{"gene":"STAP2","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2003,"finding":"STAP-2 (also known as BKS) was identified as a novel adaptor protein containing PH and SH2-like domains that modulates STAT3 activity through its YXXQ motif. In STAP-2-deficient hepatocytes, IL-6-induced STAT3 tyrosine phosphorylation and acute-phase gene expression were reduced at the late phase (6–24 h). Overexpression of wild-type STAP-2 but not YXXQ-motif mutants enhanced acute-phase response element reporter activity.","method":"STAP-2 knockout mice, reporter assays, overexpression of domain mutants, immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — KO mouse phenotype combined with mutagenesis (YXXQ motif) and reporter assays, replicated in hepatocytes","pmids":["12540842"],"is_preprint":false},{"year":2004,"finding":"STAP-2/BKS physically binds STAT5 through its PH and SH2-like domains interacting with the C-terminal region of STAT5. STAP-2 and STAT5 co-localize in the cytoplasm of resting cells but dissociate upon STAT5 phosphorylation. Overexpression of STAP-2 diminishes cytokine-induced STAT5 tyrosine phosphorylation and transcriptional activation, and STAP-2-deficient thymocytes show enhanced IL-2-dependent cell growth.","method":"Co-immunoprecipitation, intracellular staining, mutational analysis, STAP-2 knockout mice, overexpression assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, domain mutagenesis, KO mouse phenotype with defined cellular readout","pmids":["15611091"],"is_preprint":false},{"year":2003,"finding":"STAP-2/BKS associates with PLC-γ in vivo and suppresses FcεRI-mediated tyrosine phosphorylation of PLC-γ (but not Syk), leading to inhibition of calcium mobilization and degranulation in RBL-2H3 mast cells.","method":"Overexpression of STAP-2/BKS and domain mutants in RBL-2H3 cells, co-immunoprecipitation, calcium flux assay, degranulation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with functional readout (calcium, degranulation), single lab","pmids":["12810085"],"is_preprint":false},{"year":2007,"finding":"STAP-2 directly interacts with c-Fms/M-CSF receptor through its PH domain independently of M-CSF stimulation. Overexpression of STAP-2 suppresses M-CSF-induced c-Fms tyrosine phosphorylation, Akt and ERK activation, and impairs macrophage migration and wound-healing in Raw 264.7 cells.","method":"Co-immunoprecipitation (PH domain mapping), kinase/phosphorylation assays, overexpression in Raw 264.7 cells, wound-healing assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with domain mapping and functional cellular phenotype, single lab","pmids":["17512498"],"is_preprint":false},{"year":2008,"finding":"STAP-2 loss-of-function in knockout macrophages results in enhanced c-Fms/M-CSF receptor signaling and increased wound-healing capacity, confirming STAP-2 as an endogenous negative regulator of M-CSF receptor signaling.","method":"STAP-2 knockout mouse-derived bone marrow macrophages, signaling assays, wound-healing assay","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse primary cells with defined phenotypic readout, corroborating overexpression findings","pmids":["18758078"],"is_preprint":false},{"year":2008,"finding":"STAP-2 negatively regulates EBV LMP1-mediated NF-κB signaling (both canonical and non-canonical). STAP-2 associates with LMP1 through its PH and SH2-like domains, and regulates LMP1 signaling through interactions with TRAF3 and TRADD. STAP-2 knockout mouse embryonic fibroblasts show enhanced LMP1-induced cell growth.","method":"Co-immunoprecipitation, overexpression, STAP-2 KO MEFs, NF-κB reporter assays, cell growth assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — domain mapping by co-IP, KO functional validation, NF-κB reporter, multiple orthogonal methods","pmids":["18573890"],"is_preprint":false},{"year":2007,"finding":"STAP-2 is phosphorylated at tyrosine-250 (Tyr250) by v-Src and Jak2. Phosphorylation at Tyr250 is induced by leukemia inhibitory factor (LIF) stimulation of cells and is required for STAP-2's STAT3-enhancing activity, as Tyr250 mutants fail to enhance STAT3 activation.","method":"Phospho-specific antibody against pY250, mutational analysis (Y250F), LIF stimulation of 293T, Hep3B, and M1 cells, reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 — phospho-specific antibody plus mutagenesis with functional readout, single lab","pmids":["17368569"],"is_preprint":false},{"year":2009,"finding":"STAP-2 is phosphorylated at Tyr250 by Brk (breast tumor kinase). Phosphorylated STAP-2 Y250 promotes Brk-mediated STAT3 activation; the Y250F mutant and siRNA-mediated STAP-2 knockdown both decrease Brk-mediated STAT3 activation.","method":"STAP-2 YF mutant panel, phospho-specific anti-pY250 antibody, siRNA knockdown, STAT3 phosphorylation assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro phosphorylation with mutagenesis, phospho-specific antibody, siRNA confirmation","pmids":["19393627"],"is_preprint":false},{"year":2009,"finding":"E3 ubiquitin ligase Cbl directly binds STAP-2 through its PH and SH2-like domains and controls STAP-2 protein levels via ubiquitin-mediated degradation. Cbl siRNA restores STAP-2 levels; Cbl overexpression induces STAP-2 degradation. Cbl-mediated STAP-2 degradation reduces Brk/STAP-2-induced STAT3 activation.","method":"Co-immunoprecipitation, siRNA knockdown of Cbl, Cbl overexpression, STAT3 reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with domain mapping, siRNA and overexpression functional readout, single lab","pmids":["19401194"],"is_preprint":false},{"year":2010,"finding":"STAP-2 interacts with both Brk and STAT3, with its PH domain mediating Brk-STAP-2 binding and contributing to Brk activation and STAT3 tyrosine phosphorylation. STAP-2 knockdown in T47D breast cancer cells decreases Brk-mediated STAT3 activation and cell proliferation as strongly as Brk or STAT3 knockdown. A STAP-2 PH-Brk fusion protein exhibits robust kinase activity and enhanced STAT3 activation.","method":"Co-immunoprecipitation, siRNA knockdown, PH domain mutants, fusion protein kinase assays, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal approaches including domain mapping, fusion protein kinase assay, siRNA with cellular phenotype","pmids":["20929863"],"is_preprint":false},{"year":2011,"finding":"STAP-2 promotes Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells via its PH domain. STAP-2 knockdown in T47D cells reduces proliferation equivalently to Brk or STAT5b knockdown.","method":"Ectopic expression, siRNA knockdown, STAT5 transcriptional activity assays, domain mutants, proliferation assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional readout with domain mapping, siRNA, single lab","pmids":["21205088"],"is_preprint":false},{"year":2012,"finding":"STAP-2 binds BCR-ABL (and BCR and ABL proteins) through its SH2-like domain. BCR-ABL phosphorylates STAP-2 at Tyr250, and phosphorylated STAP-2 in turn upregulates BCR-ABL phosphorylation, enhancing