{"gene":"STAP2","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2003,"finding":"STAP-2/BKS was identified as a novel adaptor protein containing PH and SH2-like domains and a YXXQ motif. It is tyrosine-phosphorylated and translocates to the plasma membrane in response to EGF. In STAP-2 knockout 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, establishing the YXXQ motif as the STAT3-binding element responsible for STAP-2's modulatory function.","method":"Knockout mouse generation, IL-6 stimulation of hepatocytes, reporter assays, co-immunoprecipitation, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional validation with KO mice, mutagenesis of YXXQ motif, and reporter assays in two orthogonal systems","pmids":["12540842"],"is_preprint":false},{"year":2004,"finding":"STAP-2/BKS directly binds STAT5 through its PH and SH2-like domains interacting with the C-terminal region of STAT5. STAP-2/BKS and STAT5 constitutively co-localize in the cytoplasm of resting cells, but STAP-2/BKS dissociates upon STAT5 phosphorylation. Overexpression of STAP-2/BKS diminished cytokine-induced STAT5 tyrosine phosphorylation and transcriptional activation. STAP-2-deficient thymocytes showed enhanced IL-2-dependent cell growth.","method":"Co-immunoprecipitation, intracellular staining, domain-deletion mutational analysis, STAP-2 KO mouse thymocyte proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, and KO mouse phenotype across multiple orthogonal methods","pmids":["15611091"],"is_preprint":false},{"year":2003,"finding":"STAP-2/BKS overexpression in RBL-2H3 mast cells suppresses FcεRI-mediated calcium mobilization and degranulation. STAP-2/BKS associates with PLC-γ in vivo and significantly suppresses FcεRI-induced tyrosine phosphorylation of PLC-γ (but not Syk), establishing STAP-2 as a negative regulator of FcεRI signaling upstream of PLC-γ.","method":"Overexpression in RBL-2H3 cells, co-immunoprecipitation, calcium flux assay, degranulation assay, phosphotyrosine immunoblotting","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional assays (calcium, degranulation) in a single lab with multiple orthogonal methods","pmids":["12810085"],"is_preprint":false},{"year":2008,"finding":"STAP-2 negatively regulates EBV LMP1-mediated NF-κB signaling. STAP-2 associates with LMP1 through its PH and SH2-like domains and interacts with TRAF3 and TRADD. STAP-2 knockout mouse embryonic fibroblasts showed enhanced LMP1-induced cell growth. STAP-2 overexpression in EBV-positive human B cells decreased cell growth.","method":"Co-immunoprecipitation, overexpression in EBV+ B cells, STAP-2 KO MEFs, NF-κB reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping by Co-IP, KO MEF phenotype, and overexpression in human B cells with NF-κB reporters across multiple orthogonal methods","pmids":["18573890"],"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 in Raw 264.7 macrophages markedly suppressed M-CSF-induced tyrosine phosphorylation of c-Fms and activation of Akt and ERK, and impaired M-CSF-induced macrophage migration and wound healing.","method":"Co-immunoprecipitation with domain mapping, overexpression in Raw 264.7 cells, Akt/ERK phosphorylation assay, wound-healing migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific Co-IP plus functional signaling and migration assays in a single lab","pmids":["17512498"],"is_preprint":false},{"year":2008,"finding":"Loss of STAP-2 in bone marrow-derived macrophages from STAP-2 knockout mice results in markedly enhanced c-Fms/M-CSF receptor signaling (ERK and Akt activation) and enhanced wound-healing/migration process, confirming STAP-2 as an endogenous negative regulator of M-CSF receptor signaling in primary macrophages.","method":"STAP-2 KO mouse-derived bone marrow macrophages, M-CSF stimulation, ERK/Akt phosphorylation assay, wound-healing assay","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary KO macrophage validation of signaling and migration phenotype, single lab","pmids":["18758078"],"is_preprint":false},{"year":2007,"finding":"STAP-2 Tyr250 is a major phosphorylation site by v-Src and Jak2, identified using a phospho-specific anti-pTyr250 antibody and mutagenesis. Tyr250 phosphorylation is required for STAP-2's STAT3-enhancing activity. Endogenous STAP-2 is phosphorylated at Tyr250 following LIF stimulation in 293T, Hep3B, and murine M1 cells.","method":"Site-directed mutagenesis (Y250F), phospho-specific antibody, kinase assay, LIF stimulation of cell lines including M1 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — phospho-specific antibody with mutagenesis and endogenous validation, single lab","pmids":["17368569"],"is_preprint":false},{"year":2009,"finding":"STAP-2 Tyr250 is phosphorylated by Brk (breast tumor kinase), identified using a series of YF mutants and an anti-phospho-STAP-2 Tyr250 antibody. A STAP-2 Y250F mutant impaired Brk-mediated STAT3 activation. siRNA-mediated knockdown of endogenous STAP-2 decreased Brk-mediated STAT3 activation.","method":"Site-directed mutagenesis (YF series), phospho-specific antibody, in vitro/cell-based kinase assay with Brk, siRNA knockdown, STAT3 activation reporter/immunoblot","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phospho-site mapping by mutagenesis panel plus phospho-specific antibody, validated by both overexpression and siRNA knockdown","pmids":["19393627"],"is_preprint":false},{"year":2009,"finding":"E3 ubiquitin ligase Cbl directly controls STAP-2 protein levels. STAP-2 physically interacts with Cbl through its PH and SH2-like domains. siRNA knockdown of endogenous Cbl restored STAP-2 protein levels; overexpression of Cbl induced STAP-2 degradation. Cbl-mediated regulation of STAP-2 protein levels affected Brk/STAP-2-induced STAT3 activation.","method":"Co-immunoprecipitation with domain mapping, siRNA knockdown of Cbl, Cbl overexpression, immunoblot for STAP-2 protein levels, STAT3 activation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function for Cbl plus Co-IP domain mapping, single lab","pmids":["19401194"],"is_preprint":false},{"year":2010,"finding":"STAP-2 interacts with both Brk and STAT3 in breast cancer cells. The PH domain of STAP-2 is required for Brk-STAP-2 binding, Brk kinase activation, and STAT3 tyrosine phosphorylation. A STAP-2 PH-Brk fusion protein exhibited robust kinase activity and enhanced STAT3 activation. siRNA knockdown of STAP-2 in T47D cells decreased Brk-mediated STAT3 activation and strongly reduced proliferation.","method":"Co-immunoprecipitation, domain deletion/fusion constructs, siRNA knockdown, STAT3 phosphorylation assay, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping, fusion protein kinase activity assay, and siRNA knockdown phenotype in breast cancer cells with multiple orthogonal methods","pmids":["20929863"],"is_preprint":false},{"year":2011,"finding":"STAP-2 is involved in Brk-mediated STAT5 activation in breast cancer cells. The PH domain of STAP-2 participates in Brk-mediated phosphorylation of STAT5. STAP-2 knockdown in T47D cells reduced proliferation as strongly as Brk or STAT5b knockdown.","method":"Ectopic expression, domain analysis, STAT5 transcriptional activity assay, siRNA knockdown, cell proliferation assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain analysis plus siRNA functional phenotype in breast cancer cells, single lab","pmids":["21205088"],"is_preprint":false},{"year":2012,"finding":"STAP-2 binds to BCR-ABL, BCR, and ABL proteins via its SH2-like domain. BCR-ABL phosphorylates STAP-2 at Tyr250, and phosphorylated STAP-2 in turn upregulates BCR-ABL phosphorylation and downstream ERK, STAT5, BCL-xL, and BCL-2 activation. STAP-2 interaction with BCR-ABL also alters chemokine receptor expression (down-regulates CXCR4, up-regulates CCR7). STAP-2 knockdown in K562 CML cells abolished tumor formation in mice.","method":"Co-immunoprecipitation with domain mapping, phosphorylation assays, signaling pathway immunoblots, siRNA knockdown, in vivo xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific Co-IP, phospho-site validation, downstream signaling readouts, and in vivo tumor model with knockdown","pmids":["22231445"],"is_preprint":false},{"year":2017,"finding":"STAP-2 interacts with EGFR and enhances EGFR stability by inhibiting