{"gene":"SORBS1","run_date":"2026-06-10T07:46:38","timeline":{"discoveries":[{"year":1999,"finding":"Ponsin (SORBS1) directly binds l-afadin via its second and third SH3 domains interacting with the third proline-rich region of l-afadin, and directly binds vinculin via its first and second SH3 domains interacting with vinculin's proline-rich region. l-Afadin and vinculin bind ponsin in a competitive manner and these three proteins hardly form a ternary complex. Ponsin localizes at zonula adherens in epithelial cells, cell-cell adherens junctions in nonepithelial cells, and cell-matrix adherens junctions in both cell types.","method":"Pulldown assays, co-immunoprecipitation, immunofluorescence localization, domain mapping with deletion constructs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays with domain mapping, replicated across multiple interaction pairs in a single rigorous study with multiple orthogonal methods","pmids":["10085297"],"is_preprint":false},{"year":1999,"finding":"Ponsin (SORBS1) is a component of the nectin-afadin-ponsin (NAP) system at cadherin-based cell-cell adherens junctions. During formation of polarized junctional alignment, nectin, afadin, and ponsin are simultaneously recruited to primordial spot-like junctions and subsequently to belt-like adherens junctions. Unlike cadherin, nectin and afadin (and by association ponsin) are not internalized upon low-calcium disruption of cell-cell junctions.","method":"Immunofluorescence, live-cell junction disruption assays (calcium depletion and TPA treatment) in MTD-1A and MDCK cells","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional disruption context, single lab with two orthogonal approaches","pmids":["10583506"],"is_preprint":false},{"year":2001,"finding":"Human SORBS1 associates with c-Abl protein upon insulin stimulation in hepatoma Hep3B cells. This interaction is mediated through the third SH3 domain of SORBS1 and is accompanied by partial dissociation of SORBS1 from the insulin receptor complex, suggesting a possible conformational change induced by insulin.","method":"Co-immunoprecipitation from insulin-stimulated Hep3B cells, domain mapping using deletion constructs","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with domain mapping, single lab, two methods confirming the interaction","pmids":["11374898"],"is_preprint":false},{"year":2005,"finding":"The intracellular domain of teneurin-1 interacts with CAP/ponsin (SORBS1). This interaction recruits the soluble intracellular domain of teneurin-1 to the cell membrane enriched in CAP/ponsin, and conversely leads to translocation of CAP/ponsin to the nucleus where the intracellular domain of teneurin-1 accumulates.","method":"Yeast two-hybrid identification, co-immunoprecipitation, subcellular fractionation, immunofluorescence colocalization, hormone-inducible full-length teneurin-1 expression system","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, fractionation, imaging) in single lab","pmids":["15777793"],"is_preprint":false},{"year":2007,"finding":"Ponsin (SORBS1) interacts with paxillin in nascent costameres during muscle differentiation. This interaction is mediated by the second SH3 domain of ponsin binding to the proline-rich region of paxillin, with the paxillin peptide adopting a polyproline-II helix conformation in the complex. The interaction has weak binding affinity. All three SH3 domains of ponsin synergize in targeting the protein to force-transducing structures. Overexpression of ponsin alters muscle cell-matrix contact morphology, indicating a role in costamere establishment. Ponsin expression is downregulated in end-stage failing hearts and restored upon mechanical unloading.","method":"Co-immunoprecipitation, X-ray crystallography of the SH3 domain at 0.83 Å and SH3-paxillin peptide complex at 1.63 Å, fluorescence titration, transfection overexpression with morphological readout, immunoblotting","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, fluorescence titration, and cell-based overexpression phenotype, multiple orthogonal methods in single rigorous study","pmids":["17462669"],"is_preprint":false},{"year":2007,"finding":"The crystal structure of the second SH3 domain of ponsin (SORBS1) was determined to high resolution from powder diffraction data, yielding a 67-residue domain structure with resolution comparable to single-crystal techniques.","method":"Powder X-ray diffraction, structure determination and refinement","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure solved by a novel powder diffraction method; single study but rigorous structural determination","pmids":["17784760"],"is_preprint":false},{"year":2008,"finding":"CAP/ponsin (SORBS1) is recruited to focal contacts at the plasma membrane by reggies/flotillins. Expression of a trans-negative reggie-1/flotillin-2 deletion mutant (R1EA) impaired recruitment of CAP/ponsin to focal contacts, leading to perturbed Rac1 and cdc42 GTPase activation balance and enhanced FAK activity, thereby inhibiting IGF-induced neurite outgrowth and neuronal differentiation.","method":"Dominant-negative (trans-negative) reggie-1 deletion mutant expression, immunofluorescence localization, Rho-GTPase activation assays, FAK activity assay, neurite outgrowth quantification in N2a cells and primary hippocampal neurons","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic perturbation (dominant-negative) with defined signaling readouts and localization, single lab with multiple orthogonal methods","pmids":["18722032"],"is_preprint":false},{"year":2008,"finding":"Ponsin (SORBS1) is abundantly expressed in lens tissue and localizes predominantly to focal adhesions in lens epithelial cells, with some isoforms enriched in the Triton X-100-insoluble fraction. Constitutively active RhoA induces ponsin clustering at leading edges, while inhibition of Rho kinase or latrunculin treatment decreases ponsin protein levels, demonstrating that ponsin expression and localization depend on Rho GTPase-regulated actin cytoskeletal integrity.","method":"cDNA microarray (identifying downregulation), immunofluorescence, immunoblot, subcellular fractionation, treatment with constitutively active RhoA, Rho kinase inhibitor, and latrunculin","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional perturbation experiments, single lab with multiple approaches","pmids":["19029030"],"is_preprint":false},{"year":2010,"finding":"A skeletal muscle-specific isoform of ponsin (SORBS1) contains a large carboxy-terminal insertion that binds the adapter proteins Nck1 and Nck2. Increased co-localization of ponsin with Nck2 occurs at remodeling cell-matrix contacts of differentiating skeletal muscle cells. The novel ponsin insertion can be phosphorylated, potentially adjusting interaction affinity with Nck adapter proteins.","method":"Isoform