": \"In vitro kinase assay with purified proteins, siRNA knockdown, transgenic overexpression, epistasis analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay identifying p70S6K as direct substrate, complemented by cellular epistasis, single lab\",\n      \"pmids\": [\"19342653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DRAK2 participates in a negative feedback loop controlling TGF-β signaling: TGF-β1 stimulation induces DRAK2 expression and promotes endogenous interaction of DRAK2 with the type I TGF-β receptor (TβRI), thereby blocking R-Smads recruitment. DRAK2 depletion markedly augmented TGF-β1 responses.\",\n      \"method\": \"Co-immunoprecipitation of DRAK2 with TβRI, siRNA knockdown, TGF-β signaling reporter assays, tumor cell line functional studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of endogenous proteins, knockdown with functional signaling readout, single lab\",\n      \"pmids\": [\"23122956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Protein kinase D (PKD) is an essential upstream activator of DRAK2 following TCR ligation, requiring Ca2+ influx through Orai1 (CRAC channels). PKD physically interacts with DRAK2, phosphorylates it, and a constitutively active PKD mutant promoted DRAK2 function while kinase-dead PKD or PKD knockdown blocked DRAK2 activation. Mitochondrial reactive oxygen species generation was necessary and sufficient for DRAK2 activation in response to Ca2+ influx.\",\n      \"method\": \"PKD inhibitor (Gö6976), kinase-dead and constitutively active PKD mutants, PKD knockdown, Co-IP of DRAK2-PKD interaction, Orai1-dependent calcium influx assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including inhibitor, dominant-negative, constitutively active mutant, knockdown, and physical interaction data in single study\",\n      \"pmids\": [\"21148796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The MYB oncogene transcriptionally represses DRAK2 expression by binding to a conserved element upstream of the DRAK2 transcription start site. MYB knockdown upregulates DRAK2, activates caspase-9, and promotes apoptosis; DRAK2 siRNA knockdown rescues cells from this apoptosis.\",\n      \"method\": \"siRNA knockdown of MYB and DRAK2, ChIP assay showing MYB binding to DRAK2 promoter, caspase-9 activity assay\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, epistatic siRNA rescue, single lab\",\n      \"pmids\": [\"23398943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DRAK2 does NOT regulate TGF-β/Smad signaling in primary T cells. Smad2/Smad3 activation, TGF-β-mediated effects on naïve T cell proliferation, CD8+ T cell survival, Treg induction, and enhanced T cell death in Drak2-/- mice were all independent of TGF-β signaling.\",\n      \"method\": \"In vitro TGF-β signaling assays in wildtype vs Drak2-/- primary T cells, Smad phosphorylation assays, proliferation and survival assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro assays in primary cells, direct contradiction of prior report (PMID:23122956) in T cell context, single lab\",\n      \"pmids\": [\"25951457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"X-ray crystallography of STK17B with inhibitor SGC-STK17B-1 (thieno[3,2-d]pyrimidine) revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor, explaining selectivity over closely related STK17A. The compound is an ATP-competitive inhibitor.\",\n      \"method\": \"X-ray crystallography, kinase selectivity profiling, molecular dynamics simulation\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray crystal structure with functional (selectivity) validation and MD simulation, multiple orthogonal methods\",\n      \"pmids\": [\"33215924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DRAK2 directly binds the splicing factor SRSF6 and inhibits its phosphorylation by SRPK1, thereby regulating alternative splicing of mitochondrial function-related genes and driving NAFLD/NASH progression. Hepatic deletion of DRAK2 suppressed hepatic steatosis progression to NASH.\",\n      \"method\": \"Phosphoproteome and transcriptome analyses, Co-IP/pulldown identifying SRSF6 as direct DRAK2 binding partner, DRAK2 conditional liver knockout mice, RNA splicing analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction identified, phosphoproteomics, transcriptomics, and conditional KO with defined phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34614409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STK17B is strongly expressed in cerebellar Purkinje cells and functions as a downstream effector of PKC. STK17B overexpression potentiates PKC-induced morphological changes in Purkinje cell dendritic trees; a phosphorylation-mimetic STK17B variant caused marked reduction in dendritic tree size; and STK17B inhibition partially rescued PKC activation-induced dendritic changes.\",\n      \"method\": \"Overexpression and pharmacological inhibition in primary Purkinje cell cultures, phospho-mimetic mutant (STK17B-S350D equivalent), morphological quantification\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and pharmacological inhibition with quantified morphological readout, multiple approaches, single lab\",\n      \"pmids\": [\"34536317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DRAK2 regulates IL-2 signaling by inhibiting STAT5A phosphorylation, not by limiting TCR signaling as previously hypothesized. Enhanced sensitivity to IL-2 in Drak2-/- mice augments thymic regulatory T cell (Treg) development, and resistance to T1D requires Treg presence.