c-CBL-mediated EGFR ubiquitination. STAP-2 knockdown in DU145 prostate cancer cells reduced EGF-induced phosphorylation of AKT, ERK, and STAT3, and strongly decreased tumor growth.","method":"Co-immunoprecipitation, EGFR ubiquitination assay, STAP-2 siRNA knockdown, signaling phosphorylation assays, in vivo tumor growth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, siRNA knockdown with multiple signaling readouts, and in vivo tumor model","pmids":["28986450"],"is_preprint":false},{"year":2017,"finding":"STAP-2 directly interacts with Pyk2 in T cells, increasing Pyk2 phosphorylation. Pyk2 itself phosphorylates STAP-2 at Y250, and this phosphorylation is critical for maximal STAP-2–Pyk2 interactions. STAP-2-enhanced SDF-1α-induced T-cell chemotaxis is inhibited by Pyk2 siRNA or the Pyk2 inhibitor AG17.","method":"Co-immunoprecipitation, phosphorylation assay, siRNA knockdown of Pyk2, pharmacological inhibition with AG17, T-cell chemotaxis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus kinase-substrate evidence and functional chemotaxis assay with siRNA and inhibitor, single lab","pmids":["28478037"],"is_preprint":false},{"year":2019,"finding":"STAP-2 positively regulates FcεRI-mediated basophil activation. STAP-2-deficient bone marrow-derived basophils showed reduced degranulation, cytokine production, and reduced phosphorylation of Lyn, PLC-γ2, and ERK after IgE/Ag stimulation. STAP-2-deficient mice showed significantly inhibited IgE-dependent chronic allergic inflammation in vivo.","method":"STAP-2 KO mouse-derived basophil culture, degranulation assay, cytokine ELISA, phosphorylation immunoblot, in vivo allergic inflammation model","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — primary KO basophils with multiple signaling and functional readouts plus in vivo allergic inflammation model","pmids":["30726917"],"is_preprint":false},{"year":2022,"finding":"STAP-2 positively regulates TCR signaling by associating with TCR-proximal CD3ζ ITAMs and phosphorylated LCK. STAP-2-deficient T cells showed reduced TCR-mediated signaling and IL-2 production; STAP-2-overexpressing T cells showed enhanced signaling. STAP-2-deficient mice exhibited reduced CD4+ T-cell-mediated EAE disease severity, while STAP-2-overexpressing transgenic mice showed severe EAE.","method":"Co-immunoprecipitation (STAP-2 with CD3ζ ITAM and LCK), STAP-2 KO and transgenic mouse T-cell assays, IL-2 production, TCR signaling phosphorylation, EAE model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal KO and transgenic mouse phenotypes, Co-IP of TCR complex components, and multiple orthogonal functional readouts","pmids":["35725273"],"is_preprint":false},{"year":2022,"finding":"KGF-2 inhibits STAP-2 expression and STAT3 activation in fibroblasts, leading to reduced collagen I and collagen III levels and attenuated scar formation. This places STAP-2 downstream of KGF-2 signaling and upstream of STAT3-mediated collagen production in skin fibroblasts.","method":"KGF-2 treatment of fibroblasts and in vivo scar model, STAP-2 expression measurement, STAT3 activation assay, collagen I/III quantification","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional data linking KGF-2–STAP-2–STAT3–collagen axis, single lab","pmids":["34999107"],"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 dependently on STAP-2 Y250 phosphorylation by LYN. Phosphorylated STAP-2 enhances interactions between LYN and CSK, resulting in enhanced CSK-mediated LYN Y508 phosphorylation (inhibitory). STAP-2 KO B cells showed increased LYN activity, BCR-mediated signals, cytokine production, and antibody production.","method":"STAP-2 KO mouse B cells, Co-immunoprecipitation, Y250F mutant analysis, LYN Y508 phosphorylation immunoblot, cytokine and antibody production assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse primary B cells, domain/phospho-site mutagenesis, mechanistic Co-IP of CSK-LYN complex, and multiple functional readouts","pmids":["37669828"],"is_preprint":false},{"year":2023,"finding":"A STAP-2-derived synthetic peptide (iSP2) directly interacts with CD3ζ ITAM sequences and blocks STAP-2–CD3ζ interactions, suppressing T cell proliferation and TCR-induced IL-2 production in human and murine T cells, and inhibiting TCR-mediated EAE in vivo.","method":"Peptide binding assay, Co-IP blocking experiment, T-cell proliferation assay, IL-2 production, in vivo EAE model with cell-penetrating peptide","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct peptide-ITAM interaction assay plus functional T-cell and in vivo validation, single lab","pmids":["37417746"],"is_preprint":false},{"year":2024,"finding":"STAP-2 binds to CAP (c-Cbl associated protein) through its C-terminal proline-rich region, bridges CAP and c-Cbl to enhance their complex formation, and facilitates GLUT4 translocation after insulin treatment. STAP-2 KO MEFs showed suppressed adipogenesis, and STAP-2 KO mice showed reduced weight gain on a high-fat diet.","method":"Co-immunoprecipitation, domain mapping (proline-rich region), GLUT4 translocation assay in Hep3B cells, STAP-2 KO MEF adipogenesis assay, in vivo high-fat diet model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, functional GLUT4 translocation assay, and KO phenotype in cells and mice, single lab","pmids":["38461189"],"is_preprint":false},{"year":2024,"finding":"STAP2 promotes renal fibrosis. STAP2 knockout in mice mitigated EMT, reduced inflammatory cell infiltration, and reduced collagen deposition in renal fibrosis models. Mechanistically, STAP2 interacts with HSP27 (identified by co-immunoprecipitation and mass spectrometry) and modulates the PI3K/AKT signaling pathway.","method":"STAP2 KO mouse fibrosis models (IRI and cisplatin), co-immunoprecipitation, mass spectrometry, RNA-seq, STAP2 overexpression in cells, fibrosis marker quantification","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype in two in vivo models, Co-IP/MS identification of HSP27 partner, single lab","pmids":["39533293"],"is_preprint":false},{"year":2022,"finding":"A STAP-2-derived peptide (2D5) blocks STAP-2–EGFR interactions and suppresses EGFR-mediated proliferation in prostate and lung cancer cell lines, and inhibits tumor growth of DU145 and A549 xenografts, confirming that the STAP-2–EGFR interaction is required for full EGFR signaling and stability.","method":"STAP-2-derived peptide competitive inhibition assay, cell proliferation assay, EGFR stability/signaling immunoblot, murine xenograft model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide-based interaction block with functional validation in cells and in vivo xenografts, single lab","pmids":["36410436"],"is_preprint":false},{"year":2015,"finding":"STAP-2 cooperates with BCR-ABL to upregulate CCR7 expression in Ba/F3 hematopoietic cells via the MAPK/ERK pathway. STAP-2 and BCR-ABL together induce production of CCR7 ligands CCL19 and CCL21, contributing to cell growth.","method":"BCR-ABL/STAP-2 co-expression in Ba/F3 cells, ERK pathway inhibitor studies, CCR7/CCL19/CCL21 expression assays, cell growth assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression system with pharmacological inhibitor, single lab, single cell line","pmids":["26102025"],"is_preprint":false}],"current_model":"STAP-2 (also known as BKS) is an adaptor protein with PH and SH2-like domains and a C-terminal YXXQ/proline-rich region that scaffolds and modulates multiple signaling pathways: it enhances STAT3 activation via its YXXQ motif (acting as a STAT3-docking site), suppresses STAT5 by binding its C-terminal region in resting cells, is phosphorylated at Tyr250 by kinases including Brk, Jak2, v-Src, Pyk2, LYN, and BCR-ABL, and this phosphorylation event regulates its protein-protein interactions; it negatively regulates FcεRI (in mast cells) and M-CSF receptor (c-Fms) signaling, positively regulates BCR-ABL, Brk-STAT3/STAT5, TCR-proximal signaling (by recruiting to CD3ζ ITAMs and LCK), and FcεRI-mediated basophil activation (via Lyn/PLC-γ2/ERK); it suppresses BCR signaling by facilitating CSK-mediated inhibitory phosphorylation of LYN Y508; it promotes EGFR stability by blocking c-CBL-mediated ubiquitination; it facilitates insulin signaling by bridging CAP and c-Cbl to enhance GLUT4 translocation; and its protein levels are regulated by E3 ubiquitin ligase Cbl-mediated degradation."