cloning, co-immunoprecipitation, immunofluorescence colocalization, phosphorylation analysis","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and colocalization with phosphorylation evidence, single lab, multiple orthogonal methods","pmids":["20129698"],"is_preprint":false},{"year":2013,"finding":"The third SH3 domain (SH3C) of R85FL/ponsin (SORBS1) specifically interacts with the second proline-rich region (PRR) of ataxin-7. NMR structural analysis revealed that SH3C contains a large negatively charged surface that binds the RRTR motif of ataxin-7. This SH3C-PRR interaction mediates the sequestration of ponsin by polyglutamine-expanded ataxin-7 into intranuclear inclusion bodies.","method":"NMR structural analysis of SH3C domain and its complex with ataxin-7 PRR, microscopy imaging of polyQ-expanded Atx7 sequestration in cells, domain mapping","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation in cells, multiple orthogonal methods in single rigorous study","pmids":["23892081"],"is_preprint":false},{"year":2015,"finding":"Sorbs1 and Sorbs2 associate with the initiating MuSK/Dok-7/Crk/CrkL complex at the neuromuscular synapse, functioning downstream of MuSK and Dok-7. Sorbs1 and Sorbs2 are functionally redundant, regulate acetylcholine receptor (AChR) clustering in vitro, and are localized at synapses in vivo.","method":"Mass spectrometry identification of CrkL binding partners, co-immunoprecipitation, AChR clustering assays in vitro, in vivo synaptic localization by immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry-based interactome plus functional AChR clustering assay plus in vivo localization, multiple orthogonal methods","pmids":["26527617"],"is_preprint":false},{"year":2016,"finding":"The cytoplasmic domain of atypical cadherin Fat1 interacts with SoHo adaptor proteins CAP/ponsin-1 and -2 (Sorbs1) via a proline-rich type II PXXP motif within Fat1 and the three SH3 domains within ponsin. Knockdown of Fat1 causes loss of endogenous ponsin-2 expression at cellular leading edges.","method":"Yeast two-hybrid screen, pulldown assays, cell culture expression, immunofluorescence, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Y2H, pulldown, and cell-based functional consequence, single lab, multiple methods","pmids":["26903299"],"is_preprint":false},{"year":2017,"finding":"Depletion of SORBS1 in breast cancer cells increases filopodium-like protrusion formation and migratory/invasive ability via activation of JNK/cJun signaling. Silencing of SORBS1 also promotes epithelial-to-mesenchymal transition (EMT) and attenuates cisplatin sensitivity by inhibiting p53.","method":"siRNA knockdown, migration/invasion assays, Western blot for JNK/cJun and p53 pathway components, EMT marker analysis, drug sensitivity assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway readouts (JNK/cJun, p53), single lab, multiple assays","pmids":["27791200"],"is_preprint":false},{"year":2018,"finding":"Homocysteine increases SORBS1 promoter methylation in human umbilical vein endothelial cells, reducing SORBS1 expression. siRNA knockdown of SORBS1 increases MDA levels and reduces SOD2 expression, recapitulating the oxidative stress phenotype induced by homocysteine. Folic acid and vitamin B12 treatment attenuates Hcy-induced methylation of SORBS1 and the associated oxidative stress.","method":"Genome-wide DNA methylation assay (Infinium 450K BeadChip), bisulfite sequencing, siRNA knockdown, Western blot, RT-PCR, biochemical oxidative stress assays (MDA, SOD2)","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — methylation profiling plus functional siRNA knockdown with phenotypic readout, single lab, orthogonal methods","pmids":["30402861"],"is_preprint":false},{"year":2020,"finding":"SORBS1 forms a protein complex with AHNAK nucleoprotein in colorectal cancer cells, as demonstrated by co-immunoprecipitation and co-localization by confocal microscopy. SORBS1 knockdown reduces cancer cell migration. AHNAK functions as a tumor suppressor through inhibition of phosphorylated-ERK and ROCK1, and SORBS1 inhibits AHNAK, suggesting SORBS1 promotes cancer cell migration and growth via suppression of AHNAK.","method":"Co-immunoprecipitation, confocal microscopy colocalization, Boyden chamber migration assay, colony formation assay, vector transfection/lentivirus-mediated overexpression and knockdown, Western blot","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus colocalization plus functional assays, single lab, multiple orthogonal methods","pmids":["32319594"],"is_preprint":false},{"year":2024,"finding":"Sorbs1 is required for secondary sprouting and formation of lymphatic and venous vascular structures in zebrafish, particularly for precursor parachordal lymphatic structures. Mechanistically, Sorbs1 controls FAK/Src signaling and impacts cytoskeletal processes regulated by Rac1 and RhoA GTPases. Inactivation of Sorbs1 alters cell-ECM contact rearrangement and cytoskeletal dynamics, leading to defects in endothelial cell migration and adhesion. Sorbs1 interacts with the BMP pathway and functions independently of Vegfc signaling.","method":"Zebrafish genetic mutant analysis (loss-of-function), in vitro endothelial cell assays, FAK/Src signaling assays, Rac1/RhoA GTPase activity assays, cell adhesion and migration assays, epistasis with BMP and Vegfc pathways","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic mutant combined with in vitro mechanistic assays and pathway epistasis, multiple orthogonal methods across in vivo and in vitro systems","pmids":["38414014"],"is_preprint":false},{"year":2024,"finding":"SORBS1 inhibits the PI3K/AKT signaling pathway and blocks EMT in breast cancer cells. High SORBS1 expression reduces breast cancer cell migration and invasion. SORBS1 expression induces macrophage polarization toward the M1 phenotype and enhances macrophage killing of breast cancer cells in co-culture.","method":"SORBS1-overexpressing and knockout cell lines, cell viability/invasion/migration assays, Western blot for PI3K/AKT pathway components and EMT markers, macrophage-cancer cell co-culture system with polarization assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function with defined signaling pathway readouts and co-culture functional assay, single lab, multiple orthogonal methods","pmids":["38451194"],"is_preprint":false},{"year":2025,"finding":"MBNL-regulated alternative splicing of SORBS1 exon 25 is required for neuromuscular junction (NMJ) formation and maintenance. In DM1 patients, SORBS1 exon 25 inclusion is significantly reduced. Forced exclusion of Sorbs1 exon 25 in mice leads to NMJ degeneration with increased denervation and postsynaptic destabilization. In zebrafish, exon 25 misregulation impairs locomotion and disrupts AChR cluster morphology. In hiPSC-derived skeletal muscle cells, exon 25 exclusion