{"gene":"SORBS3","run_date":"2026-06-10T07:46:38","timeline":{"discoveries":[{"year":1999,"finding":"Vinexin (SORBS3) was identified as a vinculin-binding protein; the interaction is mediated by the first and second SH3 domains of vinexin binding to the proline-rich hinge region of vinculin. Both vinexin α and β localize to focal adhesions in fibroblasts and cell-cell junctions in epithelial cells. Expression of vinexin increases focal adhesion size, promotes actin stress fiber formation (vinexin α), and enhances cell spreading on fibronectin.","method":"Yeast two-hybrid system, in vitro binding assay, immunofluorescence localization, stable cell line overexpression with morphological readout","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal yeast two-hybrid + in vitro binding + direct localization experiments with functional phenotypic readouts, foundational paper replicated by subsequent work","pmids":["9885244"],"is_preprint":false},{"year":1999,"finding":"The third SH3 domain of vinexin binds Sos (a guanine nucleotide exchange factor for Ras and Rac) both in vitro and in vivo. Growth factor stimulation (EGF, PDGF, serum) causes Sos phosphorylation that disrupts the vinexin-Sos complex. Exogenous vinexin β enhances JNK/SAPK activation but not ERK activation in response to EGF; a point mutation in the third SH3 domain abolishes EGF-induced JNK/SAPK activation in a dominant-negative manner.","method":"In vitro binding assay, co-immunoprecipitation, phosphatase treatment, dominant-negative mutant expression, JNK/SAPK kinase activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro binding, co-IP, site-directed mutagenesis, and functional kinase assay in a single study with clear mechanistic readout","pmids":["10585480"],"is_preprint":false},{"year":2002,"finding":"Vinexin β expression enables anchorage-independent ERK2 activation stimulated by EGF. The linker region between the second and third SH3 domains of vinexin β (not the SH3 domains themselves) is required for this function. This activity operates through a PKA-PAK signaling pathway: dominant-negative PAK suppresses vinexin β-induced anchorage-independent ERK2 activation, and dominant-negative vinexin β inhibits PKA inhibitor-induced anchorage-independent ERK2 activation.","method":"Deletion mutant analysis, dominant-negative constructs, pharmacological inhibitors (H89), ERK2 activation assay in suspended vs. adherent cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via dominant-negative constructs plus pharmacological inhibitors, single lab but multiple orthogonal approaches","pmids":["11825889"],"is_preprint":false},{"year":2003,"finding":"Vinexin α interacts in vitro with estrogen receptor α (ERα), ERβ, androgen receptor, and glucocorticoid receptor; the SH3 domains are not required for this interaction. Co-expression of vinexin α with ERα leads to loss of ERα serine phosphorylation and partial redistribution of vinexin α into the nucleus where it co-localizes with ERα. Vinexin α stimulates ligand-induced transactivation of these receptors.","method":"In vitro binding assay, co-immunoprecipitation, immunofluorescence localization, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding + co-IP + reporter assays + localization, single lab study","pmids":["14625289"],"is_preprint":false},{"year":2003,"finding":"Vinexin binds lp-dlg/KIAA0583 (a MAGUK family protein) via the third SH3 domain of vinexin interacting with a proline-rich sequence between the second and third PDZ domains of lp-dlg. lp-dlg co-localizes with vinexin at cell-cell contacts in epithelial cells, co-immunoprecipitates with β-catenin, and the three proteins can form a ternary complex, linking the vinexin-vinculin complex to β-catenin at adherens junctions.","method":"Yeast two-hybrid screening, co-immunoprecipitation with deletion mutants, immunofluorescence co-localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid + reciprocal co-IP + localization, single lab","pmids":["12657639"],"is_preprint":false},{"year":2004,"finding":"ERK1/2 directly phosphorylates vinexin upon growth factor stimulation. ERK2 phosphorylates serine 189 (in the linker region between the second and third SH3 domains) of vinexin β. Vinexin interacts with the active (but not inactive) form of ERK1/2 via a DEF (FXFP) docking domain in its linker region. Cell adhesion to fibronectin also induces vinexin-ERK2 association and vinexin phosphorylation; vinexin and ERK co-localize at the cell periphery during spreading.","method":"In vitro kinase assay, site-directed mutagenesis (Ser189), co-immunoprecipitation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay combined with mutagenesis identifying specific phosphorylation site and docking domain, plus in vivo co-IP validation","pmids":["15184391"],"is_preprint":false},{"year":2004,"finding":"SOCS-7 interacts with vinexin through proline-rich regions N-terminal to the SOCS-7 SH2 domain (likely binding an SH3 domain of vinexin). Vinexin-α co-precipitates with SOCS-7, and part of SOCS-7-GFP merges with vinexin and actin by confocal microscopy, linking SOCS-7 to the actin cytoskeleton via vinexin.","method":"Yeast two-hybrid screen, co-immunoprecipitation, confocal immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid + co-IP + localization, single lab, no functional mutagenesis","pmids":["15242778"],"is_preprint":false},{"year":2005,"finding":"Vinexin β interacts with the non-phosphorylated AF-1 domain of RARγ (identified by yeast two-hybrid). Vinexin β co-localizes with RARγ in the nucleus. Phosphorylation of the AF-1 domain of RARγ prevents vinexin β binding. Stable overexpression of vinexin β or vinexin knockdown by RNAi demonstrates that vinexin β is an inhibitor of RARγ-mediated transcription.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, stable overexpression, siRNA knockdown, transcriptional reporter assays in F9 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (yeast two-hybrid, co-IP, localization, gain- and loss-of-function transcriptional assays) in single study","pmids":["15734736"],"is_preprint":false},{"year":2005,"finding":"SHIP2 interacts with vinexin via its C-terminal region (identified by yeast two-hybrid). The interaction was confirmed by co-immunoprecipitation in COS-7 cells and mouse embryonic fibroblasts. Vinexin α and SHIP2 co-localize at the cell periphery. Vinexin does not affect SHIP2 phosphatase activity in vitro. Co-expression of SHIP2 and vinexin enhances cell adhesion to collagen-I; this requires the SHIP2 C-terminus and catalytic activity.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro phosphatase assay, cell adhesion assay with SHIP2 mutants and knockout MEFs","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP in two cell types, in vitro phosphatase assay, functional adhesion assay, single lab","pmids":["16302969"],"is_preprint":false},{"year":2006,"finding":"Vinexin β regulates EGFR phosphorylation by suppressing EGFR dephosphorylation (sustaining phosphorylation), requiring both the first and third SH3 domains. Vinexin β binds E3 ubiquitin ligase c-Cbl through its third SH3 domain, decreases the cytosolic pool of c-Cbl and increases membrane-associated c-Cbl; overexpression of c-Cbl abolishes the vinexin β-mediated sustained EGFR phosphorylation.","method":"Western blot with phospho-specific antibodies, mutational analysis, siRNA knockdown, co-immunoprecipitation, subcellular fractionation","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutational analysis + co-IP + siRNA loss-of-function + rescue experiment, single lab","pmids":["16923119"],"is_preprint":false},{"year":2006,"finding":"Vinexin β interacts with WAVE2 (and also WAVE1 and N-WASP) through its first and second SH3 domains binding the proline-rich region of WAVE2. Vinexin β increases the amount of WAVE2 protein and induces a phosphorylation-dependent mobility shift. This effect requires PKA activity (PKA inhibition suppresses it; PKA activation mimics it) and involves proteasome-dependent regulation of WAVE2 degradation.","method":"Co-immunoprecipitation, deletion/point mutant analysis, proteasome inhibitor treatment, PKA pharmacological modulation, SDS-PAGE mobility shift assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis + pharmacological epistasis, single lab, multiple orthogonal methods","pmids":["16483316"],"is_preprint":false},{"year":2006,"finding":"Abl kinase interacts with vinexin α and β primarily through the third SH3 domain; both co-localize at membrane ruffles in rat astrocytes and the interaction is reduced by the F-actin disruptor latrunculin B (indicating F-actin-mediated regulation). c-Abl and v-Abl phosphorylate vinexin α (but not β) at tyrosine 127, identified by mutational analysis.","method":"Co-immunoprecipitation, immunofluorescence, latrunculin B treatment, in vivo phosphorylation assay, site-directed mutagenesis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP + mutagenesis identifying phosphorylation site + localization, single lab","pmids":["16831423"],"is_preprint":false},{"year":2007,"finding":"ERK-mediated phosphorylation of vinexin β at Ser189 is spatiotemporally regulated: phosphorylated vinexin β is enriched at the leading edge of migrating cells and at the cell periphery during spreading but not at focal adhesions of well-spread cells. Using phosphomimetic and non-phosphorylatable Ser189 mutants, phosphorylation of vinexin β inhibits cell spreading and migration, while unphosphorylated vinexin β inhibits anchorage-independent cell growth.","method":"Phosphorylation-state-specific antibody immunofluorescence, stable cell lines expressing GFP-vinexin β phosphomimetic/non-phosphorylatable mutants, cell spreading, migration, and soft-agar growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-specific antibody + structure-function mutants + multiple functional assays, single lab","pmids":["17486060"],"is_preprint":false},{"year":2007,"finding":"Vinexin