\",\n      \"method\": \"Drak2-/- NOD mice, T cell-specific conditional approaches, adoptive transfer with/without Tregs, STAT5A phosphorylation assays, Treg development analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Treg depletion epistasis, STAT5A phosphorylation measurement, adoptive transfer, single lab\",\n      \"pmids\": [\"36773294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DRAK2 directly phosphorylates ULK1 at Ser56, leading to ULK1 ubiquitylation and suppression of autophagy. In pancreatic β cells, this DRAK2-ULK1 axis impairs mitochondrial function and insulin secretion upon lipotoxic stress. Conditional β cell-specific DRAK2 knockout preserved autophagy and mitochondrial function under high-fat diet.\",\n      \"method\": \"Phosphoproteome analysis of primary mouse islets, ULK1-S56A point mutant rescue, DRAK2 conditional KO mice, in vitro kinase assay (direct phosphorylation), autophagy and mitochondrial function assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation, site-specific mutagenesis (S56A rescue), phosphoproteomics, and conditional KO with defined phenotype in one study\",\n      \"pmids\": [\"38324636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DRAK2 phosphorylates myosin light chain 2 (MLC2) in T cells. In the absence of DRAK2, polymerized actin is decreased, and myosin-dependent T cell functions including migration, TCR microcluster accumulation, and conjugation to antigen-presenting cells are impaired.\",\n      \"method\": \"Drak2-/- T cell functional assays, actin polymerization assay, phosphorylation analysis of MLC2, T cell-APC conjugation assay, TCR microcluster imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with multiple defined functional readouts, phosphoproteomic substrate identification in companion paper (PMID:39502695), single lab\",\n      \"pmids\": [\"39421891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pharmacological STK17B inhibitors identify Ser19 on myosin light chain 2 (MLC2) as a STK17B substrate by mass spectrometry-based phosphoproteomics. In mouse T cell activation assays, STK17B inhibitors enhanced IL-2 production and enhanced T cell priming (CD69, IL-2, IFN-γ upregulation) in vivo.\",\n      \"method\": \"MS-based phosphoproteomics with selective kinase inhibitors, flow cytometry pharmacodynamic assay, in vivo T cell activation assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics substrate identification with pharmacological inhibitors, in vivo PD readout, single lab\",\n      \"pmids\": [\"39502695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STK17B phosphorylates IREB2 at Ser157 and HSPB1 at Ser15, identified by proximity labeling combined with phosphoproteomic analysis. This modulates the balance between proferroptotic transferrin receptor and antiferroptotic ferritin heavy chain, suppressing ferroptosis in multiple myeloma cells. STK17B also indirectly maintains activating phosphorylation of STAT3.\",\n      \"method\": \"Proximity labeling (BioID or similar) combined with phosphoproteomics, site-specific phosphorylation validation, ferroptosis assays (labile iron pool, lipid peroxidation), xenograft mouse model, selective STK17B inhibitor\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling plus phosphoproteomics identifying direct substrates, functional ferroptosis assays, single lab\",\n      \"pmids\": [\"40953235\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STK17B/DRAK2 is a serine/threonine kinase of the DAPK family that is activated downstream of TCR/Ca2+ influx via a PKD-ROS signaling module, autophosphorylates at Ser12, and translocates between nucleus and cytoplasm under control of PKC-gamma-mediated Ser350 phosphorylation; it raises the threshold for T cell activation by inhibiting STAT5A (not TCR signaling directly) to limit IL-2 sensitivity and Treg development, phosphorylates myosin light chain 2 to control actomyosin dynamics and T cell migration, directly phosphorylates ULK1 at Ser56 to suppress autophagy in pancreatic β cells, binds and sequesters the splicing factor SRSF6 to modulate alternative splicing of mitochondrial genes in liver, and phosphorylates IREB2 (Ser157) and HSPB1 (Ser15) to suppress ferroptosis; its kinase activity is negatively regulated by the calcium-binding protein CHP, and its expression is transcriptionally repressed by MYB and induced as a negative-feedback antagonist by TGF-β.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STK17B (DRAK2) is a calcium-responsive serine/threonine kinase best characterized as a negative regulator that raises the threshold for lymphocyte activation and as a stress-responsive kinase controlling cell survival and metabolism across multiple tissues [#0, #10]. In T cells its activation is driven by TCR ligation through Orai1/CRAC-dependent Ca2+ influx, a PKD-mediated phosphorylation step, and mitochondrial ROS, and it autophosphorylates at Ser12 in a calcium-dependent manner required for optimal suppression of T cell activation [#4, #10]. Rather than dampening proximal TCR signaling, STK17B limits IL-2 sensitivity by inhibiting STAT5A phosphorylation, thereby restraining regulatory T cell development [#16]; loss of the kinase sensitizes activated T cells to intrinsic mitochondrial apoptosis that is rescued by Bcl-xL [#7]. STK17B also phosphorylates myosin light chain 2 to support actin polymerization, TCR microcluster formation, and myosin-dependent T cell migration and conjugation [#18, #19]. Its