downstream ERK, STAT5, BCL-xL, and BCL-2 signaling. STAP-2 interaction with BCR-ABL also downregulates CXCR4 and upregulates CCR7 expression, and confers growth advantage and imatinib resistance.","method":"Co-immunoprecipitation (SH2-like domain mapping), phosphorylation assays, siRNA knockdown in K562 cells, Ba/F3 mouse model, chemokine receptor expression analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple binding partners mapped, in vivo mouse model validation, imatinib resistance functional readout, multiple orthogonal methods","pmids":["22231445"],"is_preprint":false},{"year":2017,"finding":"STAP-2 interacts with EGFR and enhances EGFR stability by inhibiting c-CBL-mediated ubiquitination of EGFR. STAP-2 knockdown in DU145 prostate cancer cells reduces EGF-induced AKT, ERK, and STAT3 phosphorylation and tumor growth.","method":"Co-immunoprecipitation, EGFR ubiquitination assay, siRNA knockdown, in vivo xenograft tumor growth","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — co-IP, ubiquitination assay, in vivo xenograft, multiple downstream signaling readouts","pmids":["28986450"],"is_preprint":false},{"year":2017,"finding":"STAP-2 directly interacts with Pyk2 and increases Pyk2 phosphorylation. Pyk2 itself phosphorylates STAP-2 at Y250, and this phosphorylation is required for maximal STAP-2-Pyk2 interaction. STAP-2/Pyk2 interaction enhances SDF-1α-induced T-cell chemotaxis, which is inhibited by Pyk2 siRNA or the Pyk2 inhibitor AG17.","method":"Co-immunoprecipitation, phosphorylation assays, siRNA knockdown of Pyk2, pharmacological inhibition (AG17), chemotaxis assay in Jurkat cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with phosphorylation mapping, siRNA and pharmacological inhibition with cellular functional readout","pmids":["28478037"],"is_preprint":false},{"year":2019,"finding":"STAP-2 positively regulates FcεRI-mediated basophil activation: STAP-2-deficient bone marrow-derived basophils show reduced degranulation, cytokine production, and phosphorylation of Lyn, PLC-γ2, and Erk after IgE/Ag stimulation. STAP-2 KO mice show significantly reduced IgE-dependent chronic allergic inflammation.","method":"STAP-2 KO mouse-derived basophils, degranulation assay, cytokine ELISA, signaling phosphorylation assay, in vivo allergic inflammation model","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse primary cells, multiple signaling readouts, in vivo phenotype","pmids":["30726917"],"is_preprint":false},{"year":2022,"finding":"STAP-2 positively regulates TCR signaling by associating with TCR-proximal CD3ζ ITAMs and phosphorylated LCK, enhancing their interaction after TCR stimulation. STAP-2-deficient T cells show reduced TCR-mediated signaling and IL-2 production, whereas STAP-2-overexpressing T cells show enhanced signaling. STAP-2 KO mice show reduced CD4+ T-cell-mediated inflammatory disease (EAE), while STAP-2 transgenic mice show severe EAE.","method":"Co-immunoprecipitation (CD3ζ ITAM and LCK binding), STAP-2 KO and transgenic mice, IL-2 production assay, EAE model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — binding partners mapped by co-IP, both KO and transgenic mouse models with defined in vivo inflammatory disease phenotype","pmids":["35725273"],"is_preprint":false},{"year":2023,"finding":"STAP-2 negatively regulates BCR-mediated B cell signaling by recruiting CSK to LYN. STAP-2 directly binds LYN depending on STAP-2 Y250 phosphorylation by LYN. Phosphorylated STAP-2 enhances LYN-CSK interactions, promoting CSK-mediated phosphorylation of LYN Y508 (inhibitory site). STAP-2 KO B cells show reduced LYN Y508 phosphorylation and increased BCR signaling, cytokine, and antibody production.","method":"Co-immunoprecipitation, phosphorylation assays (Y250, LYN Y508), STAP-2 KO mouse B cells, cytokine and antibody production assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — mechanistic co-IP with phosphorylation-dependent binding, KO mouse primary cells with defined signaling and functional readouts","pmids":["37669828"],"is_preprint":false},{"year":2023,"finding":"A synthetic peptide derived from STAP-2 (iSP2) directly interacts with CD3ζ ITAM sequences and blocks STAP-2-CD3ζ interactions, suppressing TCR-induced T cell proliferation and IL-2 production in human and murine T cells. iSP2 also suppresses EAE in vivo.","method":"Peptide-ITAM binding assay, cell-penetrating peptide delivery, proliferation assay, IL-2 production, EAE model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct peptide-ITAM binding validation, functional cellular and in vivo readout","pmids":["37417746"],"is_preprint":false},{"year":2024,"finding":"STAP-2 binds to CAP (c-Cbl-associated protein) through its C-terminal proline-rich region and bridges CAP and c-Cbl, enhancing their complex formation. This promotes GLUT4 translocation in response to insulin. STAP-2 expression is upregulated during adipocyte differentiation; STAP-2 overexpression promotes adipogenesis of 3T3-L1 cells and MEFs, while STAP-2 KO MEFs show suppressed adipogenesis. STAP-2 KO mice gain less weight on a high-fat diet.","method":"Co-immunoprecipitation (proline-rich region mapping), GLUT4 translocation assay, retroviral overexpression, STAP-2 KO mouse MEFs and in vivo high-fat diet","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — co-IP with domain mapping, functional assay (GLUT4 translocation), KO and overexpression in cells plus in vivo mouse phenotype","pmids":["38461189"],"is_preprint":false},{"year":2024,"finding":"STAP-2 interacts with HSP27 (identified by co-immunoprecipitation and mass spectrometry) and modulates the PI3K/AKT signaling pathway in renal fibrosis. STAP-2 KO in vivo reduces EMT, inflammatory cell infiltration, and collagen deposition in renal fibrosis models; STAP-2 overexpression in vitro exacerbates fibrosis markers. STAP-2 affects phosphorylated HSP27 levels.","method":"Co-immunoprecipitation, mass spectrometry, RNA-seq, STAP-2 KO mice (IRI and cisplatin models), STAP-2 overexpression in vitro, fibrosis marker quantification","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — MS-identified interaction with co-IP, KO in vivo phenotype, single lab","pmids":["39533293"],"is_preprint":false},{"year":2022,"finding":"KGF-2 inhibits STAP-2 expression and consequently reduces STAT3 activation, leading to decreased collagen I and collagen III levels in fibroblasts and reduced hypertrophic scar formation both in vitro and in vivo.","method":"STAP-2 expression modulation, STAT3 phosphorylation assay, collagen expression analysis, in vivo scar model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic pathway (KGF-2→STAP-2→STAT3→collagen) supported by expression modulation and functional readout, single lab","pmids":["34999107"],"is_preprint":false},{"year":2022,"finding":"A STAP-2-derived peptide (2D5) blocks STAP-2-EGFR interactions and suppresses EGFR-mediated proliferation, EGFR stability, and signaling in cancer cell lines and