isoforms are expressed in rat brain in a developmental stage-dependent manner; vinexin α is enriched in adult telencephalon. In primary rat hippocampal neurons, vinexin localizes at synapses and filopodia in growth cones (confirmed by biochemical fractionation and electron microscopy). ERK-mediated phosphorylation of vinexin at Ser593 (equivalent to Ser189 in β) occurs at postsynaptic sites of hippocampal synapses (immunoelectron microscopy) and is reduced by the MEK inhibitor PD98059.","method":"Immunofluorescence, biochemical fractionation (synaptosomes), electron microscopy, immunoelectron microscopy, phospho-specific antibody, MEK inhibitor","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple localization methods (EM, immunofluorescence, fractionation) plus functional pharmacological inhibition, single lab","pmids":["17241162"],"is_preprint":false},{"year":2009,"finding":"Vinexin binds Rhotekin via the C-terminal proline-rich motif of Rhotekin and the third SH3 domain of vinexin. This interaction is little affected by RhoA but is inhibited by activated Cdc42. Vinexin α and Rhotekin partially co-localize at focal adhesions in fibroblasts.","method":"Yeast two-hybrid screening, in vitro binding assay, co-immunoprecipitation from COS7 cells and brain tissue, immunofluorescence","journal":"Medical molecular morphology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid + co-IP (in cells and tissue) + localization, single lab, no direct functional mutagenesis of the binding interface","pmids":["19294487"],"is_preprint":false},{"year":2009,"finding":"In v-Src-transformed cells, vinexin α is tyrosine phosphorylated at three tyrosine residues. A non-phosphorylatable triple mutant of vinexin α shows higher binding affinity for vinculin than wild-type, demonstrating that tyrosine phosphorylation of vinexin α attenuates its interaction with vinculin.","method":"Site-directed mutagenesis, co-immunoprecipitation, binding affinity comparison between wild-type and phosphorylation mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis + co-IP functional readout, single lab","pmids":["19580787"],"is_preprint":false},{"year":2010,"finding":"Vinexin is required for keratinocyte migration and cutaneous wound healing. Vinexin knockdown delays migration of HaCaT and A431 cells in scratch assay without affecting proliferation. Scratch-induced cell migration activates EGFR and ERK; vinexin knockdown inhibits scratch-induced EGFR activation (but not ERK activation), placing vinexin upstream of EGFR in the migration pathway. Vinexin-knockout mice show delayed cutaneous wound healing in vivo.","method":"siRNA knockdown, scratch migration assay, pharmacological inhibition (AG1478, U0126), knockout mouse model, in vivo wound healing assay, Western blot for EGFR/ERK activation","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown + knockout mouse model + pharmacological epistasis, multiple cell types and in vivo validation","pmids":["20361963"],"is_preprint":false},{"year":2013,"finding":"Vinexin β protects against cardiac hypertrophy by blocking AKT signaling. Vinexin β overexpression in the heart attenuates pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction, while vinexin β knockout exaggerates these responses. Both in vitro and in vivo analyses show that vinexin β's protective effects are associated with AKT signaling abrogation.","method":"Transgenic overexpression, knockout mouse model, aortic banding (pressure overload), echocardiography, molecular signaling analysis (AKT phosphorylation), histopathology","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic gain- and loss-of-function in vivo models with defined molecular pathway (AKT) and functional cardiac readout","pmids":["23429936"],"is_preprint":false},{"year":2014,"finding":"The proline-rich linker (PRL) region of vinculin and its binding protein vinexin α are required for sensing ECM stiffness. On rigid substrates, vinculin more stably localizes to focal adhesions; mutations in the PRL region or depletion of vinexin impair this stiffness response. Vinexin depletion also impairs stiffness-dependent regulation of cell migration.","method":"Vinexin siRNA knockdown, vinculin PRL mutants, FRAP (fluorescence recovery after photobleaching) at focal adhesions, cell migration assays on substrates of varying stiffness","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRAP + mutagenesis + functional migration assay, multiple orthogonal methods, mechanistic linkage established","pmids":["24554436"],"is_preprint":false},{"year":2014,"finding":"Vinexin (CPEB4-interacting protein) is a novel component of stress granules (SGs). Under arsenite-induced stress, vinexin translocates from focal adhesions to SGs; this translocation depends on its interaction with CPEB4. JNK signaling activated by arsenite enhances the CPEB4-vinexin association and promotes SG localization of vinexin. Vinexin localization to SGs influences SG formation and cell survival.","method":"Co-immunoprecipitation, immunofluorescence (FA-to-SG translocation), JNK signaling pharmacological inhibition, siRNA knockdown, cell survival assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP + live-cell imaging/immunofluorescence + pharmacological epistasis + functional survival readout, single lab","pmids":["25237887"],"is_preprint":false},{"year":2015,"finding":"Vinexin β binds HCV NS5A via conserved Pro-X-X-Pro-X-Arg motifs at the NS5A C-terminus and the third SH3 domain of vinexin β (residues W307 and Y325 are indispensable). Vinexin β modulates NS5A hyperphosphorylation in a casein kinase 1α-dependent manner; knockdown of vinexin β suppresses NS5A hyperphosphorylation and decreases HCV replication, which is rescued by shRNA-resistant vinexin β.","method":"Co-immunoprecipitation (endogenous and exogenous), site-directed mutagenesis (W307, Y325 in SH3; PxxPxR in NS5A), siRNA/shRNA knockdown, HCV replication assay, rescue experiment","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP + interface mutagenesis on both partners + functional rescue experiment, multiple orthogonal methods in single study","pmids":["25972535"],"is_preprint":false},{"year":2016,"finding":"SORBS3 (vinexin) co-activates estrogen receptor α (ERα) signaling, which indirectly represses STAT3 signaling in hepatocellular carcinoma cells. SORBS3 overexpression leads to decreased IL-6 target gene expression and reduced STAT3 signaling. SORBS3 and SH2D4A cooperate to inhibit HCC cell growth and clonogenicity more than either alone.","method":"Gene overexpression in HCC cells, gene expression profiling, STAT3 signaling assays, cell growth and clonogenicity assays, in situ and in vitro co-immunoprecipitation","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression gain-of-function + co-IP + target gene expression, single lab, indirect STAT3 inhibition via ERα","pmids":["27311882"],"is_preprint":false},{"year":2017,"finding":"Vinexin α and CAP (another SORBS family member) co-localize with vinculin at focal adhesions and promote vinculin-rich FAs and ECM stiffness-dependent vinculin behavior, whereas ArgBP2 co-localizes with α-actinin at proximal FA ends and on actin stress fibers, stabilizes α-actinin, and enhances intracellular contractile forces. These results define distinct mechanosensing roles of vinexin α vs. ArgBP2 within the SORBS family.","method":"Reconstituted MEF cell lines expressing individual SORBS proteins, immunofluorescence, traction force microscopy, FA morphometry","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic reconstituted cell lines with multiple functional assays, single lab but orthogonal readouts (imaging, force microscopy)","pmids":["28864765"],"is_preprint":false},{"year":2017,"finding":"Vinexin localizes to the midbody during cell division and recruits Rhotekin to the midbody via a rhotekin-binding motif; this is required for cytokinetic abscission. Knockdown of vinexin or overexpression of a vinexin mutant lacking the rhotekin-binding motif impairs cytokinetic abscission and increases cells arrested at the midbody stage.","method":"Immunofluorescence localization during cell division, siRNA knockdown, mutant overexpression, time-lapse imaging of cytokinesis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function + dominant-negative mutant + live imaging with defined mitotic readout, single lab","pmids":["28118077"],"is_preprint":false},{"year":2018,"finding":"Vinexin α and CAP are necessary for association of vinculin with the cytoskeleton and for YAP/TAZ nuclear localization in mesenchymal stem cells (MSCs) grown on rigid substrates. CAP regulates stiffness-dependent MSC differentiation, while vinexin depletion suppresses adipocyte differentiation independently of YAP/TAZ.","method":"siRNA knockdown, rigid/soft substrate culture, immunofluorescence of vinculin-cytoskeleton association, YAP/TAZ nuclear/cytoplasmic fractionation, MSC differentiation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown + biochemical fractionation + differentiation assay, single lab","pmids":["30068914"],"is_preprint":false},{"year":2019,"finding":"An amphipathic helix (H2) in vinexin α constitutes a novel vinculin-binding site, interacting with the vinculin D1b subdomain and promoting formation of a talin-vinculin-vinexin α ternary complex. H2 mutations impair the ability of vinexin α to induce an ECM stiffness-dependent 'open' conformational change in vinculin and to promote nuclear localization of YAP/TAZ on rigid ECM.","method":"Mutagenesis of H2 helix, co-immunoprecipitation, in vitro binding assays, FRET-based vinculin conformation assay, YAP/TAZ nuclear localization assay on substrates of varying stiffness","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis + in vitro binding + FRET conformational assay + functional YAP/TAZ nuclear readout, multiple orthogonal