},"narrative":{"mechanistic_narrative":"STAP-2/BKS is a cytoplasmic adaptor protein, built from a PH domain, an SH2-like domain, and a C-terminal YXXQ/proline-rich region, that scaffolds and tunes the output of multiple receptor and kinase signaling pathways rather than carrying intrinsic catalytic activity [PMID:12540842, PMID:15611091]. Its most conserved scaffolding function is modulation of STAT transcription factors: the YXXQ motif acts as a STAT3-docking site that enhances IL-6/LIF-induced STAT3 activation and acute-phase gene expression [PMID:12540842], while direct binding of its PH and SH2-like domains to the C-terminal region of STAT5 suppresses STAT5 activation in resting cells and dissociates upon STAT5 phosphorylation [PMID:15611091]. STAP-2 function is gated by phosphorylation of a single tyrosine, Tyr250, which is targeted by diverse kinases — v-Src and Jak2, Brk, BCR-ABL, Pyk2, and LYN — and is required for its STAT3-enhancing and partner-binding activities [PMID:17368569, PMID:19393627, PMID:22231445, PMID:28478037, PMID:37669828]. Through these interactions STAP-2 acts as a context-dependent positive or negative regulator: it promotes oncogenic Brk-STAT3/STAT5 signaling and proliferation in breast cancer [PMID:20929863, PMID:21205088], potentiates BCR-ABL signaling and tumor formation in CML [PMID:22231445], stabilizes EGFR by blocking c-CBL-mediated ubiquitination to sustain AKT/ERK/STAT3 signaling and tumor growth [PMID:28986450], and conversely restrains FcεRI signaling in mast cells [PMID:12810085], M-CSF receptor signaling in macrophages [PMID:17512498, PMID:18758078], and BCR signaling in B cells by recruiting CSK to LYN to enforce inhibitory LYN Y508 phosphorylation [PMID:37669828]. In T cells STAP-2 binds CD3ζ ITAMs and phosphorylated LCK to amplify TCR-proximal signaling and IL-2 production, shaping CD4+ T-cell-mediated autoimmune disease in vivo [PMID:35725273]. STAP-2 also bridges CAP and c-Cbl to facilitate insulin-induced GLUT4 translocation and adipogenesis [PMID:38461189], and its own abundance is controlled by Cbl-mediated degradation [PMID:19401194].","teleology":[{"year":2003,"claim":"Established STAP-2 as an adaptor that enhances STAT3 signaling through a defined YXXQ docking motif, answering how this novel PH/SH2-like protein modulates cytokine responses.","evidence":"Knockout hepatocytes with IL-6 stimulation, YXXQ mutagenesis, and acute-phase reporter assays","pmids":["12540842"],"confidence":"High","gaps":["Structural basis of YXXQ–STAT3 docking not resolved","Did not address STAP-2 effects on other STAT family members"]},{"year":2003,"claim":"Showed STAP-2 also acts as a negative regulator in a distinct receptor context, suppressing FcεRI-mediated mast cell activation upstream of PLC-γ.","evidence":"Overexpression in RBL-2H3 mast cells with calcium flux, degranulation, and PLC-γ Co-IP/phosphorylation assays","pmids":["12810085"],"confidence":"Medium","gaps":["Based on overexpression rather than endogenous loss-of-function","Mechanism of PLC-γ suppression not defined"]},{"year":2004,"claim":"Defined an opposing STAT-modulating role: STAP-2 binds and suppresses STAT5, establishing it as a bidirectional STAT regulator depending on the family member.","evidence":"Reciprocal Co-IP, domain-deletion mapping, co-localization in resting cells, and KO thymocyte proliferation","pmids":["15611091"],"confidence":"High","gaps":["How STAP-2 discriminates STAT3 versus STAT5 outcomes unresolved","Cytokine specificity of STAT5 suppression not mapped"]},{"year":2007,"claim":"Extended STAP-2's negative regulatory function to the M-CSF receptor, showing direct PH-domain binding to c-Fms dampens receptor signaling and macrophage migration.","evidence":"Domain-mapped Co-IP and overexpression in Raw 264.7 macrophages with Akt/ERK and wound-healing assays","pmids":["17512498"],"confidence":"Medium","gaps":["Overexpression-based; endogenous role addressed only in later work"]},{"year":2007,"claim":"Identified Tyr250 as the major regulatory phosphosite (by v-Src and Jak2) required for STAP-2's STAT3-enhancing activity, providing the switch that gates adaptor function.","evidence":"Y250F mutagenesis, phospho-specific antibody, kinase assays, and endogenous LIF-induced phosphorylation in multiple lines","pmids":["17368569"],"confidence":"Medium","gaps":["Single lab","Which interactions are gained or lost upon Tyr250 phosphorylation not comprehensively mapped"]},{"year":2008,"claim":"Confirmed endogenous negative regulation of M-CSF receptor signaling in primary cells and revealed a parallel role in restraining EBV LMP1/NF-κB signaling via TRAF3/TRADD.","evidence":"KO bone marrow macrophages with M-CSF stimulation; KO MEFs and EBV+ B cells with NF-κB reporters and LMP1 Co-IP","pmids":["18758078","18573890"],"confidence":"High","gaps":["Mechanism by which STAP-2 inhibits LMP1/TRAF3 signaling not detailed"]},{"year":2009,"claim":"Connected STAP-2 to the oncogenic Brk kinase by mapping Tyr250 as a Brk substrate site required for Brk-driven STAT3 activation, and showed Cbl controls STAP-2 abundance.","evidence":"YF mutant panel, phospho-specific antibody, Brk kinase assays, siRNA knockdown; reciprocal Cbl gain/loss-of-function with domain-mapped Co-IP","pmids":["19393627","19401194"],"confidence":"High","gaps":["Whether Cbl ubiquitinates STAP-2 directly versus indirectly not established"]},{"year":2010,"claim":"Established STAP-2 as a required cofactor for Brk-STAT3 signaling and proliferation in breast cancer, with the PH domain driving Brk activation, then extended this to Brk-STAT5.","evidence":"Domain deletion/fusion constructs, PH-Brk fusion kinase activity, siRNA knockdown and proliferation assays in T47D cells; STAT5 transcriptional and proliferation readouts","pmids":["20929863","21205088"],"confidence":"High","gaps":["Structural mechanism of PH-domain-mediated Brk activation unresolved"]},{"year":2012,"claim":"Demonstrated a feed-forward oncogenic loop in CML where STAP-2 binds BCR-ABL via its SH2-like domain, is phosphorylated at Tyr250, and amplifies BCR-ABL and downstream survival signaling required for tumor formation.","evidence":"Domain-mapped Co-IP, phospho-site analysis, downstream signaling immunoblots, siRNA knockdown, and K562 xenografts","pmids":["22231445"],"confidence":"High","gaps":["Mechanism of reciprocal BCR-ABL phosphorylation enhancement not detailed"]},{"year":2015,"claim":"Linked the STAP-2/BCR-ABL axis to chemokine signaling by showing cooperative CCR7/CCL19/CCL21 induction via ERK contributes to growth.","evidence":"BCR-ABL/STAP-2 co-expression in Ba/F3 cells with ERK inhibitors and chemokine expression assays","pmids":["26102025"],"confidence":"Low","gaps":["Overexpression in a single cell line without endogenous validation","Causal role of CCR7 axis in vivo not tested"]},{"year":2017,"claim":"Revealed a stabilizing role for STAP-2 in EGFR-driven cancer by antagonizing c-CBL-mediated EGFR ubiquitination, and identified Pyk2 as another Tyr250 kinase coupling STAP-2 to T-cell chemotaxis.","evidence":"EGFR Co-IP/ubiquitination assays and siRNA knockdown with tumor model in DU145; Pyk2 Co-IP, knockdown, AG17 inhibition, and SDF-1α chemotaxis","pmids":["28986450","28478037"],"confidence":"High","gaps":["Whether STAP-2 sterically blocks CBL or competes for EGFR not defined","Pyk2 work is single-lab Medium confidence"]},{"year":2019,"claim":"Showed STAP-2 can be a positive regulator of innate effector signaling, promoting FcεRI-mediated basophil activation via Lyn/PLC-γ2/ERK and driving chronic allergic inflammation.","evidence":"KO basophils with degranulation, cytokine, and phosphorylation readouts plus in vivo allergic inflammation model","pmids":["30726917"],"confidence":"High","gaps":["Contrast with negative FcεRI regulation in mast cells not mechanistically reconciled"]},{"year":2022,"claim":"Established STAP-2 as a positive amplifier of TCR-proximal signaling by binding CD3ζ ITAMs and phospho-LCK, with reciprocal KO/transgenic mice defining its role in CD4+ T-cell autoimmunity, and validated the interaction as druggable with the iSP2 peptide.","evidence":"Co-IP of CD3ζ ITAM/LCK, KO and transgenic mouse T-cell assays, EAE