{"gene":"SH3PXD2A","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1998,"finding":"Fish (SH3PXD2A/Tks5) was identified as a novel Src tyrosine kinase substrate containing five SH3 domains and a PX domain; it is tyrosine-phosphorylated in Src-transformed fibroblasts and in normal cells following growth factor treatment or cytochalasin D treatment, implicating it in actin cytoskeleton signaling downstream of tyrosine kinases.","method":"Anti-phosphotyrosine antibody screening of cDNA expression libraries; in vivo phosphorylation assays in Src-transformed and growth factor-treated cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — original identification paper with multiple orthogonal assays (library screen, in vivo phosphorylation, cytochalasin D treatment), foundational study","pmids":["9687503"],"is_preprint":false},{"year":2003,"finding":"The PX domain of Fish (Tks5) binds 3-phosphorylated phosphatidylinositols (PI3P and PI(3,4)P2); full-length Fish is largely cytoplasmic in normal fibroblasts but dramatically relocalizes to actin-rich podosomes in Src-transformed cells, with the PX domain necessary and sufficient for this relocalization. Fish interacts with ADAM family members (ADAM12, 15, 19) via its fifth SH3 domain, and ADAM12 co-localizes with Fish at podosomes.","method":"PX domain lipid-binding assays; GFP-fusion localization imaging; phage display screen with SH3 domain; co-immunoprecipitation and co-localization in Src-transformed cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (lipid binding, live imaging, phage display, Co-IP, co-localization) in a single rigorous study","pmids":["12615925"],"is_preprint":false},{"year":2005,"finding":"Tks5/Fish is required for podosome formation and function in Src-transformed cells; knockdown of Tks5/Fish abolishes podosome formation, gelatin degradation, and matrigel invasion. Co-expression of Tks5/Fish and Src in epithelial cells is sufficient to induce podosomes. Tks5/Fish expression is detected in podosomes of invasive cancer cells and in human breast cancer and melanoma samples.","method":"siRNA knockdown with invasion and gelatin degradation assays; co-expression experiments; immunolocalization in cancer cell lines and tumor samples","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with specific cellular phenotypes (podosome loss, invasion, degradation) replicated across multiple cancer cell lines","pmids":["15710328"],"is_preprint":false},{"year":2008,"finding":"Tks5 is required for tumor growth in vivo; Src-transformed NIH-3T3 cells with stable Tks5 knockdown form significantly smaller subcutaneous tumors with reduced vascularization. Tail vein injection produced smaller lung metastases but no difference in lesion number, suggesting podosomes mediate tumor growth and angiogenesis but not extravasation.","method":"Stable shRNA knockdown; subcutaneous and tail vein injection tumor models in mice; histological analysis of vascularization","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss-of-function with defined tumor growth and vascularization phenotypes","pmids":["18417249"],"is_preprint":false},{"year":2009,"finding":"Tks5 functions as a p47(phox)-related organizer that selectively supports NADPH oxidase 1 (Nox1) and Nox3 activity (but not Nox2 or Nox4) in reconstituted cellular systems, interacting with the NoxA1 activator protein through an SH3 domain-mediated interaction. Tks5 recruits Nox1 to invadopodia, linking localized ROS production to invadopodium formation.","method":"Reconstituted Nox activity assays; Co-IP with NoxA1; immunolocalization at invadopodia; siRNA knockdown of Tks4/Tks5","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution assays combined with Co-IP and loss-of-function, multiple orthogonal methods","pmids":["19755710"],"is_preprint":false},{"year":2012,"finding":"Tks5 is required for osteoclast fusion downstream of PI3K and Src; Tks5 expression is induced during osteoclastogenesis and is necessary for circumferential podosome formation and cell-cell fusion without affecting differentiation. Tyrosine phosphorylation of Tks5 by Src is required for proper podosome organization and multinucleation. Tks5 also mediates circumferential invadopodia formation in melanoma cells enabling melanoma-osteoclast hybrid cell formation.","method":"shRNA knockdown during osteoclastogenesis; Src−/− osteoclast analysis; phosphorylation assays; co-culture fusion assays; live imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (KO, KD, phosphorylation assays, co-culture) with defined mechanistic pathway placement","pmids":["22584907"],"is_preprint":false},{"year":2013,"finding":"Tks5 is not required for invadopodium precursor initiation but is essential for precursor stabilization; the PX domain of Tks5 interacts with PI(3,4)P2 locally accumulated at the invadopodium core, and Tks5 arrives after the initial cortactin/N-WASP/cofilin/actin core. SHIP2 (a 5'-inositol phosphatase) arrives coincident with PI(3,4)P2 accumulation and regulates mature