methods","pmids":["30578314"],"is_preprint":false},{"year":2021,"finding":"SORBS3/vinexin is a negative regulator of autophagy. SORBS3 knockdown increases F-actin structures, which compete with YAP/TAZ for binding to angiomotins (AMOTs) in the cytosol, freeing YAP/TAZ to translocate to the nucleus and increase transcriptional activity, thereby upregulating autophagosome biogenesis. Increased SORBS3 expression in aging mouse and human brains correlates with autophagic decline.","method":"siRNA knockdown, autophagy flux assays, F-actin imaging, YAP/TAZ nuclear/cytoplasmic localization assay, co-immunoprecipitation (YAP/TAZ-AMOT), gene expression analysis in aged brain tissue","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown + multiple pathway readouts (F-actin, AMOT co-IP, YAP/TAZ localization, autophagy flux), single lab","pmids":["34848853"],"is_preprint":false},{"year":2022,"finding":"SORBS3 depletion upregulates YAP1-WWTR1/TAZ target gene expression (including myosin- and actin-related genes) by releasing YAP/TAZ from AMOT-mediated cytosolic retention via increased F-actin structures, thereby promoting autophagosome formation. YAP1-WWTR1/TAZ target genes are downregulated in older mouse and human brains alongside increased SORBS3 expression.","method":"siRNA knockdown, YAP/TAZ nuclear translocation assay, target gene expression (RNA-seq/qPCR), autophagy flux assay, brain tissue gene expression analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function + transcriptomic + localization + autophagy assays, replication of 2021 findings with mechanistic detail, single lab","pmids":["35822241"],"is_preprint":false},{"year":2024,"finding":"UBE2T mediates ubiquitination and proteasomal degradation of SORBS3 in lung adenocarcinoma cells. Co-immunoprecipitation and ubiquitination assays demonstrate direct interaction between UBE2T and SORBS3. UBE2T-mediated SORBS3 degradation enhances IL-6/STAT3 signaling; restoration of SORBS3 suppresses this signaling and inhibits LUAD progression in vitro and in xenograft models.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, in vitro cell function assays (proliferation, migration, invasion, apoptosis), xenograft mouse model","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP + ubiquitination assay + in vivo validation, single lab","pmids":["38816989"],"is_preprint":false},{"year":2025,"finding":"SORBS3-β (vinexin β isoform) directly binds β-catenin and recruits UBA1 to enhance ubiquitination and proteasomal degradation of β-catenin, thereby inhibiting Wnt/β-catenin signaling. Downstream, this reduces VEGFC expression and suppresses lymphangiogenesis. In vivo, SORBS3-β overexpression attenuates lymphatic metastasis in cervical cancer xenograft models.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, lentiviral overexpression, Transwell invasion/migration assay, lymphangiogenesis assay, in vivo footpad xenograft model, LC-MS/MS, RNA-seq","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP + ubiquitination assay + in vivo model + proteomics, multiple orthogonal methods, single lab","pmids":["40200335"],"is_preprint":false},{"year":2013,"finding":"In zebrafish, Sorbs3 (ouchless mutant) is required for dorsal root ganglion (DRG) neurogenesis. Sorbs3 interacts genetically with erbb3 (ErbB receptor) in DRG development, and Sorbs3 is proposed to integrate ErbB signals through MAPK to upregulate neurogenin1. MEK inhibitors phenocopy the ouchless DRG defect.","method":"Zebrafish forward genetic screen (ouchless mutant), genetic epistasis with erbb3 allele, pharmacological MEK inhibition, in situ hybridization","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo + pharmacological epistasis, but mechanistic link is inferred rather than directly biochemically demonstrated","pmids":["24004948"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, SORB-1/vinexin interacts with RTKN-1/Rhotekin and DEB-1/vinculin in a complex that promotes axon regeneration. RTKN-1 links the DEB-1-SORB-1 complex to ALP-1 (which scaffolds phosphorylated myosin light chain), physically connecting MLC phosphorylation to the actin cytoskeleton during axon regeneration.","method":"Genetic epistasis in C. elegans, co-immunoprecipitation, in vivo axon regeneration assay","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis + co-IP + in vivo functional assay in C. elegans ortholog; invertebrate model","pmids":["38150455"],"is_preprint":false}],"current_model":"SORBS3/vinexin is a multi-SH3 domain adaptor protein that localizes to focal adhesions (and cell-cell junctions), where it binds vinculin through its first and second SH3 domains and an amphipathic H2 helix to act as an ECM stiffness mechanosensor—promoting a vinculin 'open' conformation and YAP/TAZ nuclear translocation on rigid substrates; its third SH3 domain recruits signaling proteins including Sos, c-Cbl, Rhotekin, and the HCV NS5A protein; vinexin is phosphorylated by ERK2 (Ser189/Ser593), Abl (Tyr127 on α isoform), and v-Src (multiple tyrosines), with ERK phosphorylation spatiotemporally regulating cell spreading, migration, and anchorage-independent growth; vinexin β inhibits RARγ-mediated transcription by binding the non-phosphorylated AF-1 domain, and negatively regulates AKT signaling to modulate cardiac hypertrophy and ischemic injury; at the cellular level vinexin also regulates EGFR phosphorylation (via c-Cbl sequestration), WAVE2 stability (via PKA-dependent proteasomal regulation), stress granule assembly (via CPEB4/JNK-mediated relocalization from FAs), autophagosome biogenesis (via F-actin-AMOT-YAP/TAZ signaling), and cytokinesis (via midbody recruitment of Rhotekin); UBE2T-mediated ubiquitination targets SORBS3 for proteasomal degradation, enhancing IL-6/STAT3 signaling, while SORBS3-β promotes β-catenin ubiquitination via UBA1 to suppress Wnt signaling and lymphangiogenesis."},"narrative":{"mechanistic_narrative":"SORBS3 (vinexin) is a multi-SH3-domain adaptor protein that couples the actin cytoskeleton and focal adhesions to signaling, transcription, and mechanotransduction [PMID:9885244, PMID:24554436]. It binds vinculin through its first and second SH3 domains and through an amphipathic H2 helix that contacts the vinculin D1b subdomain, building a talin–vinculin–vinexin ternary complex; on rigid ECM this interaction drives an 'open' vinculin conformation and promotes nuclear translocation of YAP/TAZ, defining vinexin as a stiffness mechanosensor at focal adhesions [PMID:9885244, PMID:24554436, PMID:30578314]. Its third SH3 domain serves as a hub for distinct partners—Sos to control JNK/SAPK activation downstream of growth factors [PMID:10585480], the E3 ligase c-Cbl to sustain EGFR phosphorylation [PMID:16923119], and Rhotekin, which vinexin recruits to the midbody to enable cytokinetic abscission [PMID:19294487, PMID:28118077]. Vinexin function is gated by phosphorylation: ERK1/2 directly phosphorylates the linker region at Ser189 (Ser593 in the α isoform), and this spatiotemporally regulated event shifts vinexin between promoting cell spreading/migration and inhibiting anchorage-independent growth [PMID:15184391, PMID:17486060, PMID:17241162], while v-Src-mediated tyrosine phosphorylation attenuates vinexin–vinculin binding [PMID:19580787]. Beyond adhesion, vinexin acts in transcriptional and signaling control—inhibiting RARγ-mediated transcription by binding its non-phosphorylated AF-1 domain [PMID:15734736], protecting against cardiac hypertrophy by blocking AKT signaling [PMID:23429936], and negatively regulating autophagy by restraining an F-actin–AMOT–YAP/TAZ axis [PMID:34848853, PMID:35822241]. Vinexin is required for keratinocyte migration and cutaneous wound healing in vivo, acting upstream of EGFR [PMID:20361963]. SORBS3 abundance is itself controlled by UBE2T-mediated ubiquitination and proteasomal degradation, which de-represses IL-6/STAT3 signaling in lung adenocarcinoma [PMID:38816989].","teleology":[{"year":1999,"claim":"Establishing vinexin as a vinculin-binding focal adhesion adaptor defined its core cytoskeletal scaffolding role and its capacity to remodel adhesions.","evidence":"Yeast two-hybrid, in vitro binding, immunofluorescence, and overexpression morphology in fibroblasts/epithelial cells","pmids":["9885244"],"confidence":"High","gaps":["Did not resolve how vinexin alters vinculin conformation or force transmission","Functional consequences of cell-cell junction localization left undefined"]},{"year":1999,"claim":"Identifying Sos binding to the third SH3 domain and growth-factor-regulated complex disruption connected vinexin to JNK/SAPK signaling and showed its SH3 domains are functionally distinct signaling docks.","evidence":"In vitro binding, co-IP, phosphatase treatment, dominant-negative SH3 mutant, JNK/SAPK kinase assay","pmids":["10585480"],"confidence":"High","gaps":["Did not establish the in vivo physiological pathway downstream of JNK activation","Selectivity for JNK over ERK mechanistically unexplained"]},{"year":2002,"claim":"Demonstrating linker-dependent, PKA-PAK-mediated anchorage-independent ERK2 activation showed vinexin can confer growth signaling independent of adhesion.","evidence":"Deletion mutants, dominant-negative constructs, H89 inhibitor, ERK2 assays in suspension vs adherent cells","pmids":["11825889"],"confidence":"Medium","gaps":["Direct biochemical link from the linker region to PKA/PAK not established","Physiological context of anchorage-independent signaling untested in vivo"]},{"year":2004,"claim":"Identifying ERK as a direct vinexin kinase that docks via a DEF motif and phosphorylates Ser189 placed vinexin in a feedback loop with the MAPK pathway it helps activate.","evidence":"In vitro kinase assay, Ser189 mutagenesis, DEF-domain mapping, co-IP, immunofluorescence","pmids":["15184391"],"confidence":"High","gaps":["Functional consequence of Ser189 phosphorylation not yet defined here","Whether ERK docking competes with