reduces large AChR cluster formation upon agrin stimulation by 34%.","method":"Antisense oligonucleotide-mediated exon skipping in mice, zebrafish, and hiPSC-derived skeletal muscle cells; NMJ morphology analysis; AChR cluster formation assay with agrin stimulation; locomotion behavioral assay; human DM1 biopsy RNA analysis","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in three independent model systems (mouse, zebrafish, hiPSC) with defined mechanistic readouts replicated across systems","pmids":["41250834"],"is_preprint":false}],"current_model":"SORBS1 (ponsin/CAP) is a multi-domain adaptor protein with a sorbin homology domain and three SH3 domains that scaffold signaling complexes at cell-cell and cell-matrix adherens junctions by directly binding l-afadin (via SH3-2/3), vinculin (via SH3-1/2), paxillin (via SH3-2), c-Abl, Nck1/2, Fat1, and ataxin-7; it regulates actin cytoskeletal organization through FAK/Src and Rho GTPase (Rac1, RhoA, cdc42) signaling, is required for acetylcholine receptor clustering and neuromuscular junction integrity via MBNL-regulated alternative splicing of exon 25, and suppresses cancer cell EMT/invasion through JNK/cJun and PI3K/AKT pathway inhibition."},"narrative":{"mechanistic_narrative":"SORBS1 (ponsin/CAP) is a multi-SH3-domain adaptor protein that scaffolds signaling complexes at adherens junctions, focal adhesions, and force-transducing cell-matrix contacts to couple membrane receptors to actin cytoskeletal remodeling [PMID:10085297, PMID:17462669]. Its three SH3 domains engage proline-rich ligands in a domain-specific manner: l-afadin (SH3-2/3) and vinculin (SH3-1/2) bind competitively, linking ponsin to the nectin-afadin-ponsin junctional system, while paxillin (SH3-2) targets it to nascent costameres [PMID:10085297, PMID:10583506, PMID:17462669]. The third SH3 domain additionally binds c-Abl upon insulin stimulation, the atypical cadherin Fat1, and ataxin-7, by which polyglutamine-expanded ataxin-7 sequesters ponsin into intranuclear inclusions [PMID:11374898, PMID:26903299, PMID:23892081]. Ponsin is recruited to focal contacts by flotillins and depends on Rho-GTPase-driven actin integrity, controlling FAK/Src signaling and the Rac1/RhoA/cdc42 balance that governs endothelial migration, vascular and lymphatic sprouting, and neurite outgrowth [PMID:18722032, PMID:19029030, PMID:38414014]. At the neuromuscular junction it acts downstream of MuSK/Dok-7/Crk/CrkL to drive acetylcholine receptor clustering, and MBNL-regulated inclusion of its exon 25 is required for NMJ formation and maintenance, with reduced exon 25 inclusion contributing to neuromuscular pathology in myotonic dystrophy type 1 [PMID:26527617, PMID:41250834]. In cancer, SORBS1 modulates EMT, migration, and invasion through JNK/cJun, PI3K/AKT, and AHNAK-dependent pathways, acting as either suppressor or promoter depending on context [PMID:27791200, PMID:32319594, PMID:38451194].","teleology":[{"year":1999,"claim":"Establishing how ponsin physically integrates into adherens junctions defined its core role as a junctional adaptor; reciprocal binding to l-afadin and vinculin via distinct SH3 domains showed it links the nectin-afadin system to vinculin at cell-cell and cell-matrix junctions.","evidence":"Pulldown, co-IP, domain mapping and immunofluorescence in epithelial and nonepithelial cells; junction disruption assays in MTD-1A/MDCK cells","pmids":["10085297","10583506"],"confidence":"High","gaps":["Competitive l-afadin/vinculin binding leaves the in vivo stoichiometry of junctional complexes undefined","Functional consequence of ponsin loss at junctions not tested"]},{"year":2001,"claim":"Linking SORBS1 to insulin signaling addressed whether it acts in receptor signaling; insulin-induced SH3C-mediated c-Abl association coupled to partial dissociation from the insulin receptor indicated a dynamic, conformation-dependent adaptor role.","evidence":"Co-IP from insulin-stimulated Hep3B hepatoma cells with deletion-construct domain mapping","pmids":["11374898"],"confidence":"Medium","gaps":["Downstream metabolic output of the c-Abl interaction not established","Conformational change inferred rather than directly measured"]},{"year":2005,"claim":"Identifying teneurin-1 as a partner revealed a potential nucleus-membrane shuttling axis, showing ponsin can be relocalized between compartments depending on its binding partner.","evidence":"Yeast two-hybrid, co-IP, subcellular fractionation and colocalization with inducible teneurin-1 expression","pmids":["15777793"],"confidence":"Medium","gaps":["Nuclear function of ponsin not defined","Physiological trigger for translocation unknown"]},{"year":2007,"claim":"High-resolution structures of the SH3-2 domain and its paxillin complex defined the atomic basis of ligand recognition and tied ponsin to force-transducing costameres in muscle differentiation.","evidence":"X-ray crystallography (0.83 A SH3, 1.63 A complex; plus powder-diffraction structure), fluorescence titration, and overexpression morphology assays","pmids":["17462669","17784760"],"confidence":"High","gaps":["Weak paxillin affinity leaves the contribution of avidity/SH3 synergy quantitatively unresolved","Link between cardiac downregulation and contractile dysfunction correlative"]},{"year":2008,"claim":"Flotillin-dependent recruitment and Rho-GTPase-dependent localization placed ponsin functionally within actin-cytoskeleton and FAK/Rac1/cdc42 signaling at focal contacts.","evidence":"Dominant-negative flotillin, Rho-GTPase and FAK activity assays, neurite outgrowth in N2a/hippocampal neurons; microarray, fractionation and cytoskeleton-perturbation in lens epithelium","pmids":["18722032","19029030"],"confidence":"Medium","gaps":["Whether ponsin directly regulates GTPase activity or acts as a passive scaffold unresolved","Direct flotillin-ponsin contact not mapped"]},{"year":2010,"claim":"Discovery of a muscle-specific isoform with an Nck-binding insertion showed alternative splicing diversifies ponsin's interactome at remodeling cell-matrix contacts.","evidence":"Isoform cloning, co-IP, colocalization and phosphorylation analysis in differentiating skeletal muscle cells","pmids":["20129698"],"confidence":"Medium","gaps":["Functional role of Nck1/2 recruitment in costamere assembly not tested","Phosphorylation sites and regulating kinase not identified"]},{"year":2013,"claim":"NMR mapping of SH3C binding ataxin-7 explained how ponsin is sequestered into polyQ inclusions, connecting it to a neurodegenerative aggregation mechanism.","evidence":"NMR structure of SH3C and its complex with ataxin-7 PRR plus cellular sequestration imaging","pmids":["23892081"],"confidence":"High","gaps":["Functional consequence of ponsin sequestration for SCA7 pathology not established"]},{"year":2016,"claim":"Fat1 was identified as another SH3-engaging