murine xenograft models of prostate and lung cancer.","method":"Peptide competition assay, EGFR signaling assays, cell proliferation assay, in vivo xenograft model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct blocking of protein-protein interaction with functional in vitro and in vivo readouts","pmids":["36410436"],"is_preprint":false},{"year":2015,"finding":"CCR7 upregulation by STAP-2/BCR-ABL is mediated through the MAPK/ERK pathway. STAP-2 cooperates with BCR-ABL to induce CCR7 ligand (CCL19, CCL21) production, and CCR7 contributes to STAP-2-dependent enhancement of BCR-ABL-mediated cell growth in Ba/F3 cells.","method":"Chemokine receptor expression analysis, ERK pathway inhibition, CCL19/CCL21 ELISA, cell growth assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — pathway placement by pharmacological inhibition and expression analysis, single lab","pmids":["26102025"],"is_preprint":false}],"current_model":"STAP-2 is an adaptor protein containing PH, SH2-like, and proline-rich domains that acts as a scaffold to modulate multiple signaling pathways in immune and cancer cells: it enhances STAT3 activity via its YXXQ motif (direct STAT3 binding), suppresses STAT5 via PH/SH2-like domain binding, is phosphorylated at Y250 by Brk, Jak2, Pyk2, LYN, and BCR-ABL to regulate downstream signaling, negatively regulates FcεRI/PLC-γ signaling in mast cells, inhibits c-Fms/M-CSF receptor and NF-κB signaling in macrophages, positively regulates TCR signaling by bridging CD3ζ ITAMs with LCK, negatively regulates BCR signaling by recruiting CSK to LYN, promotes EGFR stability by blocking c-CBL-mediated ubiquitination, and facilitates insulin signaling by forming a CAP/STAP-2/c-Cbl ternary complex to promote GLUT4 translocation and adipogenesis."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of STAP-2 as an adaptor protein with PH, SH2-like, and YXXQ domains resolved how late-phase IL-6/STAT3 signaling is sustained in hepatocytes, establishing STAP-2 as a STAT3-enhancing scaffold.","evidence":"STAP-2 KO mouse hepatocytes, YXXQ mutagenesis, reporter assays","pmids":["12540842"],"confidence":"High","gaps":["Structural basis of YXXQ–STAT3 interaction unresolved","Upstream signals controlling STAP-2 expression unknown"]},{"year":2003,"claim":"Demonstration that STAP-2 associates with PLC-γ and suppresses FcεRI-mediated degranulation in mast cells revealed its first negative regulatory role, showing domain versatility beyond STAT3 enhancement.","evidence":"Co-IP and calcium/degranulation assays in RBL-2H3 mast cells","pmids":["12810085"],"confidence":"Medium","gaps":["STAP-2 KO mast cell validation not performed","Mechanism by which STAP-2 selectively suppresses PLC-γ but not Syk phosphorylation unclear"]},{"year":2004,"claim":"Discovery that STAP-2 binds STAT5 via PH/SH2-like domains and suppresses STAT5 activation established that STAP-2 exerts opposing effects on STAT3 (positive) and STAT5 (negative) through distinct domain interfaces.","evidence":"Reciprocal co-IP, domain mutagenesis, STAP-2 KO thymocytes with IL-2-dependent growth","pmids":["15611091"],"confidence":"High","gaps":["How phosphorylation-dependent dissociation of STAP-2–STAT5 is regulated in different cell types unclear"]},{"year":2007,"claim":"Identification of Tyr250 as a phosphorylation site targeted by v-Src/Jak2, required for STAT3-enhancing activity, established a central regulatory switch for STAP-2 scaffold function.","evidence":"Phospho-specific pY250 antibody, Y250F mutagenesis, LIF stimulation in multiple cell lines","pmids":["17368569"],"confidence":"Medium","gaps":["Kinase hierarchy at Y250 in physiological settings undetermined","Phosphatase(s) that reverse Y250 phosphorylation unknown"]},{"year":2007,"claim":"Showing that STAP-2 PH domain binds c-Fms and suppresses M-CSF-mediated macrophage signaling and migration extended STAP-2's negative regulatory role to receptor tyrosine kinase signaling in macrophages.","evidence":"Co-IP with PH domain mapping, signaling assays, wound-healing in Raw 264.7; later confirmed in KO macrophages (2008)","pmids":["17512498","18758078"],"confidence":"Medium","gaps":["Direct vs. indirect mechanism of c-Fms phosphorylation suppression not fully dissected"]},{"year":2008,"claim":"Discovery that STAP-2 binds LMP1 and suppresses both canonical and non-canonical NF-κB signaling via TRAF3/TRADD expanded STAP-2's scope to viral oncogene signaling control.","evidence":"Co-IP, domain mapping, NF-κB reporters, STAP-2 KO MEFs","pmids":["18573890"],"confidence":"High","gaps":["Relevance to EBV-associated lymphomagenesis in vivo not tested"]},{"year":2009,"claim":"Demonstration that Brk phosphorylates STAP-2 at Y250 and that STAP-2 in turn scaffolds Brk–STAT3 activation linked STAP-2 to breast cancer proliferation, with c-Cbl-mediated ubiquitination of STAP-2 providing a degradation-based counter-regulation.","evidence":"Phospho-specific antibody, siRNA, domain mutants, Cbl overexpression/siRNA, T47D proliferation assays","pmids":["19393627","19401194","20929863"],"confidence":"High","gaps":["Whether c-Cbl ubiquitination is K48-linked (proteasomal) not confirmed","In vivo breast cancer model lacking"]},{"year":2011,"claim":"Finding that STAP-2 also scaffolds Brk-mediated STAT5 activation in breast cancer cells revealed that STAP-2's effect on STAT5 is context-dependent—suppressive in thymocytes but activating when bridging Brk in cancer.","evidence":"Ectopic expression, siRNA, STAT5 transcriptional activity, T47D proliferation","pmids":["21205088"],"confidence":"Medium","gaps":["Molecular basis for context-dependent STAT5 outcome not mechanistically resolved"]},{"year":2012,"claim":"Identification of a reciprocal activating loop between STAP-2 and BCR-ABL—BCR-ABL phosphorylates Y250, phospho-STAP-2 enhances BCR-ABL activity—provided a mechanistic basis for STAP-2's role in CML progression and imatinib resistance.","evidence":"Co-IP (SH2-like domain mapping), K562 siRNA, Ba/F3 mouse model, chemokine receptor analysis","pmids":["22231445"],"confidence":"High","gaps":["Patient-derived CML validation limited","Whether STAP-2 directly affects imatinib binding or acts indirectly unclear"]},{"year":2017,"claim":"Showing that STAP-2 stabilizes EGFR by blocking c-CBL-mediated ubiquitination, and that Pyk2 phosphorylates STAP-2 Y250 to promote T-cell chemotaxis, broadened STAP-2's receptor repertoire and identified a new upstream kinase.","evidence":"Co-IP, EGFR ubiquitination assays, xenograft (EGFR); Pyk2 phosphorylation, siRNA, chemotaxis assay (Pyk2)","pmids":["28986450","28478037"],"confidence":"High","gaps":["Structural basis of STAP-2 competition with c-CBL for EGFR binding not resolved"]},{"year":2022,"claim":"STAP-2 was established as a positive regulator of proximal TCR signaling by bridging CD3ζ ITAMs with LCK, with KO and transgenic mice showing reciprocal effects on EAE severity, directly demonstrating STAP-2's role in adaptive T-cell immunity.","evidence":"Co-IP of