other linker functions unknown"]},{"year":2005,"claim":"Showing vinexin β inhibits RARγ transcription by binding the non-phosphorylated AF-1 domain extended vinexin's role into nuclear receptor-dependent transcriptional control.","evidence":"Yeast two-hybrid, co-IP, immunofluorescence, gain/loss-of-function transcriptional reporters in F9 cells","pmids":["15734736"],"confidence":"High","gaps":["Mechanism by which a cytoskeletal adaptor accesses the nucleus not resolved","Whether endogenous retinoid signaling is regulated this way in vivo untested"]},{"year":2006,"claim":"Linking vinexin β to c-Cbl sequestration that sustains EGFR phosphorylation, and to PKA-dependent WAVE2 stabilization, defined how vinexin shapes receptor signaling and actin-nucleation machinery.","evidence":"Phospho-Western, mutational analysis, siRNA, co-IP, subcellular fractionation, proteasome/PKA modulation","pmids":["16923119","16483316"],"confidence":"Medium","gaps":["Direct demonstration that membrane c-Cbl is catalytically diverted not shown","PKA-to-WAVE2 stabilization mechanism only pharmacologically inferred"]},{"year":2007,"claim":"Showing Ser189 phosphorylation is spatially partitioned to the leading edge and functionally switches vinexin β between migration and anchorage-independent growth control gave a spatiotemporal logic to ERK-vinexin signaling.","evidence":"Phospho-state-specific antibody imaging, phosphomimetic/non-phosphorylatable mutants, spreading/migration/soft-agar assays","pmids":["17486060","17241162"],"confidence":"Medium","gaps":["Upstream cue determining where phosphorylation occurs not identified","Neuronal synaptic role of Ser593 phosphorylation functionally unexplored"]},{"year":2009,"claim":"Mapping Rhotekin binding to the third SH3 domain and showing v-Src tyrosine phosphorylation weakens vinexin-vinculin binding revealed both new partners and phospho-regulation of the core adhesion interaction.","evidence":"Yeast two-hybrid, in vitro binding, co-IP from cells and brain, mutagenesis of phospho-sites, affinity comparison","pmids":["19294487","19580787"],"confidence":"Medium","gaps":["Functional output of vinexin-Rhotekin at focal adhesions not yet defined here","Physiological kinase responsible for the three tyrosines not identified"]},{"year":2010,"claim":"Knockout mouse and knockdown studies established vinexin as physiologically required for keratinocyte migration and wound healing, acting upstream of EGFR.","evidence":"siRNA, scratch assay, pharmacological epistasis (AG1478, U0126), knockout mice, in vivo wound healing","pmids":["20361963"],"confidence":"High","gaps":["Molecular mechanism by which vinexin promotes EGFR activation in migration unresolved","Tissue specificity of the wound-healing requirement not defined"]},{"year":2013,"claim":"In vivo cardiac and zebrafish models showed vinexin restrains AKT signaling to limit cardiac hypertrophy and integrates ErbB/MAPK signaling for neurogenesis, broadening its organismal roles.","evidence":"Transgenic/knockout mice, aortic banding, echocardiography; zebrafish ouchless mutant, erbb3 epistasis, MEK inhibition","pmids":["23429936","24004948"],"confidence":"High","gaps":["Direct biochemical mechanism of AKT inhibition by vinexin not established","Zebrafish ErbB-MAPK-neurogenin1 link inferred genetically, not biochemically"]},{"year":2014,"claim":"FRAP-based stiffness assays and stress-granule studies defined vinexin as an ECM stiffness sensor and a stress-responsive component that relocalizes from adhesions during stress.","evidence":"Vinexin siRNA, vinculin PRL mutants, FRAP, stiffness migration assays; CPEB4 co-IP, FA-to-SG translocation, JNK inhibition, survival assay","pmids":["24554436","25237887"],"confidence":"High","gaps":["How vinexin physically reports stiffness to vinculin not yet resolved at this stage","Functional contribution of vinexin within stress granules incompletely defined"]},{"year":2015,"claim":"Mapping the HCV NS5A interaction to the third SH3 domain (W307/Y325) and showing vinexin β controls NS5A hyperphosphorylation and HCV replication revealed a pathogen co-option of the adaptor.","evidence":"Reciprocal co-IP, interface mutagenesis on both partners, shRNA, HCV replication and rescue assays","pmids":["25972535"],"confidence":"High","gaps":["How vinexin promotes CK1α-dependent NS5A phosphorylation mechanistically unclear","Whether host substrates are similarly regulated not addressed"]},{"year":2017,"claim":"Reconstitution of individual SORBS proteins and midbody studies distinguished vinexin α's vinculin-centric mechanosensing from ArgBP2's α-actinin role and assigned vinexin a cytokinetic abscission function via Rhotekin recruitment.","evidence":"Reconstituted MEF lines, traction force microscopy, FA morphometry; midbody immunofluorescence, siRNA, mutant lacking Rhotekin motif, time-lapse imaging","pmids":["28864765","28118077"],"confidence":"Medium","gaps":["Structural basis for SORBS family functional divergence not resolved","How vinexin is targeted to the midbody not defined"]},{"year":2018,"claim":"Identifying vinexin α (with CAP) as required for vinculin-cytoskeleton association and stiffness-dependent YAP/TAZ nuclear localization in MSCs connected vinexin mechanosensing to transcriptional/differentiation outputs.","evidence":"siRNA, rigid/soft substrates, vinculin-cytoskeleton imaging, YAP/TAZ fractionation, MSC differentiation assays","pmids":["30068914"],"confidence":"Medium","gaps":["YAP/TAZ-independent control of adipogenesis by vinexin mechanistically unexplained","Quantitative contribution relative to CAP not resolved"]},{"year":2019,"claim":"Defining the H2 amphipathic helix as a second vinculin-binding site that drives stiffness-dependent vinculin opening and YAP/TAZ translocation provided the structural mechanism of vinexin mechanosensing.","evidence":"H2 mutagenesis, in vitro binding, FRET vinculin conformation assay, stiffness-dependent YAP/TAZ localization","pmids":["30578314"],"confidence":"High","gaps":["High-resolution structure of the talin-vinculin-vinexin complex not determined","How force is sensed and transmitted through H2 not directly measured"]},{"year":2021,"claim":"Establishing vinexin as a negative autophagy regulator via an F-actin-AMOT-YAP/TAZ axis, with rising expression in aged brain, linked it to age-associated autophagic decline.","evidence":"siRNA, autophagy flux, F-actin imaging, YAP/TAZ localization, YAP/TAZ-AMOT co-IP, transcriptomics; aged brain expression analysis","pmids":["34848853","35822241"],"confidence":"Medium","gaps":["Whether vinexin directly regulates F-actin or AMOT binding not shown","Causal role of vinexin in age-related autophagy decline in vivo not established"]},{"year":2024,"claim":"Showing UBE2T ubiquitinates and degrades SORBS3 to de-repress IL-6/STAT3 signaling defined a degradation mechanism controlling vinexin abundance in cancer, and SORBS3-β-driven β-catenin ubiquitination via UBA1 extended this to Wnt suppression.","evidence":"Co-IP, ubiquitination assays, knockdown/overexpression, xenograft models; LC-MS/MS and RNA-seq for the β-catenin axis","pmids":["38816989","40200335"],"confidence":"Medium","gaps":["Direct E3 ligase partnering UBE2T toward SORBS3 not identified","Whether SORBS3-β acts as a bona fide ubiquitin adaptor for UBA1/β-catenin needs structural validation"]},{"year":null,"claim":"How vinexin's distinct activities—mechanosensing, MAPK/AKT/STAT signaling, transcriptional control, autophagy, and ubiquitin-dependent degradation—are integrated and switched in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model coordinating focal-adhesion vs nuclear vs degradative functions","No high-resolution structure of vinexin in any of its complexes","Endogenous physiological triggers selecting among partner interactions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,9,14,18,25]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,18,22,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,17,26,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,11,24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,26]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal 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Vinexin beta isoform plays a role in cell spreading and enhances the activation of JNK/SAPK in response to EGF stimulation by using its third SH3 domain","subcellular_location":"Cell junction; Nucleus; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/O60504/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SORBS3","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/SORBS3","total_profiled":1310},"omim":[{"mim_id":"610795","title":"SORBIN AND SH3 DOMAINS-CONTAINING PROTEIN 3; SORBS3","url":"https://www.omim.org/entry/610795"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cell 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all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SORBS3"},"hgnc":{"alias_symbol":["SCAM-1","SH3D4","vinexin"],"prev_symbol":[]},"alphafold":{"accession":"O60504","domains":[{"cath_id":"2.30.30.40","chopping":"384-437","consensus_level":"high","plddt":87.9744,"start":384,"end":437},{"cath_id":"2.30.30.40","chopping":"452-521","consensus_level":"high","plddt":87.1727,"start":452,"end":521},{"cath_id":"2.30.30.40","chopping":"616-671","consensus_level":"high","plddt":91.1896,"start":616,"end":671}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60504","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60504-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60504-F1-predicted_aligned_error_v6.png","plddt_mean":56.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SORBS3","jax_strain_url":"https://www.jax.org/strain/search?query=SORBS3"},"sequence":{"accession":"O60504","fasta_url":"https://rest.uniprot.org/uniprotkb/O60504.