partner controlling ponsin localization, extending the adhesion-receptor repertoire that positions ponsin at leading edges.","evidence":"Yeast two-hybrid, pulldown, siRNA knockdown and immunofluorescence","pmids":["26903299"],"confidence":"Medium","gaps":["Downstream signaling from the Fat1-ponsin module not defined","Single-lab interaction without reciprocal in vivo validation"]},{"year":2015,"claim":"Placing Sorbs1 downstream of MuSK/Dok-7/Crk/CrkL with functional redundancy to Sorbs2 established its role in acetylcholine receptor clustering at the neuromuscular synapse.","evidence":"Mass spectrometry interactome, co-IP, in vitro AChR clustering and in vivo synaptic localization","pmids":["26527617"],"confidence":"High","gaps":["Mechanism by which Sorbs1 promotes AChR clustering downstream of CrkL unresolved"]},{"year":2024,"claim":"In vivo zebrafish loss-of-function established a developmental requirement for Sorbs1 in lymphatic/venous sprouting through FAK/Src and Rac1/RhoA control of endothelial migration and adhesion, independent of Vegfc.","evidence":"Zebrafish genetic mutants, in vitro endothelial migration/adhesion and GTPase activity assays, BMP/Vegfc epistasis","pmids":["38414014"],"confidence":"High","gaps":["Direct molecular link between Sorbs1 and the BMP pathway not defined","Endothelial binding partners mediating this role not identified"]},{"year":2024,"claim":"Cancer studies defined context-dependent roles for SORBS1 in EMT and invasion, acting through JNK/cJun, PI3K/AKT, and AHNAK, with opposing tumor-suppressive and migration-promoting outcomes across models.","evidence":"siRNA/knockout and overexpression with migration/invasion assays, pathway Western blots, AHNAK co-IP/colocalization, and macrophage co-culture","pmids":["27791200","32319594","38451194"],"confidence":"Medium","gaps":["Opposing pro- and anti-tumor effects across cancer types not mechanistically reconciled","Direct vs indirect regulation of these pathways unresolved"]},{"year":2025,"claim":"MBNL-controlled inclusion of SORBS1 exon 25 was shown to be required for NMJ formation and maintenance and its loss contributes to neuromuscular defects in myotonic dystrophy type 1.","evidence":"Antisense exon skipping in mouse, zebrafish and hiPSC muscle; NMJ morphology, AChR clustering with agrin, locomotion, and DM1 biopsy RNA analysis","pmids":["41250834"],"confidence":"High","gaps":["How the exon 25 segment alters ponsin's molecular interactions at the synapse not defined","Contribution relative to other DM1 mis-splicing events unquantified"]},{"year":null,"claim":"How ponsin's distinct partner repertoires and splice isoforms are coordinated to switch its function between junctional scaffolding, receptor signaling, and cytoskeletal control in specific tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking isoform-specific interactions to tissue-specific phenotypes","Direct enzymatic or signaling output of ponsin scaffolding undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,10,11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,6,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,15,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[15,17]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1]}],"complexes":["nectin-afadin-ponsin (NAP) system","MuSK/Dok-7/Crk/CrkL complex"],"partners":["AFDN","VCL","PXN","ABL1","NCK1","NCK2","FAT1","ATXN7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BX66","full_name":"Sorbin and SH3 domain-containing protein 1","aliases":["Ponsin","SH3 domain protein 5","SH3P12","c-Cbl-associated protein","CAP"],"length_aa":1292,"mass_kda":142.5,"function":"Plays a role in tyrosine phosphorylation of CBL by linking CBL to the insulin receptor. Required for insulin-stimulated glucose transport. Involved in formation of actin stress fibers and focal adhesions (By similarity)","subcellular_location":"Cell junction, adherens junction; Cell membrane; Cytoplasm, cytoskeleton; Cell junction, focal adhesion; Nucleus; Nucleus matrix","url":"https://www.uniprot.org/uniprotkb/Q9BX66/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SORBS1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SORBS1","total_profiled":1310},"omim":[{"mim_id":"618859","title":"NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT AUTISTIC FEATURES AND/OR STRUCTURAL BRAIN ABNORMALITIES; NEDASB","url":"https://www.omim.org/entry/618859"},{"mim_id":"605526","title":"ALZHEIMER DISEASE 6","url":"https://www.omim.org/entry/605526"},{"mim_id":"605264","title":"SORBIN AND SH3-DOMAINS CONTAINING PROTEIN 1; SORBS1","url":"https://www.omim.org/entry/605264"},{"mim_id":"601991","title":"NOVA ALTERNATIVE SPLICING REGULATOR 2; NOVA2","url":"https://www.omim.org/entry/601991"},{"mim_id":"600010","title":"INSULINOMA-ASSOCIATED 1; INSM1","url":"https://www.omim.org/entry/600010"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":482.7}],"url":"https://www.proteinatlas.org/search/SORBS1"},"hgnc":{"alias_symbol":["FLJ12406","CAP","sh3p12","ponsin","KIAA1296"],"prev_symbol":["SH3D5"]},"alphafold":{"accession":"Q9BX66","domains":[{"cath_id":"2.30.30.40","chopping":"793-852","consensus_level":"medium","plddt":88.2597,"start":793,"end":852},{"cath_id":"2.30.30.40","chopping":"866-935","consensus_level":"medium","plddt":85.084,"start":866,"end":935},{"cath_id":"2.30.30.40","chopping":"1233-1292","consensus_level":"medium","plddt":88.7517,"start":1233,"end":1292}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BX66","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BX66-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BX66-F1-predicted_aligned_error_v6.png","plddt_mean":46.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SORBS1","jax_strain_url":"https://www.jax.org/strain/search?query=SORBS1"},"sequence":{"accession":"Q9BX66","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BX66.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BX66/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BX66"}},"corpus_meta":[{"pmid":"10085297","id":"PMC_10085297","title":"Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10085297","citation_count":213,"is_preprint":false},{"pmid":"11937713","id":"PMC_11937713","title":"Vinexin, CAP/ponsin, ArgBP2: a novel adaptor protein family regulating cytoskeletal organization and signal transduction.","date":"2002","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/11937713","citation_count":180,"is_preprint":false},{"pmid":"10583506","id":"PMC_10583506","title":"Similar and differential behaviour between the nectin-afadin-ponsin and cadherin-catenin systems during the formation and disruption of the polarized junctional alignment in epithelial cells.","date":"1999","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/10583506","citation_count":85,"is_preprint":false},{"pmid":"10521485","id":"PMC_10521485","title":"nArgBP2, a novel neural member of ponsin/ArgBP2/vinexin family that interacts with synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP).","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10521485","citation_count":73,"is_preprint":false},{"pmid":"11374898","id":"PMC_11374898","title":"Cloning, mapping, and characterization of the human sorbin and SH3 domain containing 1 (SORBS1) gene: a protein associated with c-Abl during insulin signaling in the hepatoma cell line Hep3B.