invadopodium formation and matrix degradation.","method":"High-resolution spatiotemporal live-cell imaging; siRNA knockdown of Tks5 and SHIP2; SHIP2 overexpression; PI(3,4)P2 and PI(3,4,5)P3 biosensor imaging","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — high-resolution live imaging combined with KD and lipid biosensors precisely defining timing of Tks5 function","pmids":["24206842"],"is_preprint":false},{"year":2014,"finding":"Homozygous disruption of sh3pxd2a in mice by gene-trapping results in neonatal death and complete cleft of the secondary palate. Gene-trap mice lack only the highest molecular weight Tks5 isoform, revealing the existence of a second alternative isoform Tks5β, which lacks the PX domain and instead has a unique N-terminal sequence encoded by a newly discovered exon 6β. Tks5β is a Src substrate and its levels are regulated by the proteasome.","method":"Gene-trap mouse mutant analysis; 5'RACE on mouse fibroblasts; protein analysis by Western blot; Src phosphorylation assays; proteasome inhibitor treatment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic loss-of-function with defined developmental phenotype plus biochemical characterization of novel isoform","pmids":["25259869"],"is_preprint":false},{"year":2017,"finding":"TKS5 expression is upregulated in rheumatoid arthritis (RA) T cells, enabling them to form tissue-invasive podosome-like membrane structures. This upregulation is driven by reduced glycolytic flux (low ATP and pyruvate), which triggers fatty acid biosynthesis and lipid droplet formation. Restoring pyruvate or inhibiting fatty acid synthesis corrects T cell tissue invasiveness in vivo.","method":"Gene expression analysis in RA T cells; metabolic manipulation (pyruvate restoration, fatty acid synthesis inhibition); in vivo mouse arthritis model; TKS5 knockdown/overexpression","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway placement with multiple orthogonal interventions and in vivo validation","pmids":["28737753"],"is_preprint":false},{"year":1997,"finding":"SH3PXD2A (as KIAA0303) was identified and partially sequenced from human brain cDNA libraries as a large protein-coding gene, providing the first sequence information for the locus.","method":"cDNA library screening and in vitro transcription/translation","journal":"DNA research","confidence":"Low","confidence_rationale":"Tier 3 — initial sequence identification only, no functional characterization","pmids":["9455477"],"is_preprint":false},{"year":2006,"finding":"Phage display screening of the complete human SH3 proteome identified SH3 domains of Fish (SH3PXD2A) among those with preferred binding to ADAM15, providing an unbiased confirmation that Fish SH3 domains mediate specific nanomolar-affinity interactions with ADAM family members.","method":"Phage display of 296 human SH3 domains against ADAM15 ligand","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased proteome-wide phage display, but single method","pmids":["16374509"],"is_preprint":false}],"current_model":"SH3PXD2A encodes the scaffold protein Tks5/Fish, a Src tyrosine kinase substrate with a PX domain (binding PI(3,4)P2) and five SH3 domains; upon Src activation, Tks5 relocalizes via its PX domain to invadopodia/podosomes where it is required for their stabilization and maturation (but not initiation), recruits Nox1 for localized ROS production, interacts with ADAM family metalloproteinases, drives extracellular matrix degradation and cancer cell invasion, mediates osteoclast fusion and tumor growth/angiogenesis in vivo, and is essential for secondary palate formation in mice, with its activity regulated by Src-mediated tyrosine phosphorylation and by cellular metabolic state."},"narrative":{"teleology":[{"year":1998,"claim":"Identifying Tks5 as a novel Src substrate with five SH3 domains and a PX domain established it as a potential signaling scaffold linking tyrosine kinase signaling to actin cytoskeleton remodeling.","evidence":"Anti-phosphotyrosine cDNA library screen with in vivo phosphorylation assays in Src-transformed and growth factor-treated fibroblasts","pmids":["9687503"],"confidence":"High","gaps":["Cellular function of the protein was unknown","PX domain lipid specificity was uncharacterized","SH3 domain interaction partners were unidentified"]},{"year":2003,"claim":"Demonstrating that the PX domain binds PI(3,4)P₂ and mediates relocalization to podosomes in Src-transformed cells, and that SH3 domains interact with ADAM metalloproteinases, revealed how Tks5 is spatially targeted and linked to proteolytic effectors.","evidence":"PX domain lipid-binding assays, GFP-fusion imaging, phage display screen, co-immunoprecipitation and co-localization in Src-transformed fibroblasts","pmids":["12615925"],"confidence":"High","gaps":["Whether Tks5 is functionally required for podosome formation was untested","In vivo relevance was unknown","Other SH3 domain partners beyond ADAMs were uncharacterized"]},{"year":2005,"claim":"Loss-of-function experiments established