subcellular distribution is governed by a functional NLS whose adjacent Ser350 is phosphorylated by PKC-gamma to drive cytoplasmic accumulation, while nuclear localization is required for UV-induced apoptosis [#2, #3]. Beyond immunity, STK17B acts through defined substrates: it phosphorylates ULK1 at Ser56 to trigger its ubiquitylation and suppress autophagy in pancreatic beta cells [#17], binds the splicing factor SRSF6 and blocks its phosphorylation by SRPK1 to reprogram mitochondrial-gene splicing during NASH progression [#14], and phosphorylates IREB2 (Ser157) and HSPB1 (Ser15) to suppress ferroptosis in multiple myeloma [#20]. Kinase activity is inhibited in a calcium-dependent manner by the calcium-binding protein CHP, and expression is transcriptionally repressed by MYB [#1, #11]. A crystal structure with the selective inhibitor SGC-STK17B-1 defined a distinctive P-loop conformation involving an R41 salt bridge that confers selectivity over STK17A [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the first negative regulator of STK17B catalytic output, linking its kinase activity to calcium signaling at the biochemical level.\",\n      \"evidence\": \"In vitro kinase assay with CHP and MLC substrate, plus interaction studies\",\n      \"pmids\": [\"12966074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro study with exogenous substrate\", \"Cellular relevance of CHP inhibition not tested in primary cells\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the core physiological role by showing STK17B sets the activation threshold of T cells, distinguishing it from an apoptotic or selection function.\",\n      \"evidence\": \"Drak2-/- knockout mouse with T cell functional assays\",\n      \"pmids\": [\"15589167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target downstream of the kinase not identified\", \"Mechanism of threshold-raising left open\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected STK17B to calcium-tuned thymocyte selection and showed its expression is induced by TCR signaling via PKC and MAP kinase.\",\n      \"evidence\": \"Drak2-/- thymocyte assays and retroviral transduction with TCR stimulation\",\n      \"pmids\": [\"16172133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional inducers not mapped\", \"Substrate mediating threshold control unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified Ser12 autophosphorylation as a calcium-dependent activation mark required for suppressive function, providing a molecular readout of activity.\",\n      \"evidence\": \"Mass spectrometry, phospho-specific antibody, and calcium perturbation in T and B cells\",\n      \"pmids\": [\"17182616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream kinase/sensor coupling calcium to Ser12 not defined at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed overexpression promotes apoptosis of activated T cells in the presence of IL-2, linking kinase dosage to survival and memory T cell numbers.\",\n      \"evidence\": \"Transgenic Drak2-overexpressing mice with IL-2 apoptosis assays\",\n      \"pmids\": [\"16517594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct apoptotic substrate not identified\", \"Overexpression may not reflect endogenous stoichiometry\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated nuclear localization is required for apoptotic function, establishing subcellular compartmentalization as a control point.\",\n      \"evidence\": \"GFP-fusion localization, NLS mutagenesis, siRNA, UV apoptosis assay\",\n      \"pmids\": [\"16462023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear substrates driving apoptosis not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified PKC-gamma phosphorylation of Ser350 flanking the NLS as the switch controlling nucleocytoplasmic shuttling.\",\n      \"evidence\": \"GFP-fusion mutagenesis, PKC-gamma expression, PMA stimulation, S350D mutant\",\n      \"pmids\": [\"18084041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological stimuli triggering PKC-gamma-dependent relocation in vivo not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the survival phenotype by showing Drak2-/- T cells are hypersensitive to intrinsic mitochondrial apoptosis, rescuable by Bcl-xL.\",\n      \"evidence\": \"Drak2-/- mice, Bcl-xL transgenic rescue, adoptive transfer, EAE model\",\n      \"pmids\": [\"19017949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase link to mitochondrial apoptotic machinery not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Proposed p70S6 kinase as a direct substrate in beta cell apoptosis, situating STK17B within an iNOS-caspase-9 axis.\",\n      \"evidence\": \"In vitro kinase assay, siRNA, overexpression, epistasis\",\n      \"pmids\": [\"19342653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite on p70S6K not mapped\", \"Single lab; not validated in vivo\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed STK17B in a TGF-beta negative-feedback loop through interaction with TbRI that blocks R-Smad recruitment.\",\n      \"evidence\": \"Co-IP with TbRI, siRNA, TGF-beta reporter assays in tumor cells\",\n      \"pmids\": [\"23122956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Later contradicted in primary T cells (#12)\", \"Direct phosphorylation of receptor not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the activation module by showing PKD, Orai1-dependent Ca2+ influx, and mitochondrial ROS are required and sufficient for STK17B activation downstream of TCR.