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11374898","citation_count":59,"is_preprint":false},{"pmid":"15777793","id":"PMC_15777793","title":"The intracellular domain of teneurin-1 interacts with MBD1 and CAP/ponsin resulting in subcellular codistribution and 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hyperandrogenism.","date":"2003","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/12849814","citation_count":12,"is_preprint":false},{"pmid":"26962801","id":"PMC_26962801","title":"Genetic Variation in the Human SORBS1 Gene is Associated With Blood Pressure Regulation and Age at Onset of Hypertension: A SAPPHIRe Cohort Study.","date":"2016","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26962801","citation_count":11,"is_preprint":false},{"pmid":"38451194","id":"PMC_38451194","title":"SORBS1 inhibits epithelial to mesenchymal transition (EMT) of breast cancer cells by regulating PI3K/AKT signaling and macrophage phenotypic polarization.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38451194","citation_count":10,"is_preprint":false},{"pmid":"18394047","id":"PMC_18394047","title":"Polymorphism in the sorbin and SH3-domain-containing-1 (SORBS1) gene and the risk of brain infarction in the Japanese population: the Fukuoka Stroke Registry and the Hisayama study.","date":"2008","source":"European journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/18394047","citation_count":10,"is_preprint":false},{"pmid":"34944239","id":"PMC_34944239","title":"Polymorphisms of SORBS1 Gene and Their Correlation with Milk Fat Traits of Cattleyak.","date":"2021","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/34944239","citation_count":8,"is_preprint":false},{"pmid":"19029030","id":"PMC_19029030","title":"Abundant expression of ponsin, a focal adhesion protein, in lens and downregulation of its expression by impaired cytoskeletal signaling.","date":"2008","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/19029030","citation_count":8,"is_preprint":false},{"pmid":"35107206","id":"PMC_35107206","title":"A variation in SORBS1 is associated with type 2 diabetes and high-density lipoprotein cholesterol in Chinese 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Yi xue ban = Journal of Central South University. 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Ponsin localizes at zonula adherens in epithelial cells, cell-cell adherens junctions in nonepithelial cells, and cell-matrix adherens junctions in both cell types.\",\n      \"method\": \"Pulldown assays, co-immunoprecipitation, immunofluorescence localization, domain mapping with deletion constructs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays with domain mapping, replicated across multiple interaction pairs in a single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"10085297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Ponsin (SORBS1) is a component of the nectin-afadin-ponsin (NAP) system at cadherin-based cell-cell adherens junctions. During formation of polarized junctional alignment, nectin, afadin, and ponsin are simultaneously recruited to primordial spot-like junctions and subsequently to belt-like adherens junctions. Unlike cadherin, nectin and afadin (and by association ponsin) are not internalized upon low-calcium disruption of cell-cell junctions.\",\n      \"method\": \"Immunofluorescence, live-cell junction disruption assays (calcium depletion and TPA treatment) in MTD-1A and MDCK cells\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional disruption context, single lab with two orthogonal approaches\",\n      \"pmids\": [\"10583506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human SORBS1 associates with c-Abl protein upon insulin stimulation in hepatoma Hep3B cells. This interaction is mediated through the third SH3 domain of SORBS1 and is accompanied by partial dissociation of SORBS1 from the insulin receptor complex, suggesting a possible conformational change induced by insulin.\",\n      \"method\": \"Co-immunoprecipitation from insulin-stimulated Hep3B cells, domain mapping using deletion constructs\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with domain mapping, single lab, two methods confirming the interaction\",\n      \"pmids\": [\"11374898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The intracellular domain of teneurin-1 interacts with CAP/ponsin (SORBS1). This interaction recruits the soluble intracellular domain of teneurin-1 to the cell membrane enriched in CAP/ponsin, and conversely leads to translocation of CAP/ponsin to the nucleus where the intracellular domain of teneurin-1 accumulates.\",\n      \"method\": \"Yeast two-hybrid identification, co-immunoprecipitation, subcellular fractionation, immunofluorescence colocalization, hormone-inducible full-length teneurin-1 expression system\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, fractionation, imaging) in single lab\",\n      \"pmids\": [\"15777793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ponsin (SORBS1) interacts with paxillin in nascent costameres during muscle differentiation. This interaction is mediated by the second SH3 domain of ponsin binding to the proline-rich region of paxillin, with the paxillin peptide adopting a polyproline-II helix conformation in the complex. The interaction has weak binding affinity. All three SH3 domains of ponsin synergize in targeting the protein to force-transducing structures. Overexpression of ponsin alters muscle cell-matrix contact morphology, indicating a role in costamere establishment. Ponsin expression is downregulated in end-stage failing hearts and restored upon mechanical unloading.\",\n      \"method\": \"Co-immunoprecipitation, X-ray crystallography of the SH3 domain at 0.83 Å and SH3-paxillin peptide complex at 1.63 Å, fluorescence titration, transfection overexpression with morphological readout, immunoblotting\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, fluorescence titration, and cell-based overexpression phenotype, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"17462669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The crystal structure of the second SH3 domain of ponsin (SORBS1) was determined to high resolution from powder diffraction data, yielding a 67-residue domain structure with resolution comparable to single-crystal techniques.