models; iSP2 peptide blocking with proliferation, IL-2, and EAE readouts","pmids":["35725273","37417746"],"confidence":"High","gaps":["Structural basis of STAP-2–ITAM recognition not resolved","iSP2 study is Medium confidence single-lab"]},{"year":2023,"claim":"Defined the molecular basis of STAP-2's negative regulation of BCR signaling: LYN-dependent Tyr250 phosphorylation enables STAP-2 to recruit CSK to LYN and enforce inhibitory LYN Y508 phosphorylation.","evidence":"KO B cells, Y250F mutant analysis, CSK-LYN Co-IP, LYN Y508 immunoblot, and antibody/cytokine production assays","pmids":["37669828"],"confidence":"High","gaps":["How STAP-2 simultaneously engages LYN and CSK structurally not defined"]},{"year":2024,"claim":"Expanded STAP-2's adaptor repertoire to metabolic and fibrotic contexts: it bridges CAP–c-Cbl to enable insulin-induced GLUT4 translocation and adipogenesis, and promotes renal fibrosis through HSP27 binding and PI3K/AKT modulation.","evidence":"Proline-rich domain Co-IP and GLUT4 translocation assays with KO MEF/mouse metabolic phenotypes; KO fibrosis models with Co-IP/MS identification of HSP27 and RNA-seq","pmids":["38461189","39533293"],"confidence":"Medium","gaps":["Single-lab studies","Direct versus scaffold-mediated control of PI3K/AKT in fibrosis not separated"]},{"year":null,"claim":"How STAP-2 selects between positive and negative regulatory outcomes across receptors, and the structural determinants of its PH/SH2-like/YXXQ domains, remain the central unresolved questions.","evidence":"No structural or systematic determinant study present in the corpus","pmids":[],"confidence":"Low","gaps":["No three-dimensional structure of STAP-2 or its complexes reported","Rules governing context-dependent positive versus negative signaling not established","Tissue-specific kinase usage at Tyr250 not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,9,15,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,12,17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,11,12,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,14,15,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,11,12,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["STAT3","STAT5","BRK","BCR-ABL","EGFR","LYN","CBL","PLCG"],"other_free_text":[]}},"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":91,"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":86,"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 Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15611091","citation_count":50,"is_preprint":false},{"pmid":"19393627","id":"PMC_19393627","title":"STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19393627","citation_count":44,"is_preprint":false},{"pmid":"20929863","id":"PMC_20929863","title":"Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20929863","citation_count":41,"is_preprint":false},{"pmid":"21412687","id":"PMC_21412687","title":"Reduced proliferation and a high apoptotic frequency of pancreatic beta cells contribute to genetically-determined diabetes susceptibility of db/db BKS mice.","date":"2011","source":"Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme","url":"https://pubmed.ncbi.nlm.nih.gov/21412687","citation_count":39,"is_preprint":false},{"pmid":"27870582","id":"PMC_27870582","title":"Markers of Islet Endothelial Dysfunction Occur in Male B6.BKS(D)-Leprdb/J Mice and May Contribute to Reduced Insulin Release.","date":"2017","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27870582","citation_count":38,"is_preprint":false},{"pmid":"21205088","id":"PMC_21205088","title":"Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells.","date":"2011","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/21205088","citation_count":31,"is_preprint":false},{"pmid":"18573890","id":"PMC_18573890","title":"STAP-2 negatively regulates both canonical and noncanonical NF-kappaB activation induced by Epstein-Barr virus-derived latent membrane protein 1.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18573890","citation_count":31,"is_preprint":false},{"pmid":"12612136","id":"PMC_12612136","title":"Altering dietary protein type and quantity reduces urinary albumin excretion without affecting plasma glucose concentrations in BKS.cg-m +Lepr db/+Lepr db (db/db) mice.","date":"2003","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/12612136","citation_count":30,"is_preprint":false},{"pmid":"28986450","id":"PMC_28986450","title":"STAP-2 protein promotes prostate cancer growth by enhancing epidermal growth factor receptor stabilization.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28986450","citation_count":25,"is_preprint":false},{"pmid":"22231445","id":"PMC_22231445","title":"STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22231445","citation_count":25,"is_preprint":false},{"pmid":"10360960","id":"PMC_10360960","title":"CpG oligodeoxynucleotides rescue BKS-2 immature B cell lymphoma from anti-IgM-mediated growth inhibition by up-regulation of egr-1.","date":"1999","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10360960","citation_count":22,"is_preprint":false},{"pmid":"12810085","id":"PMC_12810085","title":"Regulation of FcepsilonRI-mediated signaling by an adaptor protein STAP-2/BSK in rat basophilic leukemia RBL-2H3 cells.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12810085","citation_count":22,"is_preprint":false},{"pmid":"34902403","id":"PMC_34902403","title":"Identification of StAP2/ERF genes of potato (Solanum tuberosum) and their multiple functions in detoxification and accumulation of cadmium in yest: 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 Responses.","date":"2021","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/34193686","citation_count":14,"is_preprint":false},{"pmid":"18758078","id":"PMC_18758078","title":"Enhanced c-Fms/M-CSF receptor signaling and wound-healing process in bone marrow-derived macrophages of signal-transducing adaptor protein-2 (STAP-2) deficient mice.","date":"2008","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/18758078","citation_count":14,"is_preprint":false},{"pmid":"1915562","id":"PMC_1915562","title":"Cyclosporin A blocks surface IgM-mediated growth inhibition in an immature B lymphoma, BKS-2.","date":"1991","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1915562","citation_count":14,"is_preprint":false},{"pmid":"34999107","id":"PMC_34999107","title":"KGF-2 Regulates STAP-2-Mediated Signal Transducer and Activator of Transcription 3 Signaling and Reduces Skin Scar Formation.","date":"2022","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/34999107","citation_count":13,"is_preprint":false},{"pmid":"25086370","id":"PMC_25086370","title":"Oral administration of Nitraria retusa ethanolic extract enhances hepatic lipid metabolism in db/db mice model 'BKS.Cg-Dock7(m)+/+ Lepr(db/)J' through the modulation of lipogenesis-lipolysis balance.","date":"2014","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/25086370","citation_count":13,"is_preprint":false},{"pmid":"28478037","id":"PMC_28478037","title":"STAP-2 interacts with Pyk2 and enhances Pyk2 activity in T-cells.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28478037","citation_count":12,"is_preprint":false},{"pmid":"35725273","id":"PMC_35725273","title":"STAP-2 Is a Novel Positive Regulator of TCR-Proximal Signals.","date":"2022","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/35725273","citation_count":11,"is_preprint":false},{"pmid":"32235499","id":"PMC_32235499","title":"Immunolocalization of Keratan Sulfate in Rat Spinal Tissues Using the Keratanase Generated BKS-1(+) Neoepitope: Correlation of Expression Patterns with the Class II SLRPs, Lumican and Keratocan.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32235499","citation_count":11,"is_preprint":false},{"pmid":"30726917","id":"PMC_30726917","title":"STAP-2 positively regulates FcεRI-mediated basophil activation and basophil-dependent allergic inflammatory reactions.","date":"2019","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30726917","citation_count":10,"is_preprint":false},{"pmid":"19401194","id":"PMC_19401194","title":"The protein content of an adaptor protein, STAP-2 is controlled by E3 ubiquitin ligase Cbl.