\",\n      \"evidence\": \"PKD inhibitor, kinase-dead/constitutively active mutants, knockdown, Co-IP, calcium influx assays\",\n      \"pmids\": [\"21148796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKD phosphosite on STK17B not pinpointed\", \"Connection to Ser12 autophosphorylation not directly bridged\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified MYB as a direct transcriptional repressor of STK17B, linking its expression to apoptotic control in leukemia cells.\",\n      \"evidence\": \"siRNA of MYB and DRAK2, ChIP at the promoter, caspase-9 assay\",\n      \"pmids\": [\"23398943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this regulation operates in normal lymphocytes unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Corrected the TGF-beta model by showing STK17B does not regulate TGF-beta/Smad signaling in primary T cells, narrowing the receptor-interaction finding to specific contexts.\",\n      \"evidence\": \"TGF-beta signaling and Smad phosphorylation assays in WT vs Drak2-/- primary T cells\",\n      \"pmids\": [\"25951457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with the tumor-cell TbRI finding (#9) not resolved mechanistically\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Delivered a structural basis for selective inhibition, defining a unique P-loop conformation distinguishing STK17B from STK17A.\",\n      \"evidence\": \"X-ray crystallography with SGC-STK17B-1, selectivity profiling, MD simulation\",\n      \"pmids\": [\"33215924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate-bound or active-state structure\", \"Apo conformational dynamics not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified SRSF6 as a direct binding partner whose SRPK1-mediated phosphorylation STK17B blocks, linking the kinase to mitochondrial-gene splicing and NASH.\",\n      \"evidence\": \"Co-IP/pulldown, phosphoproteomics, transcriptomics, conditional liver KO\",\n      \"pmids\": [\"34614409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STK17B phosphorylates SRSF6 directly versus only sequestering it not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the PKC-effector role to neurons, showing STK17B mediates PKC-driven Purkinje cell dendritic remodeling.\",\n      \"evidence\": \"Overexpression, pharmacological inhibition, phospho-mimetic mutant in primary Purkinje cultures\",\n      \"pmids\": [\"34536317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal substrates not identified\", \"In vivo dendritic phenotype not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reframed the immune mechanism: STK17B limits IL-2 sensitivity by inhibiting STAT5A rather than dampening TCR signaling, controlling Treg development and autoimmunity.\",\n      \"evidence\": \"Drak2-/- NOD mice, STAT5A phosphorylation assays, Treg-depletion adoptive transfer\",\n      \"pmids\": [\"36773294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation target linking STK17B to STAT5A inhibition not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a direct ULK1 Ser56 phosphorylation-ubiquitylation axis through which STK17B suppresses autophagy and impairs beta cell mitochondrial function.\",\n      \"evidence\": \"Islet phosphoproteomics, in vitro kinase assay, ULK1-S56A rescue, conditional beta cell KO\",\n      \"pmids\": [\"38324636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase coupling Ser56 phosphorylation to ULK1 ubiquitylation not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified MLC2 as a cytoskeletal substrate, explaining STK17B control of actomyosin dynamics, T cell migration, and immune synapse formation.\",\n      \"evidence\": \"Drak2-/- T cell functional assays, actin and MLC2 phosphorylation analysis, conjugation and microcluster imaging; phosphosite mapped by companion phosphoproteomics\",\n      \"pmids\": [\"39421891\", \"39502695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro phosphorylation of MLC2 by purified STK17B not shown in these reports\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified IREB2 (Ser157) and HSPB1 (Ser15) as direct substrates through which STK17B suppresses ferroptosis in multiple myeloma, linking it to iron handling and STAT3.\",\n      \"evidence\": \"Proximity labeling plus phosphoproteomics, site-specific validation, ferroptosis assays, xenografts, selective inhibitor\",\n      \"pmids\": [\"40953235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which STK17B maintains STAT3 phosphorylation indirect/unmapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STK17B selects among its diverse substrates (STAT5A pathway, ULK1, SRSF6, MLC2, IREB2/HSPB1) in different tissues, and how upstream calcium/PKD/PKC-gamma inputs are integrated to direct context-specific outputs, remains unresolved.\",\n      \"evidence\": \"No single study reconciles the tissue-specific substrate repertoire\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying determinant of substrate choice identified\", \"Cross-tissue regulatory logic uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 14, 17, 18, 19, 20]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [4, 8, 17, 18, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 7, 16, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 7, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 16]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CHP\", \"PKD\", \"TGFBR1\", \"SRSF6\", \"ULK1\", \"MYB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}