CD3ζ/LCK, STAP-2 KO and transgenic mice, IL-2 production, EAE model","pmids":["35725273"],"confidence":"High","gaps":["Whether STAP-2 binds phosphorylated or unphosphorylated ITAMs preferentially not dissected"]},{"year":2022,"claim":"Therapeutic proof-of-concept peptides (2D5 blocking EGFR and iSP2 blocking CD3ζ binding) validated STAP-2 protein–protein interfaces as druggable nodes.","evidence":"Peptide competition, xenograft tumor suppression (2D5); peptide-ITAM binding, T-cell proliferation suppression, EAE suppression (iSP2)","pmids":["36410436","37417746"],"confidence":"Medium","gaps":["Peptide pharmacokinetics, selectivity, and off-target effects not characterized","Efficacy in non-murine models untested"]},{"year":2023,"claim":"Discovery that STAP-2 recruits CSK to LYN in a Y250-phosphorylation-dependent manner, promoting inhibitory LYN Y508 phosphorylation to dampen BCR signaling, resolved STAP-2's role as a negative regulator of B-cell activation.","evidence":"Co-IP with phospho-dependent binding, KO B cells with signaling and antibody production readouts","pmids":["37669828"],"confidence":"High","gaps":["Whether STAP-2 similarly regulates other Src-family kinases in B cells unknown","In vivo humoral immune response phenotype not fully characterized"]},{"year":2024,"claim":"Identification of STAP-2 as a bridge between CAP and c-Cbl that promotes GLUT4 translocation and adipogenesis revealed a metabolic function independent of immune signaling.","evidence":"Co-IP (proline-rich region), GLUT4 translocation assay, KO MEFs, KO mice on high-fat diet","pmids":["38461189"],"confidence":"High","gaps":["Whether STAP-2 affects insulin receptor phosphorylation directly or acts solely at the CAP/c-Cbl node unclear","Tissue-specific contributions (adipose vs. muscle) not resolved"]},{"year":2024,"claim":"STAP-2 interaction with HSP27 and modulation of PI3K/AKT signaling in renal fibrosis suggested a role in tissue injury/repair beyond immune cells.","evidence":"Co-IP/MS identification of HSP27, STAP-2 KO mice in IRI and cisplatin renal injury models","pmids":["39533293"],"confidence":"Medium","gaps":["Functional significance of STAP-2–HSP27 interaction not mechanistically resolved","Renal fibrosis findings from single lab, awaits independent replication"]},{"year":null,"claim":"No high-resolution structural information exists for STAP-2 or its complexes, the phosphatase(s) reversing Y250 phosphorylation are unknown, and the molecular rules determining whether STAP-2 activates or suppresses a given pathway in different cell types remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of any STAP-2 domain or complex","Identity of Y250-targeting phosphatase(s) unknown","Context-dependent signaling logic (activating vs. suppressive) lacks a unifying mechanistic model"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,9,11,12,15,16,18]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[15,18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6,7,9,11,12,15,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,14,15,16,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,12,22]}],"complexes":["CAP/STAP-2/c-Cbl ternary complex","STAP-2/Brk/STAT3 signaling complex"],"partners":["STAT3","STAT5","BRK","LYN","CSK","BCR-ABL","EGFR","CBL"],"other_free_text":[]},"mechanistic_narrative":"STAP2 is a multidomain adaptor/scaffold protein that integrates and tunes signaling downstream of diverse receptors in immune, cancer, and metabolic cells. Its PH domain, SH2-like domain, YXXQ motif, and C-terminal proline-rich region each mediate distinct protein–protein interactions: the YXXQ motif directly binds and sustains STAT3 activation during cytokine signaling, while the PH and SH2-like domains engage STAT5, c-Fms, LMP1/TRAF3/TRADD, EGFR, BCR-ABL, and the Src-family kinase LYN, enabling context-dependent positive or negative regulation of JAK-STAT, NF-κB, MAPK/ERK, and PI3K/AKT pathways [PMID:12540842, PMID:15611091, PMID:18573890, PMID:28986450, PMID:22231445, PMID:37669828]. Phosphorylation of STAP2 at Tyr250 by kinases including Brk, Jak2, Pyk2, LYN, and BCR-ABL is a convergent regulatory switch that controls its scaffolding activity—enabling STAT3 enhancement, Brk activation in breast cancer, BCR-ABL amplification in CML, and CSK-mediated negative regulation of LYN in B cells [PMID:17368569, PMID:19393627, PMID:20929863, PMID:37669828]. In T cells STAP2 bridges CD3ζ ITAMs with LCK to promote proximal TCR signaling and inflammatory responses, whereas in B cells it recruits CSK to LYN to dampen BCR signaling; in adipocytes it forms a CAP/STAP2/c-Cbl complex that facilitates insulin-stimulated GLUT4 translocation and adipogenesis [PMID:35725273, PMID:37669828, PMID:38461189]."},"prefetch_data":{"uniprot":{"accession":"Q9UGK3","full_name":"Signal-transducing adaptor protein 2","aliases":["Breast tumor kinase substrate","BRK substrate"],"length_aa":403,"mass_kda":44.9,"function":"Substrate of protein kinase PTK6. May play a regulatory role in the acute-phase response in systemic inflammation and may modulate STAT3 activity","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UGK3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STAP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STAP2","total_profiled":1310},"omim":[{"mim_id":"607881","title":"SIGNAL-TRANSDUCING ADAPTOR PROTEIN 2; STAP2","url":"https://www.omim.org/entry/607881"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":89.7}],"url":"https://www.proteinatlas.org/search/STAP2"},"hgnc":{"alias_symbol":["STAP-2","BKS"],"prev_symbol":[]},"alphafold":{"accession":"Q9UGK3","domains":[{"cath_id":"2.30.29.30","chopping":"23-149","consensus_level":"high","plddt":86.4517,"start":23,"end":149},{"cath_id":"3.30.505.10","chopping":"160-238","consensus_level":"high","plddt":89.6234,"start":160,"end":238}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGK3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGK3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGK3-F1-predicted_aligned_error_v6.png","plddt_mean":71.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STAP2","jax_strain_url":"https://www.jax.org/strain/search?query=STAP2"},"sequence":{"accession":"Q9UGK3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UGK3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UGK3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGK3"}},"corpus_meta":[{"pmid":"21617178","id":"PMC_21617178","title":"Transcriptional profiling of diabetic neuropathy in the BKS db/db mouse: a model of type 2 diabetes.","date":"2011","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/21617178","citation_count":90,"is_preprint":false},{"pmid":"32357914","id":"PMC_32357914","title":"Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice.","date":"2020","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32357914","citation_count":85,"is_preprint":false},{"pmid":"12540842","id":"PMC_12540842","title":"STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12540842","citation_count":70,"is_preprint":false},{"pmid":"15611091","id":"PMC_15611091","title":"Physical and functional interactions between STAP-2/BKS and STAT5.","date":"2004","source":"The 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Implication for Genetic-based phytoremediation.","date":"2021","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/34902403","citation_count":21,"is_preprint":false},{"pmid":"17512498","id":"PMC_17512498","title":"STAP-2 regulates c-Fms/M-CSF receptor signaling in murine macrophage Raw 264.7 cells.