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19401194","citation_count":10,"is_preprint":false},{"pmid":"24492713","id":"PMC_24492713","title":"Adaptor protein STAP-2 modulates cellular signaling in immune systems.","date":"2014","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/24492713","citation_count":8,"is_preprint":false},{"pmid":"39533293","id":"PMC_39533293","title":"STAP2 promotes the progression of renal fibrosis via HSP27.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39533293","citation_count":7,"is_preprint":false},{"pmid":"36410436","id":"PMC_36410436","title":"A peptide derived from adaptor protein STAP-2 inhibits tumor progression by downregulating epidermal growth factor receptor signaling.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36410436","citation_count":7,"is_preprint":false},{"pmid":"26102025","id":"PMC_26102025","title":"CCR7 is involved in BCR-ABL/STAP-2-mediated cell growth in hematopoietic Ba/F3 cells.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26102025","citation_count":7,"is_preprint":false},{"pmid":"30974944","id":"PMC_30974944","title":"Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2',3,3'-Tetrabromo-4,4',5,5'-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice.","date":"2019","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/30974944","citation_count":6,"is_preprint":false},{"pmid":"37417746","id":"PMC_37417746","title":"STAP-2-Derived Peptide Suppresses TCR-Mediated Signals to Initiate Immune Responses.","date":"2023","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/37417746","citation_count":4,"is_preprint":false},{"pmid":"38461189","id":"PMC_38461189","title":"STAP-2 facilitates insulin signaling through binding to CAP/c-Cbl and regulates adipocyte differentiation.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38461189","citation_count":3,"is_preprint":false},{"pmid":"37669828","id":"PMC_37669828","title":"STAP-2 negatively regulates BCR-mediated B cell activation by recruiting tyrosine-protein kinase CSK to LYN.","date":"2023","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/37669828","citation_count":3,"is_preprint":false},{"pmid":"23538907","id":"PMC_23538907","title":"Draft Genome Sequence of Rhodococcus triatomae Strain BKS 15-14.","date":"2013","source":"Genome announcements","url":"https://pubmed.ncbi.nlm.nih.gov/23538907","citation_count":3,"is_preprint":false},{"pmid":"23599292","id":"PMC_23599292","title":"Draft Genome Sequence of Streptomyces gancidicus Strain BKS 13-15.","date":"2013","source":"Genome announcements","url":"https://pubmed.ncbi.nlm.nih.gov/23599292","citation_count":3,"is_preprint":false},{"pmid":"20519854","id":"PMC_20519854","title":"[Novel adaptor protein, STAP-2 functions as a signal modulator in immune system].","date":"2010","source":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","url":"https://pubmed.ncbi.nlm.nih.gov/20519854","citation_count":2,"is_preprint":false},{"pmid":"35725532","id":"PMC_35725532","title":"Verification of the folkloric and anecdotal antidiabetic effects of Hypoxis hemerocallidea (Fisch., C.A. Mey. & Avé-Lall) and isolated, β-sitosterol using early-stage type II spontaneous diabetic mutant BKS-Leprdb mice.","date":"2022","source":"BMC complementary medicine and therapies","url":"https://pubmed.ncbi.nlm.nih.gov/35725532","citation_count":2,"is_preprint":false},{"pmid":"41300448","id":"PMC_41300448","title":"BKS-112, a Selective Histone Deacetylase 6 Inhibitor, Suppresses Triple-Negative Breast Cancer Cells via AKT/mTOR Pathway.","date":"2025","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41300448","citation_count":2,"is_preprint":false},{"pmid":"23558535","id":"PMC_23558535","title":"Draft Genome Sequence of Rhodococcus ruber Strain BKS 20-38.","date":"2013","source":"Genome announcements","url":"https://pubmed.ncbi.nlm.nih.gov/23558535","citation_count":2,"is_preprint":false},{"pmid":"28424924","id":"PMC_28424924","title":"Effects of GW002, a novel recombinant human glucagon-like peptide-1 (GLP-1) analog fusion protein, on CHO recombinant cells and BKS-db mice.","date":"2017","source":"Acta diabetologica","url":"https://pubmed.ncbi.nlm.nih.gov/28424924","citation_count":0,"is_preprint":false},{"pmid":"42204454","id":"PMC_42204454","title":"Functional potential of the APETALA2 transcription factors StAP2-13/18 in modulating tuberization under long-day (LD) conditions in potato.","date":"2026","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42204454","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.18.647076","title":"Single Cell Landscape of Sex-specific Drivers of Alzheimer’s Disease","date":"2025-04-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.18.647076","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.23.683531","title":"Targeting serine dehydratase supports amino acid homeostasis and skin repair","date":"2025-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.23.683531","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.29.615683","title":"Radical Footprinting in Mammalian Whole Blood","date":"2024-09-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.29.615683","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24291,"output_tokens":6590,"usd":0.085861,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15301,"output_tokens":5188,"usd":0.103102,"stage2_stop_reason":"end_turn"},"total_usd":0.188963,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"STAP-2/BKS was identified as a novel adaptor protein containing PH and SH2-like domains and a YXXQ motif. It is tyrosine-phosphorylated and translocates to the plasma membrane in response to EGF. In STAP-2 knockout 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, establishing the YXXQ motif as the STAT3-binding element responsible for STAP-2's modulatory function.\",\n      \"method\": \"Knockout mouse generation, IL-6 stimulation of hepatocytes, reporter assays, co-immunoprecipitation, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional validation with KO mice, mutagenesis of YXXQ motif, and reporter assays in two orthogonal systems\",\n      \"pmids\": [\"12540842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"STAP-2/BKS directly binds STAT5 through its PH and SH2-like domains interacting with the C-terminal region of STAT5. STAP-2/BKS and STAT5 constitutively co-localize in the cytoplasm of resting cells, but STAP-2/BKS dissociates upon STAT5 phosphorylation. Overexpression of STAP-2/BKS diminished cytokine-induced STAT5 tyrosine phosphorylation and transcriptional activation. STAP-2-deficient thymocytes showed enhanced IL-2-dependent cell growth.\",\n      \"method\": \"Co-immunoprecipitation, intracellular staining, domain-deletion mutational analysis, STAP-2 KO mouse thymocyte proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, and KO mouse phenotype across multiple orthogonal methods\",\n      \"pmids\": [\"15611091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"STAP-2/BKS overexpression in RBL-2H3 mast cells suppresses FcεRI-mediated calcium mobilization and degranulation. STAP-2/BKS associates with PLC-γ in vivo and significantly suppresses FcεRI-induced tyrosine phosphorylation of PLC-γ (but not Syk), establishing STAP-2 as a negative regulator of FcεRI signaling upstream of PLC-γ.\",\n      \"method\": \"Overexpression in RBL-2H3 cells, co-immunoprecipitation, calcium flux assay, degranulation assay, phosphotyrosine immunoblotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional assays (calcium, degranulation) in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12810085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STAP-2 negatively regulates EBV LMP1-mediated NF-κB signaling. STAP-2 associates with LMP1 through its PH and SH2-like domains and interacts with TRAF3 and TRADD. STAP-2 knockout mouse embryonic fibroblasts showed enhanced LMP1-induced cell growth. STAP-2 overexpression in EBV-positive human B cells decreased cell growth.\",\n      \"method\": \"Co-immunoprecipitation, overexpression in EBV+ B cells, STAP-2 KO MEFs, NF-κB reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping by Co-IP, KO MEF phenotype, and overexpression in human B cells with NF-κB reporters across multiple orthogonal methods\",\n      \"pmids\": [\"18573890\"],\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 in Raw 264.7 macrophages markedly suppressed M-CSF-induced tyrosine phosphorylation of c-Fms and activation of Akt and ERK, and impaired M-CSF-induced macrophage migration and wound healing.