\",\n      \"method\": \"Powder X-ray diffraction, structure determination and refinement\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure solved by a novel powder diffraction method; single study but rigorous structural determination\",\n      \"pmids\": [\"17784760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CAP/ponsin (SORBS1) is recruited to focal contacts at the plasma membrane by reggies/flotillins. Expression of a trans-negative reggie-1/flotillin-2 deletion mutant (R1EA) impaired recruitment of CAP/ponsin to focal contacts, leading to perturbed Rac1 and cdc42 GTPase activation balance and enhanced FAK activity, thereby inhibiting IGF-induced neurite outgrowth and neuronal differentiation.\",\n      \"method\": \"Dominant-negative (trans-negative) reggie-1 deletion mutant expression, immunofluorescence localization, Rho-GTPase activation assays, FAK activity assay, neurite outgrowth quantification in N2a cells and primary hippocampal neurons\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic perturbation (dominant-negative) with defined signaling readouts and localization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18722032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ponsin (SORBS1) is abundantly expressed in lens tissue and localizes predominantly to focal adhesions in lens epithelial cells, with some isoforms enriched in the Triton X-100-insoluble fraction. Constitutively active RhoA induces ponsin clustering at leading edges, while inhibition of Rho kinase or latrunculin treatment decreases ponsin protein levels, demonstrating that ponsin expression and localization depend on Rho GTPase-regulated actin cytoskeletal integrity.\",\n      \"method\": \"cDNA microarray (identifying downregulation), immunofluorescence, immunoblot, subcellular fractionation, treatment with constitutively active RhoA, Rho kinase inhibitor, and latrunculin\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional perturbation experiments, single lab with multiple approaches\",\n      \"pmids\": [\"19029030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A skeletal muscle-specific isoform of ponsin (SORBS1) contains a large carboxy-terminal insertion that binds the adapter proteins Nck1 and Nck2. Increased co-localization of ponsin with Nck2 occurs at remodeling cell-matrix contacts of differentiating skeletal muscle cells. The novel ponsin insertion can be phosphorylated, potentially adjusting interaction affinity with Nck adapter proteins.\",\n      \"method\": \"Isoform cloning, co-immunoprecipitation, immunofluorescence colocalization, phosphorylation analysis\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and colocalization with phosphorylation evidence, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"20129698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The third SH3 domain (SH3C) of R85FL/ponsin (SORBS1) specifically interacts with the second proline-rich region (PRR) of ataxin-7. NMR structural analysis revealed that SH3C contains a large negatively charged surface that binds the RRTR motif of ataxin-7. This SH3C-PRR interaction mediates the sequestration of ponsin by polyglutamine-expanded ataxin-7 into intranuclear inclusion bodies.\",\n      \"method\": \"NMR structural analysis of SH3C domain and its complex with ataxin-7 PRR, microscopy imaging of polyQ-expanded Atx7 sequestration in cells, domain mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation in cells, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"23892081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sorbs1 and Sorbs2 associate with the initiating MuSK/Dok-7/Crk/CrkL complex at the neuromuscular synapse, functioning downstream of MuSK and Dok-7. Sorbs1 and Sorbs2 are functionally redundant, regulate acetylcholine receptor (AChR) clustering in vitro, and are localized at synapses in vivo.\",\n      \"method\": \"Mass spectrometry identification of CrkL binding partners, co-immunoprecipitation, AChR clustering assays in vitro, in vivo synaptic localization by immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry-based interactome plus functional AChR clustering assay plus in vivo localization, multiple orthogonal methods\",\n      \"pmids\": [\"26527617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The cytoplasmic domain of atypical cadherin Fat1 interacts with SoHo adaptor proteins CAP/ponsin-1 and -2 (Sorbs1) via a proline-rich type II PXXP motif within Fat1 and the three SH3 domains within ponsin. Knockdown of Fat1 causes loss of endogenous ponsin-2 expression at cellular leading edges.\",\n      \"method\": \"Yeast two-hybrid screen, pulldown assays, cell culture expression, immunofluorescence, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Y2H, pulldown, and cell-based functional consequence, single lab, multiple methods\",\n      \"pmids\": [\"26903299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Depletion of SORBS1 in breast cancer cells increases filopodium-like protrusion formation and migratory/invasive ability via activation of JNK/cJun signaling. Silencing of SORBS1 also promotes epithelial-to-mesenchymal transition (EMT) and attenuates cisplatin sensitivity by inhibiting p53.\",\n      \"method\": \"siRNA knockdown, migration/invasion assays, Western blot for JNK/cJun and p53 pathway components, EMT marker analysis, drug sensitivity assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway readouts (JNK/cJun, p53), single lab, multiple assays\",\n      \"pmids\": [\"27791200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Homocysteine increases SORBS1 promoter methylation in human umbilical vein endothelial cells, reducing SORBS1 expression. siRNA knockdown of SORBS1 increases MDA levels and reduces SOD2 expression, recapitulating the oxidative stress phenotype induced by homocysteine. Folic acid and vitamin B12 treatment attenuates Hcy-induced methylation of SORBS1 and the associated oxidative stress.\",\n      \"method\": \"Genome-wide DNA methylation assay (Infinium 450K BeadChip), bisulfite sequencing, siRNA knockdown, Western blot, RT-PCR, biochemical oxidative stress assays (MDA, SOD2)\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — methylation profiling plus functional siRNA knockdown with phenotypic readout, single lab, orthogonal methods\",\n      \"pmids\": [\"30402861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SORBS1 forms a protein complex with AHNAK nucleoprotein in colorectal cancer cells, as demonstrated by co-immunoprecipitation and co-localization by confocal microscopy. SORBS1 knockdown reduces cancer cell migration. AHNAK functions as a tumor suppressor through inhibition of phosphorylated-ERK and ROCK1, and SORBS1 inhibits AHNAK, suggesting SORBS1 promotes cancer cell migration and growth via suppression of AHNAK.