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17512498","citation_count":19,"is_preprint":false},{"pmid":"17368569","id":"PMC_17368569","title":"Leukemia inhibitory factor-induced phosphorylation of STAP-2 on tyrosine-250 is involved in its STAT3-enhancing activity.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17368569","citation_count":15,"is_preprint":false},{"pmid":"34193686","id":"PMC_34193686","title":"STAP-2 Adaptor Protein Regulates Multiple Steps of Immune and Inflammatory 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In STAP-2-deficient hepatocytes, IL-6-induced STAT3 tyrosine phosphorylation and acute-phase gene expression were reduced at the late phase (6–24 h). Overexpression of wild-type STAP-2 but not YXXQ-motif mutants enhanced acute-phase response element reporter activity.\",\n      \"method\": \"STAP-2 knockout mice, reporter assays, overexpression of domain mutants, immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse phenotype combined with mutagenesis (YXXQ motif) and reporter assays, replicated in hepatocytes\",\n      \"pmids\": [\"12540842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"STAP-2/BKS physically binds STAT5 through its PH and SH2-like domains interacting with the C-terminal region of STAT5. STAP-2 and STAT5 co-localize in the cytoplasm of resting cells but dissociate upon STAT5 phosphorylation. Overexpression of STAP-2 diminishes cytokine-induced STAT5 tyrosine phosphorylation and transcriptional activation, and STAP-2-deficient thymocytes show enhanced IL-2-dependent cell growth.\",\n      \"method\": \"Co-immunoprecipitation, intracellular staining, mutational analysis, STAP-2 knockout mice, overexpression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, domain mutagenesis, KO mouse phenotype with defined cellular readout\",\n      \"pmids\": [\"15611091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"STAP-2/BKS associates with PLC-γ in vivo and suppresses FcεRI-mediated tyrosine phosphorylation of PLC-γ (but not Syk), leading to inhibition of calcium mobilization and degranulation in RBL-2H3 mast cells.\",\n      \"method\": \"Overexpression of STAP-2/BKS and domain mutants in RBL-2H3 cells, co-immunoprecipitation, calcium flux assay, degranulation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional readout (calcium, degranulation), single lab\",\n      \"pmids\": [\"12810085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STAP-2 directly interacts with c-Fms/M-CSF receptor through its PH domain independently of M-CSF stimulation. Overexpression of STAP-2 suppresses M-CSF-induced c-Fms tyrosine phosphorylation, Akt and ERK activation, and impairs macrophage migration and wound-healing in Raw 264.7 cells.\",\n      \"method\": \"Co-immunoprecipitation (PH domain mapping), kinase/phosphorylation assays, overexpression in Raw 264.7 cells, wound-healing assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with domain mapping and functional cellular phenotype, single lab\",\n      \"pmids\": [\"17512498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STAP-2 loss-of-function in knockout macrophages results in enhanced c-Fms/M-CSF receptor signaling and increased wound-healing capacity, confirming STAP-2 as an endogenous negative regulator of M-CSF receptor signaling.\",\n      \"method\": \"STAP-2 knockout mouse-derived bone marrow macrophages, signaling assays, wound-healing assay\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse primary cells with defined phenotypic readout, corroborating overexpression findings\",\n      \"pmids\": [\"18758078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STAP-2 negatively regulates EBV LMP1-mediated NF-κB signaling (both canonical and non-canonical). STAP-2 associates with LMP1 through its PH and SH2-like domains, and regulates LMP1 signaling through interactions with TRAF3 and TRADD. STAP-2 knockout mouse embryonic fibroblasts show enhanced LMP1-induced cell growth.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, STAP-2 KO MEFs, NF-κB reporter assays, cell growth assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping by co-IP, KO functional validation, NF-κB reporter, multiple orthogonal methods\",\n      \"pmids\": [\"18573890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STAP-2 is phosphorylated at tyrosine-250 (Tyr250) by v-Src and Jak2. Phosphorylation at Tyr250 is induced by leukemia inhibitory factor (LIF) stimulation of cells and is required for STAP-2's STAT3-enhancing activity, as Tyr250 mutants fail to enhance STAT3 activation.\",\n      \"method\": \"Phospho-specific antibody against pY250, mutational analysis (Y250F), LIF stimulation of 293T, Hep3B, and M1 cells, reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — phospho-specific antibody plus mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"17368569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"STAP-2 is phosphorylated at Tyr250 by Brk (breast tumor kinase). Phosphorylated STAP-2 Y250 promotes Brk-mediated STAT3 activation; the Y250F mutant and siRNA-mediated STAP-2 knockdown both decrease Brk-mediated STAT3 activation.\",\n      \"method\": \"STAP-2 YF mutant panel, phospho-specific anti-pY250 antibody, siRNA knockdown, STAT3 phosphorylation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro phosphorylation with mutagenesis, phospho-specific antibody, siRNA confirmation\",\n      \"pmids\": [\"19393627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"E3 ubiquitin ligase Cbl directly binds STAP-2 through its PH and SH2-like domains and controls STAP-2 protein levels via ubiquitin-mediated degradation. Cbl siRNA restores STAP-2 levels; Cbl overexpression induces STAP-2 degradation. Cbl-mediated STAP-2 degradation reduces Brk/STAP-2-induced STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of Cbl, Cbl overexpression, STAT3 reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with domain mapping, siRNA and overexpression functional readout, single lab\",\n      \"pmids\": [\"19401194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"STAP-2 interacts with both Brk and STAT3, with its PH domain mediating Brk-STAP-2 binding and contributing to Brk activation and STAT3 tyrosine phosphorylation. STAP-2 knockdown in T47D breast cancer cells decreases Brk-mediated STAT3 activation and cell proliferation as strongly as Brk or STAT3 knockdown. A STAP-2 PH-Brk fusion protein exhibits robust kinase activity and enhanced STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, PH domain mutants, fusion protein kinase assays, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal approaches including domain mapping, fusion protein kinase assay, siRNA with cellular phenotype\",\n      \"pmids\": [\"20929863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STAP-2 promotes Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells via its PH domain. STAP-2 knockdown in T47D cells reduces proliferation equivalently to Brk or STAT5b knockdown.