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60504/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60504"}},"corpus_meta":[{"pmid":"11937713","id":"PMC_11937713","title":"Vinexin, 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Both vinexin α and β localize to focal adhesions in fibroblasts and cell-cell junctions in epithelial cells. Expression of vinexin increases focal adhesion size, promotes actin stress fiber formation (vinexin α), and enhances cell spreading on fibronectin.\",\n      \"method\": \"Yeast two-hybrid system, in vitro binding assay, immunofluorescence localization, stable cell line overexpression with morphological readout\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal yeast two-hybrid + in vitro binding + direct localization experiments with functional phenotypic readouts, foundational paper replicated by subsequent work\",\n      \"pmids\": [\"9885244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The third SH3 domain of vinexin binds Sos (a guanine nucleotide exchange factor for Ras and Rac) both in vitro and in vivo. Growth factor stimulation (EGF, PDGF, serum) causes Sos phosphorylation that disrupts the vinexin-Sos complex. Exogenous vinexin β enhances JNK/SAPK activation but not ERK activation in response to EGF; a point mutation in the third SH3 domain abolishes EGF-induced JNK/SAPK activation in a dominant-negative manner.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, phosphatase treatment, dominant-negative mutant expression, JNK/SAPK kinase activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding, co-IP, site-directed mutagenesis, and functional kinase assay in a single study with clear mechanistic readout\",\n      \"pmids\": [\"10585480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Vinexin β expression enables anchorage-independent ERK2 activation stimulated by EGF. The linker region between the second and third SH3 domains of vinexin β (not the SH3 domains themselves) is required for this function. This activity operates through a PKA-PAK signaling pathway: dominant-negative PAK suppresses vinexin β-induced anchorage-independent ERK2 activation, and dominant-negative vinexin β inhibits PKA inhibitor-induced anchorage-independent ERK2 activation.\",\n      \"method\": \"Deletion mutant analysis, dominant-negative constructs, pharmacological inhibitors (H89), ERK2 activation assay in suspended vs. adherent cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via dominant-negative constructs plus pharmacological inhibitors, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"11825889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Vinexin α interacts in vitro with estrogen receptor α (ERα), ERβ, androgen receptor, and glucocorticoid receptor; the SH3 domains are not required for this interaction. Co-expression of vinexin α with ERα leads to loss of ERα serine phosphorylation and partial redistribution of vinexin α into the nucleus where it co-localizes with ERα. Vinexin α stimulates ligand-induced transactivation of these receptors.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, immunofluorescence localization, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding + co-IP + reporter assays + localization, single lab study\",\n      \"pmids\": [\"14625289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Vinexin binds lp-dlg/KIAA0583 (a MAGUK family protein) via the third SH3 domain of vinexin interacting with a proline-rich sequence between the second and third PDZ domains of lp-dlg. lp-dlg co-localizes with vinexin at cell-cell contacts in epithelial cells, co-immunoprecipitates with β-catenin, and the three proteins can form a ternary complex, linking the vinexin-vinculin complex to β-catenin at adherens junctions.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation with deletion mutants, immunofluorescence co-localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid + reciprocal co-IP + localization, single lab\",\n      \"pmids\": [\"12657639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ERK1/2 directly phosphorylates vinexin upon growth factor stimulation. ERK2 phosphorylates serine 189 (in the linker region between the second and third SH3 domains) of vinexin β. Vinexin interacts with the active (but not inactive) form of ERK1/2 via a DEF (FXFP) docking domain in its linker region. Cell adhesion to fibronectin also induces vinexin-ERK2 association and vinexin phosphorylation; vinexin and ERK co-localize at the cell periphery during spreading.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (Ser189), co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay combined with mutagenesis identifying specific phosphorylation site and docking domain, plus in vivo co-IP validation\",\n      \"pmids\": [\"15184391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SOCS-7 interacts with vinexin through proline-rich regions N-terminal to the SOCS-7 SH2 domain (likely binding an SH3 domain of vinexin). Vinexin-α co-precipitates with SOCS-7, and part of SOCS-7-GFP merges with vinexin and actin by confocal microscopy, linking SOCS-7 to the actin cytoskeleton via vinexin.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, confocal immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid + co-IP + localization, single lab, no functional mutagenesis\",\n      \"pmids\": [\"15242778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Vinexin β interacts with the non-phosphorylated AF-1 domain of RARγ (identified by yeast two-hybrid). Vinexin β co-localizes with RARγ in the nucleus. Phosphorylation of the AF-1 domain of RARγ prevents vinexin β binding. Stable overexpression of vinexin β or vinexin knockdown by RNAi demonstrates that vinexin β is an inhibitor of RARγ-mediated transcription.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, stable overexpression, siRNA knockdown, transcriptional reporter assays in F9 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (yeast two-hybrid, co-IP, localization, gain- and loss-of-function transcriptional assays) in single study\",\n      \"pmids\": [\"15734736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SHIP2 interacts with vinexin via its C-terminal region (identified by yeast two-hybrid). The interaction was confirmed by co-immunoprecipitation in COS-7 cells and mouse embryonic fibroblasts. Vinexin α and SHIP2 co-localize at the cell periphery. Vinexin does not affect SHIP2 phosphatase activity in vitro. Co-expression of SHIP2 and vinexin enhances cell adhesion to collagen-I; this requires the SHIP2 C-terminus and catalytic activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro phosphatase assay, cell adhesion assay with SHIP2 mutants and knockout MEFs\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP in two cell types, in vitro phosphatase assay, functional adhesion assay, single lab\",\n      \"pmids\": [\"16302969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Vinexin β regulates EGFR phosphorylation by suppressing EGFR dephosphorylation (sustaining phosphorylation), requiring both the first and third SH3 domains. Vinexin β binds E3 ubiquitin ligase c-Cbl through its third SH3 domain, decreases the cytosolic pool of c-Cbl and increases membrane-associated c-Cbl; overexpression of c-Cbl abolishes the vinexin β-mediated sustained EGFR phosphorylation.\",\n      \"method\": \"Western blot with phospho-specific antibodies, mutational analysis, siRNA knockdown, co-immunoprecipitation, subcellular fractionation\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutational analysis + co-IP + siRNA loss-of-function + rescue experiment, single lab\",\n      \"pmids\": [\"16923119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Vinexin β interacts with WAVE2 (and also WAVE1 and N-WASP) through its first and second SH3 domains binding the proline-rich region of WAVE2. Vinexin β increases the amount of WAVE2 protein and induces a phosphorylation-dependent mobility shift. This effect requires PKA activity (PKA inhibition suppresses it; PKA activation mimics it) and involves proteasome-dependent regulation of WAVE2 degradation.\",\n      \"method\": \"Co-immunoprecipitation, deletion/point mutant analysis, proteasome inhibitor treatment, PKA pharmacological modulation, SDS-PAGE mobility shift assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis + pharmacological epistasis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16483316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Abl kinase interacts with vinexin α and β primarily through the third SH3 domain; both co-localize at membrane ruffles in rat astrocytes and the interaction is reduced by the F-actin disruptor latrunculin B (indicating F-actin-mediated regulation). c-Abl and v-Abl phosphorylate vinexin α (but not β) at tyrosine 127, identified by mutational analysis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, latrunculin B treatment, in vivo phosphorylation assay, site-directed mutagenesis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP + mutagenesis identifying phosphorylation site + localization, single lab\",\n      \"pmids\": [\"16831423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ERK-mediated phosphorylation of vinexin β at Ser189 is spatiotemporally regulated: phosphorylated vinexin β is enriched at the leading edge of migrating cells and at the cell periphery during spreading but not at focal adhesions of well-spread cells. Using phosphomimetic and non-phosphorylatable Ser189 mutants, phosphorylation of vinexin β inhibits cell spreading and migration, while unphosphorylated vinexin β inhibits anchorage-independent cell growth.