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy colocalization, Boyden chamber migration assay, colony formation assay, vector transfection/lentivirus-mediated overexpression and knockdown, Western blot\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus colocalization plus functional assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32319594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sorbs1 is required for secondary sprouting and formation of lymphatic and venous vascular structures in zebrafish, particularly for precursor parachordal lymphatic structures. Mechanistically, Sorbs1 controls FAK/Src signaling and impacts cytoskeletal processes regulated by Rac1 and RhoA GTPases. Inactivation of Sorbs1 alters cell-ECM contact rearrangement and cytoskeletal dynamics, leading to defects in endothelial cell migration and adhesion. Sorbs1 interacts with the BMP pathway and functions independently of Vegfc signaling.\",\n      \"method\": \"Zebrafish genetic mutant analysis (loss-of-function), in vitro endothelial cell assays, FAK/Src signaling assays, Rac1/RhoA GTPase activity assays, cell adhesion and migration assays, epistasis with BMP and Vegfc pathways\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic mutant combined with in vitro mechanistic assays and pathway epistasis, multiple orthogonal methods across in vivo and in vitro systems\",\n      \"pmids\": [\"38414014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SORBS1 inhibits the PI3K/AKT signaling pathway and blocks EMT in breast cancer cells. High SORBS1 expression reduces breast cancer cell migration and invasion. SORBS1 expression induces macrophage polarization toward the M1 phenotype and enhances macrophage killing of breast cancer cells in co-culture.\",\n      \"method\": \"SORBS1-overexpressing and knockout cell lines, cell viability/invasion/migration assays, Western blot for PI3K/AKT pathway components and EMT markers, macrophage-cancer cell co-culture system with polarization assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function with defined signaling pathway readouts and co-culture functional assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38451194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MBNL-regulated alternative splicing of SORBS1 exon 25 is required for neuromuscular junction (NMJ) formation and maintenance. In DM1 patients, SORBS1 exon 25 inclusion is significantly reduced. Forced exclusion of Sorbs1 exon 25 in mice leads to NMJ degeneration with increased denervation and postsynaptic destabilization. In zebrafish, exon 25 misregulation impairs locomotion and disrupts AChR cluster morphology. In hiPSC-derived skeletal muscle cells, exon 25 exclusion reduces large AChR cluster formation upon agrin stimulation by 34%.\",\n      \"method\": \"Antisense oligonucleotide-mediated exon skipping in mice, zebrafish, and hiPSC-derived skeletal muscle cells; NMJ morphology analysis; AChR cluster formation assay with agrin stimulation; locomotion behavioral assay; human DM1 biopsy RNA analysis\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in three independent model systems (mouse, zebrafish, hiPSC) with defined mechanistic readouts replicated across systems\",\n      \"pmids\": [\"41250834\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SORBS1 (ponsin/CAP) is a multi-domain adaptor protein with a sorbin homology domain and three SH3 domains that scaffold signaling complexes at cell-cell and cell-matrix adherens junctions by directly binding l-afadin (via SH3-2/3), vinculin (via SH3-1/2), paxillin (via SH3-2), c-Abl, Nck1/2, Fat1, and ataxin-7; it regulates actin cytoskeletal organization through FAK/Src and Rho GTPase (Rac1, RhoA, cdc42) signaling, is required for acetylcholine receptor clustering and neuromuscular junction integrity via MBNL-regulated alternative splicing of exon 25, and suppresses cancer cell EMT/invasion through JNK/cJun and PI3K/AKT pathway inhibition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SORBS1 (ponsin/CAP) is a multi-SH3-domain adaptor protein that scaffolds signaling complexes at adherens junctions, focal adhesions, and force-transducing cell-matrix contacts to couple membrane receptors to actin cytoskeletal remodeling [#0, #4]. Its three SH3 domains engage proline-rich ligands in a domain-specific manner: l-afadin (SH3-2/3) and vinculin (SH3-1/2) bind competitively, linking ponsin to the nectin-afadin-ponsin junctional system, while paxillin (SH3-2) targets it to nascent costameres [#0, #1, #4]. The third SH3 domain additionally binds c-Abl upon insulin stimulation, the atypical cadherin Fat1, and ataxin-7, by which polyglutamine-expanded ataxin-7 sequesters ponsin into intranuclear inclusions [#2, #11, #9]. Ponsin is recruited to focal contacts by flotillins and depends on Rho-GTPase-driven actin integrity, controlling FAK/Src signaling and the Rac1/RhoA/cdc42 balance that governs endothelial migration, vascular and lymphatic sprouting, and neurite outgrowth [#6, #7, #15]. At the neuromuscular junction it acts downstream of MuSK/Dok-7/Crk/CrkL to drive acetylcholine receptor clustering, and MBNL-regulated inclusion of its exon 25 is required for NMJ formation and maintenance, with reduced exon 25 inclusion contributing to neuromuscular pathology in myotonic dystrophy type 1 [#10, #17]. In cancer, SORBS1 modulates EMT, migration, and invasion through JNK/cJun, PI3K/AKT, and AHNAK-dependent pathways, acting as either suppressor or promoter depending on context [#12, #14, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing how ponsin physically integrates into adherens junctions defined its core role as a junctional adaptor; reciprocal binding to l-afadin and vinculin via distinct SH3 domains showed it links the nectin-afadin system to vinculin at cell-cell and cell-matrix junctions.\",\n      \"evidence\": \"Pulldown, co-IP, domain mapping and immunofluorescence in epithelial and nonepithelial cells; junction disruption assays in MTD-1A/MDCK cells\",\n      \"pmids\": [\"10085297\", \"10583506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Competitive l-afadin/vinculin binding leaves the in vivo stoichiometry of junctional complexes undefined\", \"Functional consequence of ponsin loss at junctions not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linking SORBS1 to insulin signaling addressed whether it acts in receptor signaling; insulin-induced SH3C-mediated c-Abl association coupled to partial dissociation from the insulin receptor indicated a dynamic, conformation-dependent adaptor role.\",\n      \"evidence\": \"Co-IP from insulin-stimulated Hep3B hepatoma cells with deletion-construct domain mapping\",\n      \"pmids\": [\"11374898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream metabolic output of the c-Abl interaction not established\", \"Conformational change inferred rather than directly measured\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying teneurin-1 as a partner revealed a potential nucleus-membrane shuttling axis, showing ponsin can be relocalized between compartments depending on its binding partner.