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, overexpression in Raw 264.7 cells, Akt/ERK phosphorylation assay, wound-healing migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific Co-IP plus functional signaling and migration assays in a single lab\",\n      \"pmids\": [\"17512498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of STAP-2 in bone marrow-derived macrophages from STAP-2 knockout mice results in markedly enhanced c-Fms/M-CSF receptor signaling (ERK and Akt activation) and enhanced wound-healing/migration process, confirming STAP-2 as an endogenous negative regulator of M-CSF receptor signaling in primary macrophages.\",\n      \"method\": \"STAP-2 KO mouse-derived bone marrow macrophages, M-CSF stimulation, ERK/Akt phosphorylation assay, wound-healing assay\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary KO macrophage validation of signaling and migration phenotype, single lab\",\n      \"pmids\": [\"18758078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STAP-2 Tyr250 is a major phosphorylation site by v-Src and Jak2, identified using a phospho-specific anti-pTyr250 antibody and mutagenesis. Tyr250 phosphorylation is required for STAP-2's STAT3-enhancing activity. Endogenous STAP-2 is phosphorylated at Tyr250 following LIF stimulation in 293T, Hep3B, and murine M1 cells.\",\n      \"method\": \"Site-directed mutagenesis (Y250F), phospho-specific antibody, kinase assay, LIF stimulation of cell lines including M1 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phospho-specific antibody with mutagenesis and endogenous validation, single lab\",\n      \"pmids\": [\"17368569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"STAP-2 Tyr250 is phosphorylated by Brk (breast tumor kinase), identified using a series of YF mutants and an anti-phospho-STAP-2 Tyr250 antibody. A STAP-2 Y250F mutant impaired Brk-mediated STAT3 activation. siRNA-mediated knockdown of endogenous STAP-2 decreased Brk-mediated STAT3 activation.\",\n      \"method\": \"Site-directed mutagenesis (YF series), phospho-specific antibody, in vitro/cell-based kinase assay with Brk, siRNA knockdown, STAT3 activation reporter/immunoblot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phospho-site mapping by mutagenesis panel plus phospho-specific antibody, validated by both overexpression and siRNA knockdown\",\n      \"pmids\": [\"19393627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"E3 ubiquitin ligase Cbl directly controls STAP-2 protein levels. STAP-2 physically interacts with Cbl through its PH and SH2-like domains. siRNA knockdown of endogenous Cbl restored STAP-2 protein levels; overexpression of Cbl induced STAP-2 degradation. Cbl-mediated regulation of STAP-2 protein levels affected Brk/STAP-2-induced STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, siRNA knockdown of Cbl, Cbl overexpression, immunoblot for STAP-2 protein levels, STAT3 activation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function for Cbl plus Co-IP domain mapping, single lab\",\n      \"pmids\": [\"19401194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"STAP-2 interacts with both Brk and STAT3 in breast cancer cells. The PH domain of STAP-2 is required for Brk-STAP-2 binding, Brk kinase activation, and STAT3 tyrosine phosphorylation. A STAP-2 PH-Brk fusion protein exhibited robust kinase activity and enhanced STAT3 activation. siRNA knockdown of STAP-2 in T47D cells decreased Brk-mediated STAT3 activation and strongly reduced proliferation.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/fusion constructs, siRNA knockdown, STAT3 phosphorylation assay, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping, fusion protein kinase activity assay, and siRNA knockdown phenotype in breast cancer cells with multiple orthogonal methods\",\n      \"pmids\": [\"20929863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STAP-2 is involved in Brk-mediated STAT5 activation in breast cancer cells. The PH domain of STAP-2 participates in Brk-mediated phosphorylation of STAT5. STAP-2 knockdown in T47D cells reduced proliferation as strongly as Brk or STAT5b knockdown.\",\n      \"method\": \"Ectopic expression, domain analysis, STAT5 transcriptional activity assay, siRNA knockdown, cell proliferation assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain analysis plus siRNA functional phenotype in breast cancer cells, single lab\",\n      \"pmids\": [\"21205088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STAP-2 binds to BCR-ABL, BCR, and ABL proteins via its SH2-like domain. BCR-ABL phosphorylates STAP-2 at Tyr250, and phosphorylated STAP-2 in turn upregulates BCR-ABL phosphorylation and downstream ERK, STAT5, BCL-xL, and BCL-2 activation. STAP-2 interaction with BCR-ABL also alters chemokine receptor expression (down-regulates CXCR4, up-regulates CCR7). STAP-2 knockdown in K562 CML cells abolished tumor formation in mice.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, phosphorylation assays, signaling pathway immunoblots, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific Co-IP, phospho-site validation, downstream signaling readouts, and in vivo tumor model with knockdown\",\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 EGFR ubiquitination. STAP-2 knockdown in DU145 prostate cancer cells reduced EGF-induced phosphorylation of AKT, ERK, and STAT3, and strongly decreased tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, EGFR ubiquitination assay, STAP-2 siRNA knockdown, signaling phosphorylation assays, in vivo tumor growth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, siRNA knockdown with multiple signaling readouts, and in vivo tumor model\",\n      \"pmids\": [\"28986450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STAP-2 directly interacts with Pyk2 in T cells, increasing Pyk2 phosphorylation. Pyk2 itself phosphorylates STAP-2 at Y250, and this phosphorylation is critical for maximal STAP-2–Pyk2 interactions. STAP-2-enhanced SDF-1α-induced T-cell chemotaxis is inhibited by Pyk2 siRNA or the Pyk2 inhibitor AG17.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, siRNA knockdown of Pyk2, pharmacological inhibition with AG17, T-cell chemotaxis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus kinase-substrate evidence and functional chemotaxis assay with siRNA and inhibitor, single lab\",\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 showed reduced degranulation, cytokine production, and reduced phosphorylation of Lyn, PLC-γ2, and ERK after IgE/Ag stimulation. STAP-2-deficient mice showed significantly inhibited IgE-dependent chronic allergic inflammation in vivo.\",\n      \"method\": \"STAP-2 KO mouse-derived basophil culture, degranulation assay, cytokine ELISA, phosphorylation immunoblot, in vivo allergic inflammation model\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — primary KO basophils with multiple signaling and functional readouts plus in vivo allergic inflammation model\",\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. STAP-2-deficient T cells showed reduced TCR-mediated signaling and IL-2 production; STAP-2-overexpressing T cells showed enhanced signaling. STAP-2-deficient mice exhibited reduced CD4+ T-cell-mediated EAE disease severity, while STAP-2-overexpressing transgenic mice showed severe EAE.\",\n      \"method\": \"Co-immunoprecipitation (STAP-2 with CD3ζ ITAM and LCK), STAP-2 KO and transgenic mouse T-cell assays, IL-2 production, TCR signaling phosphorylation, EAE model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal KO and transgenic mouse phenotypes, Co-IP of TCR complex components, and multiple orthogonal functional readouts\",\n      \"pmids\": [\"35725273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KGF-2 inhibits STAP-2 expression and STAT3 activation in fibroblasts, leading to reduced collagen I and collagen III levels and attenuated scar formation. This places STAP-2 downstream of KGF-2 signaling and upstream of STAT3-mediated collagen production in skin fibroblasts.