\",\n      \"method\": \"Phosphorylation-state-specific antibody immunofluorescence, stable cell lines expressing GFP-vinexin β phosphomimetic/non-phosphorylatable mutants, cell spreading, migration, and soft-agar growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-specific antibody + structure-function mutants + multiple functional assays, single lab\",\n      \"pmids\": [\"17486060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Vinexin isoforms are expressed in rat brain in a developmental stage-dependent manner; vinexin α is enriched in adult telencephalon. In primary rat hippocampal neurons, vinexin localizes at synapses and filopodia in growth cones (confirmed by biochemical fractionation and electron microscopy). ERK-mediated phosphorylation of vinexin at Ser593 (equivalent to Ser189 in β) occurs at postsynaptic sites of hippocampal synapses (immunoelectron microscopy) and is reduced by the MEK inhibitor PD98059.\",\n      \"method\": \"Immunofluorescence, biochemical fractionation (synaptosomes), electron microscopy, immunoelectron microscopy, phospho-specific antibody, MEK inhibitor\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple localization methods (EM, immunofluorescence, fractionation) plus functional pharmacological inhibition, single lab\",\n      \"pmids\": [\"17241162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Vinexin binds Rhotekin via the C-terminal proline-rich motif of Rhotekin and the third SH3 domain of vinexin. This interaction is little affected by RhoA but is inhibited by activated Cdc42. Vinexin α and Rhotekin partially co-localize at focal adhesions in fibroblasts.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro binding assay, co-immunoprecipitation from COS7 cells and brain tissue, immunofluorescence\",\n      \"journal\": \"Medical molecular morphology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid + co-IP (in cells and tissue) + localization, single lab, no direct functional mutagenesis of the binding interface\",\n      \"pmids\": [\"19294487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In v-Src-transformed cells, vinexin α is tyrosine phosphorylated at three tyrosine residues. A non-phosphorylatable triple mutant of vinexin α shows higher binding affinity for vinculin than wild-type, demonstrating that tyrosine phosphorylation of vinexin α attenuates its interaction with vinculin.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, binding affinity comparison between wild-type and phosphorylation mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis + co-IP functional readout, single lab\",\n      \"pmids\": [\"19580787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Vinexin is required for keratinocyte migration and cutaneous wound healing. Vinexin knockdown delays migration of HaCaT and A431 cells in scratch assay without affecting proliferation. Scratch-induced cell migration activates EGFR and ERK; vinexin knockdown inhibits scratch-induced EGFR activation (but not ERK activation), placing vinexin upstream of EGFR in the migration pathway. Vinexin-knockout mice show delayed cutaneous wound healing in vivo.\",\n      \"method\": \"siRNA knockdown, scratch migration assay, pharmacological inhibition (AG1478, U0126), knockout mouse model, in vivo wound healing assay, Western blot for EGFR/ERK activation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown + knockout mouse model + pharmacological epistasis, multiple cell types and in vivo validation\",\n      \"pmids\": [\"20361963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Vinexin β protects against cardiac hypertrophy by blocking AKT signaling. Vinexin β overexpression in the heart attenuates pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction, while vinexin β knockout exaggerates these responses. Both in vitro and in vivo analyses show that vinexin β's protective effects are associated with AKT signaling abrogation.\",\n      \"method\": \"Transgenic overexpression, knockout mouse model, aortic banding (pressure overload), echocardiography, molecular signaling analysis (AKT phosphorylation), histopathology\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic gain- and loss-of-function in vivo models with defined molecular pathway (AKT) and functional cardiac readout\",\n      \"pmids\": [\"23429936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The proline-rich linker (PRL) region of vinculin and its binding protein vinexin α are required for sensing ECM stiffness. On rigid substrates, vinculin more stably localizes to focal adhesions; mutations in the PRL region or depletion of vinexin impair this stiffness response. Vinexin depletion also impairs stiffness-dependent regulation of cell migration.\",\n      \"method\": \"Vinexin siRNA knockdown, vinculin PRL mutants, FRAP (fluorescence recovery after photobleaching) at focal adhesions, cell migration assays on substrates of varying stiffness\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP + mutagenesis + functional migration assay, multiple orthogonal methods, mechanistic linkage established\",\n      \"pmids\": [\"24554436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Vinexin (CPEB4-interacting protein) is a novel component of stress granules (SGs). Under arsenite-induced stress, vinexin translocates from focal adhesions to SGs; this translocation depends on its interaction with CPEB4. JNK signaling activated by arsenite enhances the CPEB4-vinexin association and promotes SG localization of vinexin. Vinexin localization to SGs influences SG formation and cell survival.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence (FA-to-SG translocation), JNK signaling pharmacological inhibition, siRNA knockdown, cell survival assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP + live-cell imaging/immunofluorescence + pharmacological epistasis + functional survival readout, single lab\",\n      \"pmids\": [\"25237887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Vinexin β binds HCV NS5A via conserved Pro-X-X-Pro-X-Arg motifs at the NS5A C-terminus and the third SH3 domain of vinexin β (residues W307 and Y325 are indispensable). Vinexin β modulates NS5A hyperphosphorylation in a casein kinase 1α-dependent manner; knockdown of vinexin β suppresses NS5A hyperphosphorylation and decreases HCV replication, which is rescued by shRNA-resistant vinexin β.\",\n      \"method\": \"Co-immunoprecipitation (endogenous and exogenous), site-directed mutagenesis (W307, Y325 in SH3; PxxPxR in NS5A), siRNA/shRNA knockdown, HCV replication assay, rescue experiment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP + interface mutagenesis on both partners + functional rescue experiment, multiple orthogonal methods in single study\",\n      \"pmids\": [\"25972535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SORBS3 (vinexin) co-activates estrogen receptor α (ERα) signaling, which indirectly represses STAT3 signaling in hepatocellular carcinoma cells. SORBS3 overexpression leads to decreased IL-6 target gene expression and reduced STAT3 signaling. SORBS3 and SH2D4A cooperate to inhibit HCC cell growth and clonogenicity more than either alone.\",\n      \"method\": \"Gene overexpression in HCC cells, gene expression profiling, STAT3 signaling assays, cell growth and clonogenicity assays, in situ and in vitro co-immunoprecipitation\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression gain-of-function + co-IP + target gene expression, single lab, indirect STAT3 inhibition via ERα\",\n      \"pmids\": [\"27311882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Vinexin α and CAP (another SORBS family member) co-localize with vinculin at focal adhesions and promote vinculin-rich FAs and ECM stiffness-dependent vinculin behavior, whereas ArgBP2 co-localizes with α-actinin at proximal FA ends and on actin stress fibers, stabilizes α-actinin, and enhances intracellular contractile forces. These results define distinct mechanosensing roles of vinexin α vs. ArgBP2 within the SORBS family.\",\n      \"method\": \"Reconstituted MEF cell lines expressing individual SORBS proteins, immunofluorescence, traction force microscopy, FA morphometry\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic reconstituted cell lines with multiple functional assays, single lab but orthogonal readouts (imaging, force microscopy)\",\n      \"pmids\": [\"28864765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Vinexin localizes to the midbody during cell division and recruits Rhotekin to the midbody via a rhotekin-binding motif; this is required for cytokinetic abscission. Knockdown of vinexin or overexpression of a vinexin mutant lacking the rhotekin-binding motif impairs cytokinetic abscission and increases cells arrested at the midbody stage.\",\n      \"method\": \"Immunofluorescence localization during cell division, siRNA knockdown, mutant overexpression, time-lapse imaging of cytokinesis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function + dominant-negative mutant + live imaging with defined mitotic readout, single lab\",\n      \"pmids\": [\"28118077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Vinexin α and CAP are necessary for association of vinculin with the cytoskeleton and for YAP/TAZ nuclear localization in mesenchymal stem cells (MSCs) grown on rigid substrates. CAP regulates stiffness-dependent MSC differentiation, while vinexin depletion suppresses adipocyte differentiation independently of YAP/TAZ.\",\n      \"method\": \"siRNA knockdown, rigid/soft substrate culture, immunofluorescence of vinculin-cytoskeleton association, YAP/TAZ nuclear/cytoplasmic fractionation, MSC differentiation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown + biochemical fractionation + differentiation assay, single lab\",\n      \"pmids\": [\"30068914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"An amphipathic helix (H2) in vinexin α constitutes a novel vinculin-binding site, interacting with the vinculin D1b subdomain and promoting formation of a talin-vinculin-vinexin α ternary complex. H2 mutations impair the ability of vinexin α to induce an ECM stiffness-dependent 'open' conformational change in vinculin and to promote nuclear localization of YAP/TAZ on rigid ECM.