\",\n      \"method\": \"Ectopic expression, siRNA knockdown, STAT5 transcriptional activity assays, domain mutants, proliferation assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional readout with domain mapping, siRNA, single lab\",\n      \"pmids\": [\"21205088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STAP-2 binds BCR-ABL (and BCR and ABL proteins) through its SH2-like domain. BCR-ABL phosphorylates STAP-2 at Tyr250, and phosphorylated STAP-2 in turn upregulates BCR-ABL phosphorylation, enhancing downstream ERK, STAT5, BCL-xL, and BCL-2 signaling. STAP-2 interaction with BCR-ABL also downregulates CXCR4 and upregulates CCR7 expression, and confers growth advantage and imatinib resistance.\",\n      \"method\": \"Co-immunoprecipitation (SH2-like domain mapping), phosphorylation assays, siRNA knockdown in K562 cells, Ba/F3 mouse model, chemokine receptor expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding partners mapped, in vivo mouse model validation, imatinib resistance functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"22231445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STAP-2 interacts with EGFR and enhances EGFR stability by inhibiting c-CBL-mediated ubiquitination of EGFR. STAP-2 knockdown in DU145 prostate cancer cells reduces EGF-induced AKT, ERK, and STAT3 phosphorylation and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, EGFR ubiquitination assay, siRNA knockdown, in vivo xenograft tumor growth\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, ubiquitination assay, in vivo xenograft, multiple downstream signaling readouts\",\n      \"pmids\": [\"28986450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STAP-2 directly interacts with Pyk2 and increases Pyk2 phosphorylation. Pyk2 itself phosphorylates STAP-2 at Y250, and this phosphorylation is required for maximal STAP-2-Pyk2 interaction. STAP-2/Pyk2 interaction enhances SDF-1α-induced T-cell chemotaxis, which is inhibited by Pyk2 siRNA or the Pyk2 inhibitor AG17.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, siRNA knockdown of Pyk2, pharmacological inhibition (AG17), chemotaxis assay in Jurkat cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with phosphorylation mapping, siRNA and pharmacological inhibition with cellular functional readout\",\n      \"pmids\": [\"28478037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STAP-2 positively regulates FcεRI-mediated basophil activation: STAP-2-deficient bone marrow-derived basophils show reduced degranulation, cytokine production, and phosphorylation of Lyn, PLC-γ2, and Erk after IgE/Ag stimulation. STAP-2 KO mice show significantly reduced IgE-dependent chronic allergic inflammation.\",\n      \"method\": \"STAP-2 KO mouse-derived basophils, degranulation assay, cytokine ELISA, signaling phosphorylation assay, in vivo allergic inflammation model\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse primary cells, multiple signaling readouts, in vivo phenotype\",\n      \"pmids\": [\"30726917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STAP-2 positively regulates TCR signaling by associating with TCR-proximal CD3ζ ITAMs and phosphorylated LCK, enhancing their interaction after TCR stimulation. STAP-2-deficient T cells show reduced TCR-mediated signaling and IL-2 production, whereas STAP-2-overexpressing T cells show enhanced signaling. STAP-2 KO mice show reduced CD4+ T-cell-mediated inflammatory disease (EAE), while STAP-2 transgenic mice show severe EAE.\",\n      \"method\": \"Co-immunoprecipitation (CD3ζ ITAM and LCK binding), STAP-2 KO and transgenic mice, IL-2 production assay, EAE model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — binding partners mapped by co-IP, both KO and transgenic mouse models with defined in vivo inflammatory disease phenotype\",\n      \"pmids\": [\"35725273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STAP-2 negatively regulates BCR-mediated B cell signaling by recruiting CSK to LYN. STAP-2 directly binds LYN depending on STAP-2 Y250 phosphorylation by LYN. Phosphorylated STAP-2 enhances LYN-CSK interactions, promoting CSK-mediated phosphorylation of LYN Y508 (inhibitory site). STAP-2 KO B cells show reduced LYN Y508 phosphorylation and increased BCR signaling, cytokine, and antibody production.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays (Y250, LYN Y508), STAP-2 KO mouse B cells, cytokine and antibody production assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic co-IP with phosphorylation-dependent binding, KO mouse primary cells with defined signaling and functional readouts\",\n      \"pmids\": [\"37669828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A synthetic peptide derived from STAP-2 (iSP2) directly interacts with CD3ζ ITAM sequences and blocks STAP-2-CD3ζ interactions, suppressing TCR-induced T cell proliferation and IL-2 production in human and murine T cells. iSP2 also suppresses EAE in vivo.\",\n      \"method\": \"Peptide-ITAM binding assay, cell-penetrating peptide delivery, proliferation assay, IL-2 production, EAE model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct peptide-ITAM binding validation, functional cellular and in vivo readout\",\n      \"pmids\": [\"37417746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STAP-2 binds to CAP (c-Cbl-associated protein) through its C-terminal proline-rich region and bridges CAP and c-Cbl, enhancing their complex formation. This promotes GLUT4 translocation in response to insulin. STAP-2 expression is upregulated during adipocyte differentiation; STAP-2 overexpression promotes adipogenesis of 3T3-L1 cells and MEFs, while STAP-2 KO MEFs show suppressed adipogenesis. STAP-2 KO mice gain less weight on a high-fat diet.\",\n      \"method\": \"Co-immunoprecipitation (proline-rich region mapping), GLUT4 translocation assay, retroviral overexpression, STAP-2 KO mouse MEFs and in vivo high-fat diet\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with domain mapping, functional assay (GLUT4 translocation), KO and overexpression in cells plus in vivo mouse phenotype\",\n      \"pmids\": [\"38461189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STAP-2 interacts with HSP27 (identified by co-immunoprecipitation and mass spectrometry) and modulates the PI3K/AKT signaling pathway in renal fibrosis. STAP-2 KO in vivo reduces EMT, inflammatory cell infiltration, and collagen deposition in renal fibrosis models; STAP-2 overexpression in vitro exacerbates fibrosis markers. STAP-2 affects phosphorylated HSP27 levels.