\",\n      \"method\": \"KGF-2 treatment of fibroblasts and in vivo scar model, STAP-2 expression measurement, STAT3 activation assay, collagen I/III quantification\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional data linking KGF-2–STAP-2–STAT3–collagen axis, single lab\",\n      \"pmids\": [\"34999107\"],\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 dependently on STAP-2 Y250 phosphorylation by LYN. Phosphorylated STAP-2 enhances interactions between LYN and CSK, resulting in enhanced CSK-mediated LYN Y508 phosphorylation (inhibitory). STAP-2 KO B cells showed increased LYN activity, BCR-mediated signals, cytokine production, and antibody production.\",\n      \"method\": \"STAP-2 KO mouse B cells, Co-immunoprecipitation, Y250F mutant analysis, LYN Y508 phosphorylation immunoblot, cytokine and antibody production assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse primary B cells, domain/phospho-site mutagenesis, mechanistic Co-IP of CSK-LYN complex, and multiple functional readouts\",\n      \"pmids\": [\"37669828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A STAP-2-derived synthetic peptide (iSP2) directly interacts with CD3ζ ITAM sequences and blocks STAP-2–CD3ζ interactions, suppressing T cell proliferation and TCR-induced IL-2 production in human and murine T cells, and inhibiting TCR-mediated EAE in vivo.\",\n      \"method\": \"Peptide binding assay, Co-IP blocking experiment, T-cell proliferation assay, IL-2 production, in vivo EAE model with cell-penetrating peptide\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct peptide-ITAM interaction assay plus functional T-cell and in vivo validation, single lab\",\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, bridges CAP and c-Cbl to enhance their complex formation, and facilitates GLUT4 translocation after insulin treatment. STAP-2 KO MEFs showed suppressed adipogenesis, and STAP-2 KO mice showed reduced weight gain on a high-fat diet.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (proline-rich region), GLUT4 translocation assay in Hep3B cells, STAP-2 KO MEF adipogenesis assay, in vivo high-fat diet model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, functional GLUT4 translocation assay, and KO phenotype in cells and mice, single lab\",\n      \"pmids\": [\"38461189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STAP2 promotes renal fibrosis. STAP2 knockout in mice mitigated EMT, reduced inflammatory cell infiltration, and reduced collagen deposition in renal fibrosis models. Mechanistically, STAP2 interacts with HSP27 (identified by co-immunoprecipitation and mass spectrometry) and modulates the PI3K/AKT signaling pathway.\",\n      \"method\": \"STAP2 KO mouse fibrosis models (IRI and cisplatin), co-immunoprecipitation, mass spectrometry, RNA-seq, STAP2 overexpression in cells, fibrosis marker quantification\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype in two in vivo models, Co-IP/MS identification of HSP27 partner, single lab\",\n      \"pmids\": [\"39533293\"],\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 in prostate and lung cancer cell lines, and inhibits tumor growth of DU145 and A549 xenografts, confirming that the STAP-2–EGFR interaction is required for full EGFR signaling and stability.\",\n      \"method\": \"STAP-2-derived peptide competitive inhibition assay, cell proliferation assay, EGFR stability/signaling immunoblot, murine xenograft model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide-based interaction block with functional validation in cells and in vivo xenografts, single lab\",\n      \"pmids\": [\"36410436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STAP-2 cooperates with BCR-ABL to upregulate CCR7 expression in Ba/F3 hematopoietic cells via the MAPK/ERK pathway. STAP-2 and BCR-ABL together induce production of CCR7 ligands CCL19 and CCL21, contributing to cell growth.\",\n      \"method\": \"BCR-ABL/STAP-2 co-expression in Ba/F3 cells, ERK pathway inhibitor studies, CCR7/CCL19/CCL21 expression assays, cell growth assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression system with pharmacological inhibitor, single lab, single cell line\",\n      \"pmids\": [\"26102025\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STAP-2 (also known as BKS) is an adaptor protein with PH and SH2-like domains and a C-terminal YXXQ/proline-rich region that scaffolds and modulates multiple signaling pathways: it enhances STAT3 activation via its YXXQ motif (acting as a STAT3-docking site), suppresses STAT5 by binding its C-terminal region in resting cells, is phosphorylated at Tyr250 by kinases including Brk, Jak2, v-Src, Pyk2, LYN, and BCR-ABL, and this phosphorylation event regulates its protein-protein interactions; it negatively regulates FcεRI (in mast cells) and M-CSF receptor (c-Fms) signaling, positively regulates BCR-ABL, Brk-STAT3/STAT5, TCR-proximal signaling (by recruiting to CD3ζ ITAMs and LCK), and FcεRI-mediated basophil activation (via Lyn/PLC-γ2/ERK); it suppresses BCR signaling by facilitating CSK-mediated inhibitory phosphorylation of LYN Y508; it promotes EGFR stability by blocking c-CBL-mediated ubiquitination; it facilitates insulin signaling by bridging CAP and c-Cbl to enhance GLUT4 translocation; and its protein levels are regulated by E3 ubiquitin ligase Cbl-mediated degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STAP-2/BKS is a cytoplasmic adaptor protein, built from a PH domain, an SH2-like domain, and a C-terminal YXXQ/proline-rich region, that scaffolds and tunes the output of multiple receptor and kinase signaling pathways rather than carrying intrinsic catalytic activity [#0, #1]. Its most conserved scaffolding function is modulation of STAT transcription factors: the YXXQ motif acts as a STAT3-docking site that enhances IL-6/LIF-induced STAT3 activation and acute-phase gene expression [#0], while direct binding of its PH and SH2-like domains to the C-terminal region of STAT5 suppresses STAT5 activation in resting cells and dissociates upon STAT5 phosphorylation [#1]. STAP-2 function is gated by phosphorylation of a single tyrosine, Tyr250, which is targeted by diverse kinases — v-Src and Jak2, Brk, BCR-ABL, Pyk2, and LYN — and is required for its STAT3-enhancing and partner-binding activities [#6, #7, #11, #13, #17]. Through these interactions STAP-2 acts as a context-dependent positive or negative regulator: it promotes oncogenic Brk-STAT3/STAT5 signaling and proliferation in breast cancer [#9, #10], potentiates BCR-ABL signaling and tumor formation in CML [#11], stabilizes EGFR by blocking c-CBL-mediated ubiquitination to sustain AKT/ERK/STAT3 signaling and tumor growth [#12], and conversely restrains Fc\\u03b5RI signaling in mast cells [#2], M-CSF receptor signaling in macrophages [#4, #5], and BCR signaling in B cells by recruiting CSK to LYN to enforce inhibitory LYN Y508 phosphorylation [#17]. In T cells STAP-2 binds CD3\\u03b6 ITAMs and phosphorylated LCK to amplify TCR-proximal signaling and IL-2 production, shaping CD4+ T-cell-mediated autoimmune disease in vivo [#15]. STAP-2 also bridges CAP and c-Cbl to facilitate insulin-induced GLUT4 translocation and adipogenesis [#19], and its own abundance is controlled by Cbl-mediated degradation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established STAP-2 as an adaptor that enhances STAT3 signaling through a defined YXXQ docking motif, answering how this novel PH/SH2-like protein modulates cytokine responses.\",\n      \"evidence\": \"Knockout hepatocytes with IL-6 stimulation, YXXQ mutagenesis, and acute-phase reporter assays\",\n      \"pmids\": [\"12540842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of YXXQ\\u2013STAT3 docking not resolved\", \"Did not address STAP-2 effects on other STAT family members\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed STAP-2 also acts as a negative regulator in a distinct receptor context, suppressing Fc\\u03b5RI-mediated mast cell activation upstream of PLC-\\u03b3.\",\n      \"evidence\": \"Overexpression in RBL-2H3 mast cells with calcium flux, degranulation, and PLC-\\u03b3 Co-IP/phosphorylation assays\",\n      \"pmids\": [\"12810085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on overexpression rather than endogenous loss-of-function\", \"Mechanism of PLC-\\u03b3 suppression not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined an opposing STAT-modulating role: STAP-2 binds and suppresses STAT5, establishing it as a bidirectional STAT regulator depending on the family member.