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, subcellular fractionation and colocalization with inducible teneurin-1 expression\",\n      \"pmids\": [\"15777793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear function of ponsin not defined\", \"Physiological trigger for translocation unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"High-resolution structures of the SH3-2 domain and its paxillin complex defined the atomic basis of ligand recognition and tied ponsin to force-transducing costameres in muscle differentiation.\",\n      \"evidence\": \"X-ray crystallography (0.83 A SH3, 1.63 A complex; plus powder-diffraction structure), fluorescence titration, and overexpression morphology assays\",\n      \"pmids\": [\"17462669\", \"17784760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Weak paxillin affinity leaves the contribution of avidity/SH3 synergy quantitatively unresolved\", \"Link between cardiac downregulation and contractile dysfunction correlative\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Flotillin-dependent recruitment and Rho-GTPase-dependent localization placed ponsin functionally within actin-cytoskeleton and FAK/Rac1/cdc42 signaling at focal contacts.\",\n      \"evidence\": \"Dominant-negative flotillin, Rho-GTPase and FAK activity assays, neurite outgrowth in N2a/hippocampal neurons; microarray, fractionation and cytoskeleton-perturbation in lens epithelium\",\n      \"pmids\": [\"18722032\", \"19029030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ponsin directly regulates GTPase activity or acts as a passive scaffold unresolved\", \"Direct flotillin-ponsin contact not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery of a muscle-specific isoform with an Nck-binding insertion showed alternative splicing diversifies ponsin's interactome at remodeling cell-matrix contacts.\",\n      \"evidence\": \"Isoform cloning, co-IP, colocalization and phosphorylation analysis in differentiating skeletal muscle cells\",\n      \"pmids\": [\"20129698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of Nck1/2 recruitment in costamere assembly not tested\", \"Phosphorylation sites and regulating kinase not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"NMR mapping of SH3C binding ataxin-7 explained how ponsin is sequestered into polyQ inclusions, connecting it to a neurodegenerative aggregation mechanism.\",\n      \"evidence\": \"NMR structure of SH3C and its complex with ataxin-7 PRR plus cellular sequestration imaging\",\n      \"pmids\": [\"23892081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ponsin sequestration for SCA7 pathology not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Fat1 was identified as another SH3-engaging partner controlling ponsin localization, extending the adhesion-receptor repertoire that positions ponsin at leading edges.\",\n      \"evidence\": \"Yeast two-hybrid, pulldown, siRNA knockdown and immunofluorescence\",\n      \"pmids\": [\"26903299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling from the Fat1-ponsin module not defined\", \"Single-lab interaction without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placing Sorbs1 downstream of MuSK/Dok-7/Crk/CrkL with functional redundancy to Sorbs2 established its role in acetylcholine receptor clustering at the neuromuscular synapse.\",\n      \"evidence\": \"Mass spectrometry interactome, co-IP, in vitro AChR clustering and in vivo synaptic localization\",\n      \"pmids\": [\"26527617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Sorbs1 promotes AChR clustering downstream of CrkL unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In vivo zebrafish loss-of-function established a developmental requirement for Sorbs1 in lymphatic/venous sprouting through FAK/Src and Rac1/RhoA control of endothelial migration and adhesion, independent of Vegfc.\",\n      \"evidence\": \"Zebrafish genetic mutants, in vitro endothelial migration/adhesion and GTPase activity assays, BMP/Vegfc epistasis\",\n      \"pmids\": [\"38414014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between Sorbs1 and the BMP pathway not defined\", \"Endothelial binding partners mediating this role not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cancer studies defined context-dependent roles for SORBS1 in EMT and invasion, acting through JNK/cJun, PI3K/AKT, and AHNAK, with opposing tumor-suppressive and migration-promoting outcomes across models.\",\n      \"evidence\": \"siRNA/knockout and overexpression with migration/invasion assays, pathway Western blots, AHNAK co-IP/colocalization, and macrophage co-culture\",\n      \"pmids\": [\"27791200\", \"32319594\", \"38451194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing pro- and anti-tumor effects across cancer types not mechanistically reconciled\", \"Direct vs indirect regulation of these pathways unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"MBNL-controlled inclusion of SORBS1 exon 25 was shown to be required for NMJ formation and maintenance and its loss contributes to neuromuscular defects in myotonic dystrophy type 1.\",\n      \"evidence\": \"Antisense exon skipping in mouse, zebrafish and hiPSC muscle; NMJ morphology, AChR clustering with agrin, locomotion, and DM1 biopsy RNA analysis\",\n      \"pmids\": [\"41250834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the exon 25 segment alters ponsin's molecular interactions at the synapse not defined\", \"Contribution relative to other DM1 mis-splicing events unquantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ponsin's distinct partner repertoires and splice isoforms are coordinated to switch its function between junctional scaffolding, receptor signaling, and cytoskeletal control in specific tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking isoform-specific interactions to tissue-specific phenotypes\", \"Direct enzymatic or signaling output of ponsin scaffolding undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 10, 11]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005912\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 6, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 15, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [15, 17]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"nectin-afadin-ponsin (NAP) system\",\n      \"MuSK/Dok-7/Crk/CrkL complex\"\n    ],\n    \"partners\": [\n      \"AFDN\",\n      \"VCL\",\n      \"PXN\",\n      \"ABL1\",\n      \"NCK1\",\n      \"NCK2\",\n      \"FAT1\",\n      \"ATXN7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}