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RNA-seq, STAP-2 KO mice (IRI and cisplatin models), STAP-2 overexpression in vitro, fibrosis marker quantification\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — MS-identified interaction with co-IP, KO in vivo phenotype, single lab\",\n      \"pmids\": [\"39533293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KGF-2 inhibits STAP-2 expression and consequently reduces STAT3 activation, leading to decreased collagen I and collagen III levels in fibroblasts and reduced hypertrophic scar formation both in vitro and in vivo.\",\n      \"method\": \"STAP-2 expression modulation, STAT3 phosphorylation assay, collagen expression analysis, in vivo scar model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic pathway (KGF-2→STAP-2→STAT3→collagen) supported by expression modulation and functional readout, single lab\",\n      \"pmids\": [\"34999107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A STAP-2-derived peptide (2D5) blocks STAP-2-EGFR interactions and suppresses EGFR-mediated proliferation, EGFR stability, and signaling in cancer cell lines and murine xenograft models of prostate and lung cancer.\",\n      \"method\": \"Peptide competition assay, EGFR signaling assays, cell proliferation assay, in vivo xenograft model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct blocking of protein-protein interaction with functional in vitro and in vivo readouts\",\n      \"pmids\": [\"36410436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCR7 upregulation by STAP-2/BCR-ABL is mediated through the MAPK/ERK pathway. STAP-2 cooperates with BCR-ABL to induce CCR7 ligand (CCL19, CCL21) production, and CCR7 contributes to STAP-2-dependent enhancement of BCR-ABL-mediated cell growth in Ba/F3 cells.\",\n      \"method\": \"Chemokine receptor expression analysis, ERK pathway inhibition, CCL19/CCL21 ELISA, cell growth assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement by pharmacological inhibition and expression analysis, single lab\",\n      \"pmids\": [\"26102025\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STAP-2 is an adaptor protein containing PH, SH2-like, and proline-rich domains that acts as a scaffold to modulate multiple signaling pathways in immune and cancer cells: it enhances STAT3 activity via its YXXQ motif (direct STAT3 binding), suppresses STAT5 via PH/SH2-like domain binding, is phosphorylated at Y250 by Brk, Jak2, Pyk2, LYN, and BCR-ABL to regulate downstream signaling, negatively regulates FcεRI/PLC-γ signaling in mast cells, inhibits c-Fms/M-CSF receptor and NF-κB signaling in macrophages, positively regulates TCR signaling by bridging CD3ζ ITAMs with LCK, negatively regulates BCR signaling by recruiting CSK to LYN, promotes EGFR stability by blocking c-CBL-mediated ubiquitination, and facilitates insulin signaling by forming a CAP/STAP-2/c-Cbl ternary complex to promote GLUT4 translocation and adipogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"STAP2 is a multidomain adaptor/scaffold protein that integrates and tunes signaling downstream of diverse receptors in immune, cancer, and metabolic cells. Its PH domain, SH2-like domain, YXXQ motif, and C-terminal proline-rich region each mediate distinct protein–protein interactions: the YXXQ motif directly binds and sustains STAT3 activation during cytokine signaling, while the PH and SH2-like domains engage STAT5, c-Fms, LMP1/TRAF3/TRADD, EGFR, BCR-ABL, and the Src-family kinase LYN, enabling context-dependent positive or negative regulation of JAK-STAT, NF-κB, MAPK/ERK, and PI3K/AKT pathways [PMID:12540842, PMID:15611091, PMID:18573890, PMID:28986450, PMID:22231445, PMID:37669828]. Phosphorylation of STAP2 at Tyr250 by kinases including Brk, Jak2, Pyk2, LYN, and BCR-ABL is a convergent regulatory switch that controls its scaffolding activity—enabling STAT3 enhancement, Brk activation in breast cancer, BCR-ABL amplification in CML, and CSK-mediated negative regulation of LYN in B cells [PMID:17368569, PMID:19393627, PMID:20929863, PMID:37669828]. In T cells STAP2 bridges CD3ζ ITAMs with LCK to promote proximal TCR signaling and inflammatory responses, whereas in B cells it recruits CSK to LYN to dampen BCR signaling; in adipocytes it forms a CAP/STAP2/c-Cbl complex that facilitates insulin-stimulated GLUT4 translocation and adipogenesis [PMID:35725273, PMID:37669828, PMID:38461189].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of STAP-2 as an adaptor protein with PH, SH2-like, and YXXQ domains resolved how late-phase IL-6/STAT3 signaling is sustained in hepatocytes, establishing STAP-2 as a STAT3-enhancing scaffold.\",\n      \"evidence\": \"STAP-2 KO mouse hepatocytes, YXXQ mutagenesis, reporter assays\",\n      \"pmids\": [\"12540842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of YXXQ–STAT3 interaction unresolved\", \"Upstream signals controlling STAP-2 expression unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that STAP-2 associates with PLC-γ and suppresses FcεRI-mediated degranulation in mast cells revealed its first negative regulatory role, showing domain versatility beyond STAT3 enhancement.\",\n      \"evidence\": \"Co-IP and calcium/degranulation assays in RBL-2H3 mast cells\",\n      \"pmids\": [\"12810085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STAP-2 KO mast cell validation not performed\", \"Mechanism by which STAP-2 selectively suppresses PLC-γ but not Syk phosphorylation unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that STAP-2 binds STAT5 via PH/SH2-like domains and suppresses STAT5 activation established that STAP-2 exerts opposing effects on STAT3 (positive) and STAT5 (negative) through distinct domain interfaces.\",\n      \"evidence\": \"Reciprocal co-IP, domain mutagenesis, STAP-2 KO thymocytes with IL-2-dependent growth\",\n      \"pmids\": [\"15611091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation-dependent dissociation of STAP-2–STAT5 is regulated in different cell types unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of Tyr250 as a phosphorylation site targeted by v-Src/Jak2, required for STAT3-enhancing activity, established a central regulatory switch for STAP-2 scaffold function.\",\n      \"evidence\": \"Phospho-specific pY250 antibody, Y250F mutagenesis, LIF stimulation in multiple cell lines\",\n      \"pmids\": [\"17368569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase hierarchy at Y250 in physiological settings undetermined\", \"Phosphatase(s) that reverse Y250 phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing that STAP-2 PH domain binds c-Fms and suppresses M-CSF-mediated macrophage signaling and migration extended STAP-2's negative regulatory role to receptor tyrosine kinase signaling in macrophages.