\",\n      \"method\": \"Mutagenesis of H2 helix, co-immunoprecipitation, in vitro binding assays, FRET-based vinculin conformation assay, YAP/TAZ nuclear localization assay on substrates of varying stiffness\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis + in vitro binding + FRET conformational assay + functional YAP/TAZ nuclear readout, multiple orthogonal methods\",\n      \"pmids\": [\"30578314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SORBS3/vinexin is a negative regulator of autophagy. SORBS3 knockdown increases F-actin structures, which compete with YAP/TAZ for binding to angiomotins (AMOTs) in the cytosol, freeing YAP/TAZ to translocate to the nucleus and increase transcriptional activity, thereby upregulating autophagosome biogenesis. Increased SORBS3 expression in aging mouse and human brains correlates with autophagic decline.\",\n      \"method\": \"siRNA knockdown, autophagy flux assays, F-actin imaging, YAP/TAZ nuclear/cytoplasmic localization assay, co-immunoprecipitation (YAP/TAZ-AMOT), gene expression analysis in aged brain tissue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown + multiple pathway readouts (F-actin, AMOT co-IP, YAP/TAZ localization, autophagy flux), single lab\",\n      \"pmids\": [\"34848853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SORBS3 depletion upregulates YAP1-WWTR1/TAZ target gene expression (including myosin- and actin-related genes) by releasing YAP/TAZ from AMOT-mediated cytosolic retention via increased F-actin structures, thereby promoting autophagosome formation. YAP1-WWTR1/TAZ target genes are downregulated in older mouse and human brains alongside increased SORBS3 expression.\",\n      \"method\": \"siRNA knockdown, YAP/TAZ nuclear translocation assay, target gene expression (RNA-seq/qPCR), autophagy flux assay, brain tissue gene expression analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function + transcriptomic + localization + autophagy assays, replication of 2021 findings with mechanistic detail, single lab\",\n      \"pmids\": [\"35822241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2T mediates ubiquitination and proteasomal degradation of SORBS3 in lung adenocarcinoma cells. Co-immunoprecipitation and ubiquitination assays demonstrate direct interaction between UBE2T and SORBS3. UBE2T-mediated SORBS3 degradation enhances IL-6/STAT3 signaling; restoration of SORBS3 suppresses this signaling and inhibits LUAD progression in vitro and in xenograft models.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, in vitro cell function assays (proliferation, migration, invasion, apoptosis), xenograft mouse model\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP + ubiquitination assay + in vivo validation, single lab\",\n      \"pmids\": [\"38816989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SORBS3-β (vinexin β isoform) directly binds β-catenin and recruits UBA1 to enhance ubiquitination and proteasomal degradation of β-catenin, thereby inhibiting Wnt/β-catenin signaling. Downstream, this reduces VEGFC expression and suppresses lymphangiogenesis. In vivo, SORBS3-β overexpression attenuates lymphatic metastasis in cervical cancer xenograft models.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, lentiviral overexpression, Transwell invasion/migration assay, lymphangiogenesis assay, in vivo footpad xenograft model, LC-MS/MS, RNA-seq\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP + ubiquitination assay + in vivo model + proteomics, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40200335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In zebrafish, Sorbs3 (ouchless mutant) is required for dorsal root ganglion (DRG) neurogenesis. Sorbs3 interacts genetically with erbb3 (ErbB receptor) in DRG development, and Sorbs3 is proposed to integrate ErbB signals through MAPK to upregulate neurogenin1. MEK inhibitors phenocopy the ouchless DRG defect.\",\n      \"method\": \"Zebrafish forward genetic screen (ouchless mutant), genetic epistasis with erbb3 allele, pharmacological MEK inhibition, in situ hybridization\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo + pharmacological epistasis, but mechanistic link is inferred rather than directly biochemically demonstrated\",\n      \"pmids\": [\"24004948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, SORB-1/vinexin interacts with RTKN-1/Rhotekin and DEB-1/vinculin in a complex that promotes axon regeneration. RTKN-1 links the DEB-1-SORB-1 complex to ALP-1 (which scaffolds phosphorylated myosin light chain), physically connecting MLC phosphorylation to the actin cytoskeleton during axon regeneration.\",\n      \"method\": \"Genetic epistasis in C. elegans, co-immunoprecipitation, in vivo axon regeneration assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis + co-IP + in vivo functional assay in C. elegans ortholog; invertebrate model\",\n      \"pmids\": [\"38150455\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SORBS3/vinexin is a multi-SH3 domain adaptor protein that localizes to focal adhesions (and cell-cell junctions), where it binds vinculin through its first and second SH3 domains and an amphipathic H2 helix to act as an ECM stiffness mechanosensor—promoting a vinculin 'open' conformation and YAP/TAZ nuclear translocation on rigid substrates; its third SH3 domain recruits signaling proteins including Sos, c-Cbl, Rhotekin, and the HCV NS5A protein; vinexin is phosphorylated by ERK2 (Ser189/Ser593), Abl (Tyr127 on α isoform), and v-Src (multiple tyrosines), with ERK phosphorylation spatiotemporally regulating cell spreading, migration, and anchorage-independent growth; vinexin β inhibits RARγ-mediated transcription by binding the non-phosphorylated AF-1 domain, and negatively regulates AKT signaling to modulate cardiac hypertrophy and ischemic injury; at the cellular level vinexin also regulates EGFR phosphorylation (via c-Cbl sequestration), WAVE2 stability (via PKA-dependent proteasomal regulation), stress granule assembly (via CPEB4/JNK-mediated relocalization from FAs), autophagosome biogenesis (via F-actin-AMOT-YAP/TAZ signaling), and cytokinesis (via midbody recruitment of Rhotekin); UBE2T-mediated ubiquitination targets SORBS3 for proteasomal degradation, enhancing IL-6/STAT3 signaling, while SORBS3-β promotes β-catenin ubiquitination via UBA1 to suppress Wnt signaling and lymphangiogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SORBS3 (vinexin) is a multi-SH3-domain adaptor protein that couples the actin cytoskeleton and focal adhesions to signaling, transcription, and mechanotransduction [#0, #18]. It binds vinculin through its first and second SH3 domains and through an amphipathic H2 helix that contacts the vinculin D1b subdomain, building a talin–vinculin–vinexin ternary complex; on rigid ECM this interaction drives an 'open' vinculin conformation and promotes nuclear translocation of YAP/TAZ, defining vinexin as a stiffness mechanosensor at focal adhesions [#0, #18, #25]. Its third SH3 domain serves as a hub for distinct partners—Sos to control JNK/SAPK activation downstream of growth factors [#1], the E3 ligase c-Cbl to sustain EGFR phosphorylation [#9], and Rhotekin, which vinexin recruits to the midbody to enable cytokinetic abscission [#14, #23]. Vinexin function is gated by phosphorylation: ERK1/2 directly phosphorylates the linker region at Ser189 (Ser593 in the α isoform), and this spatiotemporally regulated event shifts vinexin between promoting cell spreading/migration and inhibiting anchorage-independent growth [#5, #12, #13], while v-Src-mediated tyrosine phosphorylation attenuates vinexin–vinculin binding [#15]. Beyond adhesion, vinexin acts in transcriptional and signaling control—inhibiting RARγ-mediated transcription by binding its non-phosphorylated AF-1 domain [#7], protecting against cardiac hypertrophy by blocking AKT signaling [#17], and negatively regulating autophagy by restraining an F-actin–AMOT–YAP/TAZ axis [#26, #27]. Vinexin is required for keratinocyte migration and cutaneous wound healing in vivo, acting upstream of EGFR [#16]. SORBS3 abundance is itself controlled by UBE2T-mediated ubiquitination and proteasomal degradation, which de-represses IL-6/STAT3 signaling in lung adenocarcinoma [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing vinexin as a vinculin-binding focal adhesion adaptor defined its core cytoskeletal scaffolding role and its capacity to remodel adhesions.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, immunofluorescence, and overexpression morphology in fibroblasts/epithelial cells\",\n      \"pmids\": [\"9885244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how vinexin alters vinculin conformation or force transmission\", \"Functional consequences of cell-cell junction localization left undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying Sos binding to the third SH3 domain and growth-factor-regulated complex disruption connected vinexin to JNK/SAPK signaling and showed its SH3 domains are functionally distinct signaling docks.\",\n      \"evidence\": \"In vitro binding, co-IP, phosphatase treatment, dominant-negative SH3 mutant, JNK/SAPK kinase assay\",\n      \"pmids\": [\"10585480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the in vivo physiological pathway downstream of JNK activation\", \"Selectivity for JNK over ERK mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating linker-dependent, PKA-PAK-mediated anchorage-independent ERK2 activation showed vinexin can confer growth signaling independent of adhesion.\",\n      \"evidence\": \"Deletion mutants, dominant-negative constructs, H89 inhibitor, ERK2 assays in suspension vs adherent cells\",\n      \"pmids\": [\"11825889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link from the linker region to PKA/PAK not established\", \"Physiological context of anchorage-independent signaling untested in vivo\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying ERK as a direct vinexin kinase that docks via a DEF motif and phosphorylates Ser189 placed vinexin in a feedback loop with the MAPK pathway it helps activate.