\",\n      \"evidence\": \"Reciprocal Co-IP, domain-deletion mapping, co-localization in resting cells, and KO thymocyte proliferation\",\n      \"pmids\": [\"15611091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STAP-2 discriminates STAT3 versus STAT5 outcomes unresolved\", \"Cytokine specificity of STAT5 suppression not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended STAP-2's negative regulatory function to the M-CSF receptor, showing direct PH-domain binding to c-Fms dampens receptor signaling and macrophage migration.\",\n      \"evidence\": \"Domain-mapped Co-IP and overexpression in Raw 264.7 macrophages with Akt/ERK and wound-healing assays\",\n      \"pmids\": [\"17512498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based; endogenous role addressed only in later work\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified Tyr250 as the major regulatory phosphosite (by v-Src and Jak2) required for STAP-2's STAT3-enhancing activity, providing the switch that gates adaptor function.\",\n      \"evidence\": \"Y250F mutagenesis, phospho-specific antibody, kinase assays, and endogenous LIF-induced phosphorylation in multiple lines\",\n      \"pmids\": [\"17368569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Which interactions are gained or lost upon Tyr250 phosphorylation not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Confirmed endogenous negative regulation of M-CSF receptor signaling in primary cells and revealed a parallel role in restraining EBV LMP1/NF-\\u03baB signaling via TRAF3/TRADD.\",\n      \"evidence\": \"KO bone marrow macrophages with M-CSF stimulation; KO MEFs and EBV+ B cells with NF-\\u03baB reporters and LMP1 Co-IP\",\n      \"pmids\": [\"18758078\", \"18573890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which STAP-2 inhibits LMP1/TRAF3 signaling not detailed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected STAP-2 to the oncogenic Brk kinase by mapping Tyr250 as a Brk substrate site required for Brk-driven STAT3 activation, and showed Cbl controls STAP-2 abundance.\",\n      \"evidence\": \"YF mutant panel, phospho-specific antibody, Brk kinase assays, siRNA knockdown; reciprocal Cbl gain/loss-of-function with domain-mapped Co-IP\",\n      \"pmids\": [\"19393627\", \"19401194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cbl ubiquitinates STAP-2 directly versus indirectly not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established STAP-2 as a required cofactor for Brk-STAT3 signaling and proliferation in breast cancer, with the PH domain driving Brk activation, then extended this to Brk-STAT5.\",\n      \"evidence\": \"Domain deletion/fusion constructs, PH-Brk fusion kinase activity, siRNA knockdown and proliferation assays in T47D cells; STAT5 transcriptional and proliferation readouts\",\n      \"pmids\": [\"20929863\", \"21205088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of PH-domain-mediated Brk activation unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated a feed-forward oncogenic loop in CML where STAP-2 binds BCR-ABL via its SH2-like domain, is phosphorylated at Tyr250, and amplifies BCR-ABL and downstream survival signaling required for tumor formation.\",\n      \"evidence\": \"Domain-mapped Co-IP, phospho-site analysis, downstream signaling immunoblots, siRNA knockdown, and K562 xenografts\",\n      \"pmids\": [\"22231445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of reciprocal BCR-ABL phosphorylation enhancement not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked the STAP-2/BCR-ABL axis to chemokine signaling by showing cooperative CCR7/CCL19/CCL21 induction via ERK contributes to growth.\",\n      \"evidence\": \"BCR-ABL/STAP-2 co-expression in Ba/F3 cells with ERK inhibitors and chemokine expression assays\",\n      \"pmids\": [\"26102025\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Overexpression in a single cell line without endogenous validation\", \"Causal role of CCR7 axis in vivo not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a stabilizing role for STAP-2 in EGFR-driven cancer by antagonizing c-CBL-mediated EGFR ubiquitination, and identified Pyk2 as another Tyr250 kinase coupling STAP-2 to T-cell chemotaxis.\",\n      \"evidence\": \"EGFR Co-IP/ubiquitination assays and siRNA knockdown with tumor model in DU145; Pyk2 Co-IP, knockdown, AG17 inhibition, and SDF-1\\u03b1 chemotaxis\",\n      \"pmids\": [\"28986450\", \"28478037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAP-2 sterically blocks CBL or competes for EGFR not defined\", \"Pyk2 work is single-lab Medium confidence\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed STAP-2 can be a positive regulator of innate effector signaling, promoting Fc\\u03b5RI-mediated basophil activation via Lyn/PLC-\\u03b32/ERK and driving chronic allergic inflammation.\",\n      \"evidence\": \"KO basophils with degranulation, cytokine, and phosphorylation readouts plus in vivo allergic inflammation model\",\n      \"pmids\": [\"30726917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contrast with negative Fc\\u03b5RI regulation in mast cells not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established STAP-2 as a positive amplifier of TCR-proximal signaling by binding CD3\\u03b6 ITAMs and phospho-LCK, with reciprocal KO/transgenic mice defining its role in CD4+ T-cell autoimmunity, and validated the interaction as druggable with the iSP2 peptide.\",\n      \"evidence\": \"Co-IP of CD3\\u03b6 ITAM/LCK, KO and transgenic mouse T-cell assays, EAE models; iSP2 peptide blocking with proliferation, IL-2, and EAE readouts\",\n      \"pmids\": [\"35725273\", \"37417746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STAP-2\\u2013ITAM recognition not resolved\", \"iSP2 study is Medium confidence single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the molecular basis of STAP-2's negative regulation of BCR signaling: LYN-dependent Tyr250 phosphorylation enables STAP-2 to recruit CSK to LYN and enforce inhibitory LYN Y508 phosphorylation.\",\n      \"evidence\": \"KO B cells, Y250F mutant analysis, CSK-LYN Co-IP, LYN Y508 immunoblot, and antibody/cytokine production assays\",\n      \"pmids\": [\"37669828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STAP-2 simultaneously engages LYN and CSK structurally not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded STAP-2's adaptor repertoire to metabolic and fibrotic contexts: it bridges CAP\\u2013c-Cbl to enable insulin-induced GLUT4 translocation and adipogenesis, and promotes renal fibrosis through HSP27 binding and PI3K/AKT modulation.\",\n      \"evidence\": \"Proline-rich domain Co-IP and GLUT4 translocation assays with KO MEF/mouse metabolic phenotypes; KO fibrosis models with Co-IP/MS identification of HSP27 and RNA-seq\",\n      \"pmids\": [\"38461189\", \"39533293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"Direct versus scaffold-mediated control of PI3K/AKT in fibrosis not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STAP-2 selects between positive and negative regulatory outcomes across receptors, and the structural determinants of its PH/SH2-like/YXXQ domains, remain the central unresolved questions.\",\n      \"evidence\": \"No structural or systematic determinant study present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No three-dimensional structure of STAP-2 or its complexes reported\", \"Rules governing context-dependent positive versus negative signaling not established\", \"Tissue-specific kinase usage at Tyr250 not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 9, 15, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 12, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 11, 12, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 14, 15, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 11, 12, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STAT3\", \"STAT5\", \"BRK\", \"BCR-ABL\", \"EGFR\", \"LYN\", \"CBL\", \"PLCG\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}