\",\n      \"evidence\": \"Co-IP with PH domain mapping, signaling assays, wound-healing in Raw 264.7; later confirmed in KO macrophages (2008)\",\n      \"pmids\": [\"17512498\", \"18758078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect mechanism of c-Fms phosphorylation suppression not fully dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that STAP-2 binds LMP1 and suppresses both canonical and non-canonical NF-κB signaling via TRAF3/TRADD expanded STAP-2's scope to viral oncogene signaling control.\",\n      \"evidence\": \"Co-IP, domain mapping, NF-κB reporters, STAP-2 KO MEFs\",\n      \"pmids\": [\"18573890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to EBV-associated lymphomagenesis in vivo not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that Brk phosphorylates STAP-2 at Y250 and that STAP-2 in turn scaffolds Brk–STAT3 activation linked STAP-2 to breast cancer proliferation, with c-Cbl-mediated ubiquitination of STAP-2 providing a degradation-based counter-regulation.\",\n      \"evidence\": \"Phospho-specific antibody, siRNA, domain mutants, Cbl overexpression/siRNA, T47D proliferation assays\",\n      \"pmids\": [\"19393627\", \"19401194\", \"20929863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether c-Cbl ubiquitination is K48-linked (proteasomal) not confirmed\", \"In vivo breast cancer model lacking\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Finding that STAP-2 also scaffolds Brk-mediated STAT5 activation in breast cancer cells revealed that STAP-2's effect on STAT5 is context-dependent—suppressive in thymocytes but activating when bridging Brk in cancer.\",\n      \"evidence\": \"Ectopic expression, siRNA, STAT5 transcriptional activity, T47D proliferation\",\n      \"pmids\": [\"21205088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for context-dependent STAT5 outcome not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of a reciprocal activating loop between STAP-2 and BCR-ABL—BCR-ABL phosphorylates Y250, phospho-STAP-2 enhances BCR-ABL activity—provided a mechanistic basis for STAP-2's role in CML progression and imatinib resistance.\",\n      \"evidence\": \"Co-IP (SH2-like domain mapping), K562 siRNA, Ba/F3 mouse model, chemokine receptor analysis\",\n      \"pmids\": [\"22231445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Patient-derived CML validation limited\", \"Whether STAP-2 directly affects imatinib binding or acts indirectly unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that STAP-2 stabilizes EGFR by blocking c-CBL-mediated ubiquitination, and that Pyk2 phosphorylates STAP-2 Y250 to promote T-cell chemotaxis, broadened STAP-2's receptor repertoire and identified a new upstream kinase.\",\n      \"evidence\": \"Co-IP, EGFR ubiquitination assays, xenograft (EGFR); Pyk2 phosphorylation, siRNA, chemotaxis assay (Pyk2)\",\n      \"pmids\": [\"28986450\", \"28478037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STAP-2 competition with c-CBL for EGFR binding not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"STAP-2 was established as a positive regulator of proximal TCR signaling by bridging CD3ζ ITAMs with LCK, with KO and transgenic mice showing reciprocal effects on EAE severity, directly demonstrating STAP-2's role in adaptive T-cell immunity.\",\n      \"evidence\": \"Co-IP of CD3ζ/LCK, STAP-2 KO and transgenic mice, IL-2 production, EAE model\",\n      \"pmids\": [\"35725273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAP-2 binds phosphorylated or unphosphorylated ITAMs preferentially not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Therapeutic proof-of-concept peptides (2D5 blocking EGFR and iSP2 blocking CD3ζ binding) validated STAP-2 protein–protein interfaces as druggable nodes.\",\n      \"evidence\": \"Peptide competition, xenograft tumor suppression (2D5); peptide-ITAM binding, T-cell proliferation suppression, EAE suppression (iSP2)\",\n      \"pmids\": [\"36410436\", \"37417746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide pharmacokinetics, selectivity, and off-target effects not characterized\", \"Efficacy in non-murine models untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that STAP-2 recruits CSK to LYN in a Y250-phosphorylation-dependent manner, promoting inhibitory LYN Y508 phosphorylation to dampen BCR signaling, resolved STAP-2's role as a negative regulator of B-cell activation.\",\n      \"evidence\": \"Co-IP with phospho-dependent binding, KO B cells with signaling and antibody production readouts\",\n      \"pmids\": [\"37669828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAP-2 similarly regulates other Src-family kinases in B cells unknown\", \"In vivo humoral immune response phenotype not fully characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of STAP-2 as a bridge between CAP and c-Cbl that promotes GLUT4 translocation and adipogenesis revealed a metabolic function independent of immune signaling.\",\n      \"evidence\": \"Co-IP (proline-rich region), GLUT4 translocation assay, KO MEFs, KO mice on high-fat diet\",\n      \"pmids\": [\"38461189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAP-2 affects insulin receptor phosphorylation directly or acts solely at the CAP/c-Cbl node unclear\", \"Tissue-specific contributions (adipose vs. muscle) not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"STAP-2 interaction with HSP27 and modulation of PI3K/AKT signaling in renal fibrosis suggested a role in tissue injury/repair beyond immune cells.\",\n      \"evidence\": \"Co-IP/MS identification of HSP27, STAP-2 KO mice in IRI and cisplatin renal injury models\",\n      \"pmids\": [\"39533293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of STAP-2–HSP27 interaction not mechanistically resolved\", \"Renal fibrosis findings from single lab, awaits independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structural information exists for STAP-2 or its complexes, the phosphatase(s) reversing Y250 phosphorylation are unknown, and the molecular rules determining whether STAP-2 activates or suppresses a given pathway in different cell types remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of any STAP-2 domain or complex\", \"Identity of Y250-targeting phosphatase(s) unknown\", \"Context-dependent signaling logic (activating vs. suppressive) lacks a unifying mechanistic model\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 9, 11, 12, 15, 16, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [15, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6, 7, 9, 11, 12, 15, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 14, 15, 16, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 22]}\n    ],\n    \"complexes\": [\n      \"CAP/STAP-2/c-Cbl ternary complex\",\n      \"STAP-2/Brk/STAT3 signaling complex\"\n    ],\n    \"partners\": [\n      \"STAT3\",\n      \"STAT5\",\n      \"BRK\",\n      \"LYN\",\n      \"CSK\",\n      \"BCR-ABL\",\n      \"EGFR\",\n      \"CBL\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}