\",\n      \"evidence\": \"In vitro kinase assay, Ser189 mutagenesis, DEF-domain mapping, co-IP, immunofluorescence\",\n      \"pmids\": [\"15184391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Ser189 phosphorylation not yet defined here\", \"Whether ERK docking competes with other linker functions unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing vinexin β inhibits RARγ transcription by binding the non-phosphorylated AF-1 domain extended vinexin's role into nuclear receptor-dependent transcriptional control.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, immunofluorescence, gain/loss-of-function transcriptional reporters in F9 cells\",\n      \"pmids\": [\"15734736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a cytoskeletal adaptor accesses the nucleus not resolved\", \"Whether endogenous retinoid signaling is regulated this way in vivo untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking vinexin β to c-Cbl sequestration that sustains EGFR phosphorylation, and to PKA-dependent WAVE2 stabilization, defined how vinexin shapes receptor signaling and actin-nucleation machinery.\",\n      \"evidence\": \"Phospho-Western, mutational analysis, siRNA, co-IP, subcellular fractionation, proteasome/PKA modulation\",\n      \"pmids\": [\"16923119\", \"16483316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that membrane c-Cbl is catalytically diverted not shown\", \"PKA-to-WAVE2 stabilization mechanism only pharmacologically inferred\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing Ser189 phosphorylation is spatially partitioned to the leading edge and functionally switches vinexin β between migration and anchorage-independent growth control gave a spatiotemporal logic to ERK-vinexin signaling.\",\n      \"evidence\": \"Phospho-state-specific antibody imaging, phosphomimetic/non-phosphorylatable mutants, spreading/migration/soft-agar assays\",\n      \"pmids\": [\"17486060\", \"17241162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream cue determining where phosphorylation occurs not identified\", \"Neuronal synaptic role of Ser593 phosphorylation functionally unexplored\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping Rhotekin binding to the third SH3 domain and showing v-Src tyrosine phosphorylation weakens vinexin-vinculin binding revealed both new partners and phospho-regulation of the core adhesion interaction.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP from cells and brain, mutagenesis of phospho-sites, affinity comparison\",\n      \"pmids\": [\"19294487\", \"19580787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of vinexin-Rhotekin at focal adhesions not yet defined here\", \"Physiological kinase responsible for the three tyrosines not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Knockout mouse and knockdown studies established vinexin as physiologically required for keratinocyte migration and wound healing, acting upstream of EGFR.\",\n      \"evidence\": \"siRNA, scratch assay, pharmacological epistasis (AG1478, U0126), knockout mice, in vivo wound healing\",\n      \"pmids\": [\"20361963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which vinexin promotes EGFR activation in migration unresolved\", \"Tissue specificity of the wound-healing requirement not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"In vivo cardiac and zebrafish models showed vinexin restrains AKT signaling to limit cardiac hypertrophy and integrates ErbB/MAPK signaling for neurogenesis, broadening its organismal roles.\",\n      \"evidence\": \"Transgenic/knockout mice, aortic banding, echocardiography; zebrafish ouchless mutant, erbb3 epistasis, MEK inhibition\",\n      \"pmids\": [\"23429936\", \"24004948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism of AKT inhibition by vinexin not established\", \"Zebrafish ErbB-MAPK-neurogenin1 link inferred genetically, not biochemically\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"FRAP-based stiffness assays and stress-granule studies defined vinexin as an ECM stiffness sensor and a stress-responsive component that relocalizes from adhesions during stress.\",\n      \"evidence\": \"Vinexin siRNA, vinculin PRL mutants, FRAP, stiffness migration assays; CPEB4 co-IP, FA-to-SG translocation, JNK inhibition, survival assay\",\n      \"pmids\": [\"24554436\", \"25237887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How vinexin physically reports stiffness to vinculin not yet resolved at this stage\", \"Functional contribution of vinexin within stress granules incompletely defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapping the HCV NS5A interaction to the third SH3 domain (W307/Y325) and showing vinexin β controls NS5A hyperphosphorylation and HCV replication revealed a pathogen co-option of the adaptor.\",\n      \"evidence\": \"Reciprocal co-IP, interface mutagenesis on both partners, shRNA, HCV replication and rescue assays\",\n      \"pmids\": [\"25972535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How vinexin promotes CK1α-dependent NS5A phosphorylation mechanistically unclear\", \"Whether host substrates are similarly regulated not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reconstitution of individual SORBS proteins and midbody studies distinguished vinexin α's vinculin-centric mechanosensing from ArgBP2's α-actinin role and assigned vinexin a cytokinetic abscission function via Rhotekin recruitment.\",\n      \"evidence\": \"Reconstituted MEF lines, traction force microscopy, FA morphometry; midbody immunofluorescence, siRNA, mutant lacking Rhotekin motif, time-lapse imaging\",\n      \"pmids\": [\"28864765\", \"28118077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for SORBS family functional divergence not resolved\", \"How vinexin is targeted to the midbody not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying vinexin α (with CAP) as required for vinculin-cytoskeleton association and stiffness-dependent YAP/TAZ nuclear localization in MSCs connected vinexin mechanosensing to transcriptional/differentiation outputs.\",\n      \"evidence\": \"siRNA, rigid/soft substrates, vinculin-cytoskeleton imaging, YAP/TAZ fractionation, MSC differentiation assays\",\n      \"pmids\": [\"30068914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"YAP/TAZ-independent control of adipogenesis by vinexin mechanistically unexplained\", \"Quantitative contribution relative to CAP not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining the H2 amphipathic helix as a second vinculin-binding site that drives stiffness-dependent vinculin opening and YAP/TAZ translocation provided the structural mechanism of vinexin mechanosensing.\",\n      \"evidence\": \"H2 mutagenesis, in vitro binding, FRET vinculin conformation assay, stiffness-dependent YAP/TAZ localization\",\n      \"pmids\": [\"30578314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the talin-vinculin-vinexin complex not determined\", \"How force is sensed and transmitted through H2 not directly measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing vinexin as a negative autophagy regulator via an F-actin-AMOT-YAP/TAZ axis, with rising expression in aged brain, linked it to age-associated autophagic decline.\",\n      \"evidence\": \"siRNA, autophagy flux, F-actin imaging, YAP/TAZ localization, YAP/TAZ-AMOT co-IP, transcriptomics; aged brain expression analysis\",\n      \"pmids\": [\"34848853\", \"35822241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether vinexin directly regulates F-actin or AMOT binding not shown\", \"Causal role of vinexin in age-related autophagy decline in vivo not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing UBE2T ubiquitinates and degrades SORBS3 to de-repress IL-6/STAT3 signaling defined a degradation mechanism controlling vinexin abundance in cancer, and SORBS3-β-driven β-catenin ubiquitination via UBA1 extended this to Wnt suppression.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, knockdown/overexpression, xenograft models; LC-MS/MS and RNA-seq for the β-catenin axis\",\n      \"pmids\": [\"38816989\", \"40200335\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3 ligase partnering UBE2T toward SORBS3 not identified\", \"Whether SORBS3-β acts as a bona fide ubiquitin adaptor for UBA1/β-catenin needs structural validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How vinexin's distinct activities—mechanosensing, MAPK/AKT/STAT signaling, transcriptional control, autophagy, and ubiquitin-dependent degradation—are integrated and switched in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model coordinating focal-adhesion vs nuclear vs degradative functions\", \"No high-resolution structure of vinexin in any of its complexes\", \"Endogenous physiological triggers selecting among partner interactions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 9, 14, 18, 25]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 18, 22, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 17, 26, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [0, 5, 14, 18, 19]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 11, 24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9, 17, 25]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 18, 22, 25]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [26, 27]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"talin-vinculin-vinexin focal adhesion complex\",\n      \"vinexin-vinculin-lp-dlg-\\u03b2-catenin adherens junction complex\"\n    ],\n    \"partners\": [\n      \"VCL\",\n      \"SOS1\",\n      \"CBL\",\n      \"RTKN\",\n      \"ERK2/MAPK1\",\n      \"WASF2\",\n      \"CPEB4\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}