that Tks5 is required for podosome formation, gelatin degradation, and Matrigel invasion, transforming its status from a Src substrate to a necessary functional component of the invasive machinery.","evidence":"siRNA knockdown with invasion and degradation assays in Src-transformed and cancer cell lines; immunolocalization in human tumors","pmids":["15710328"],"confidence":"High","gaps":["Whether Tks5 is needed for initiation versus stabilization of podosomes was unclear","In vivo tumor growth contribution was untested","Non-cancer physiological roles were unknown"]},{"year":2008,"claim":"In vivo tumor xenograft studies showed Tks5 knockdown reduces tumor growth and vascularization but not metastatic seeding, positioning Tks5-dependent podosomes as mediators of tumor growth and angiogenesis rather than extravasation.","evidence":"Stable shRNA knockdown; subcutaneous and tail vein injection models in mice with histological analysis","pmids":["18417249"],"confidence":"High","gaps":["Mechanism linking podosomes to vascularization was unresolved","Whether effects are cell-autonomous was not fully addressed"]},{"year":2009,"claim":"Reconstitution experiments revealed Tks5 as a p47phox-related organizer of Nox1/Nox3 NADPH oxidases, recruiting Nox1 to invadopodia for localized ROS production, thereby connecting the scaffold to redox signaling at invasive structures.","evidence":"Reconstituted Nox activity assays, co-immunoprecipitation with NoxA1, immunolocalization at invadopodia, siRNA knockdown","pmids":["19755710"],"confidence":"High","gaps":["How ROS production mechanistically promotes invadopodium maturation was unresolved","Relative contributions of Nox-organizing versus ADAM-recruiting functions were unclear"]},{"year":2012,"claim":"Demonstrating that Tks5 is induced during osteoclastogenesis and is required for circumferential podosome organization and multinucleation—dependent on Src-mediated tyrosine phosphorylation—extended its physiological role beyond cancer to bone homeostasis and cell fusion.","evidence":"shRNA knockdown during osteoclastogenesis, Src−/− osteoclast analysis, phosphorylation assays, co-culture fusion assays, live imaging","pmids":["22584907"],"confidence":"High","gaps":["Identity of phosphorylated tyrosine residues critical for function was not fully mapped","Whether Tks5 mediates other physiological fusion events was unknown"]},{"year":2013,"claim":"High-resolution live imaging resolved the temporal order of invadopodium assembly, showing Tks5 arrives after the initial cortactin/N-WASP/actin core and is dispensable for precursor initiation but essential for PI(3,4)P₂-dependent stabilization and maturation.","evidence":"Spatiotemporal live-cell imaging with PI(3,4)P₂ biosensors, siRNA knockdown of Tks5 and SHIP2","pmids":["24206842"],"confidence":"High","gaps":["Structural basis of PX domain–PI(3,4)P₂ interaction at invadopodia was unresolved","Downstream effectors recruited by stabilized Tks5 remain incompletely defined"]},{"year":2014,"claim":"Gene-trap disruption of Sh3pxd2a in mice established an essential developmental role, with homozygous loss causing neonatal lethality and complete secondary palate clefting, and revealed a PX-domain-lacking isoform (Tks5β) regulated by the proteasome.","evidence":"Gene-trap mouse model with phenotypic analysis; 5'RACE; Western blot; proteasome inhibitor treatment","pmids":["25259869"],"confidence":"High","gaps":["Whether palate defect is podosome-dependent was untested","Function of the Tks5β isoform in vivo was not determined","Whether SH3PXD2A mutations cause human craniofacial disorders was unknown"]},{"year":2017,"claim":"Discovery that altered glycolytic metabolism in rheumatoid arthritis T cells upregulates Tks5 to drive tissue-invasive podosome formation linked metabolic reprogramming to the invasive scaffold, revealing a non-cancer pathological context for Tks5 function.","evidence":"Gene expression analysis in RA T cells; metabolic interventions (pyruvate, fatty acid synthesis inhibitors); in vivo arthritis model; Tks5 knockdown/overexpression","pmids":["28737753"],"confidence":"High","gaps":["Transcriptional or post-transcriptional mechanism connecting lipid droplets to Tks5 expression was not fully elucidated","Whether Tks5 contributes to other autoimmune tissue-invasive phenotypes was untested"]},{"year":null,"claim":"Key unresolved questions include the structural basis of Tks5 scaffold assembly at invadopodia, the specific tyrosine residues controlling its function, the in vivo role of the Tks5β isoform, and whether SH3PXD2A mutations contribute to human craniofacial or skeletal disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of Tks5 or its domain complexes","Functional significance of individual SH3 domains beyond the fifth is poorly defined","Human genetic disease association not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,4,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,5,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7]}],"complexes":[],"partners":["SRC","ADAM12","ADAM15","ADAM19","NOXA1","NOX1","SHIP2"],"other_free_text":[]},"mechanistic_narrative":"SH3PXD2A (Tks5/Fish) is a multi-domain scaffold protein that functions as a critical organizer of invadopodia and podosomes, coupling Src tyrosine kinase signaling to invasive cell migration, extracellular matrix degradation, and cell–cell fusion. Identified as a Src substrate with a PX domain and five SH3 domains, Tks5 is recruited to invadopodium precursors via PX domain binding to PI(3,4)P₂, where it stabilizes nascent structures rather than initiating them, and scaffolds NADPH oxidase 1 (Nox1) for localized ROS production and ADAM family metalloproteinases for matrix remodeling [PMID:12615925, PMID:24206842, PMID:19755710]. Tks5 is required for tumor growth and vascularization in vivo, for osteoclast fusion downstream of PI3K/Src, and its expression in rheumatoid arthritis T cells—driven by altered glycolytic metabolism—confers tissue-invasive capacity [PMID:18417249, PMID:22584907, PMID:28737753]. Homozygous disruption of Sh3pxd2a in mice causes neonatal lethality with complete cleft of the secondary palate [PMID:25259869]."},"prefetch_data":{"uniprot":{"accession":"Q5TCZ1","full_name":"SH3 and PX domain-containing protein 2A","aliases":["Adapter protein TKS5","Five SH3 domain-containing protein","SH3 multiple domains protein 1","Tyrosine kinase substrate with five SH3 domains"],"length_aa":1133,"mass_kda":125.3,"function":"Adapter protein involved in invadopodia and podosome formation, extracellular matrix degradation and invasiveness of some cancer cells (PubMed:27789576). Binds matrix metalloproteinases (ADAMs), NADPH oxidases (NOXs) and phosphoinositides. Acts as an organizer protein that allows NOX1- or NOX3-dependent reactive oxygen species (ROS) generation and ROS localization. In association with ADAM12, mediates the neurotoxic effect of amyloid-beta peptide","subcellular_location":"Cytoplasm; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/Q5TCZ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3PXD2A","classification":"Not Classified","n_dependent_lines":39,"n_total_lines":1208,"dependency_fraction":0.03228476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SH3PXD2A","total_profiled":1310},"omim":[{"mim_id":"619550","title":"RAB40B, MEMBER RAS ONCOGENE FAMILY; RAB40B","url":"https://www.omim.org/entry/619550"},{"mim_id":"619455","title":"SH3 AND PX DOMAINS-CONTAINING PROTEIN 2A; SH3PXD2A","url":"https://www.omim.org/entry/619455"},{"mim_id":"610942","title":"MICRO RNA 204; MIR204","url":"https://www.omim.org/entry/610942"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Primary cilium transition zone","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SH3PXD2A"},"hgnc":{"alias_symbol":["FISH","KIAA0418"],"prev_symbol":["SH3MD1"]},"alphafold":{"accession":"Q5TCZ1","domains":[{"cath_id":"3.30.1520.10","chopping":"7-129","consensus_level":"high","plddt":89.5933,"start":7,"end":129},{"cath_id":"2.30.30.40","chopping":"169-223","consensus_level":"medium","plddt":87.2691,"start":169,"end":223},{"cath_id":"2.30.30.40","chopping":"267-324","consensus_level":"medium","plddt":87.2552,"start":267,"end":324},{"cath_id":"2.30.30.40","chopping":"453-507","consensus_level":"high","plddt":89.5713,"start":453,"end":507},{"cath_id":"2.30.30.40","chopping":"860-897","consensus_level":"high","plddt":89.6084,"start":860,"end":897},{"cath_id":"2.30.30.40","chopping":"1077-1132","consensus_level":"high","plddt":83.1743,"start":1077,"end":1132}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TCZ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TCZ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TCZ1-F1-predicted_aligned_error_v6.png","plddt_mean":56.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3PXD2A","jax_strain_url":"https://www.jax.org/strain/search?query=SH3PXD2A"},"sequence":{"accession":"Q5TCZ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5TCZ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5TCZ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TCZ1"}},"corpus_meta":[{"pmid":"19348807","id":"PMC_19348807","title":"Spermatogenesis 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integrin adhesions.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32203420","citation_count":194,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12672817","id":"PMC_12672817","title":"A Cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12672817","citation_count":178,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21706016","id":"PMC_21706016","title":"Selected reaction monitoring mass spectrometry reveals the dynamics of signaling through the GRB2 adaptor.","date":"2011","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21706016","citation_count":172,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9687503","id":"PMC_9687503","title":"A new method for isolating tyrosine kinase substrates used to identify fish, an SH3 and PX domain-containing protein, and Src substrate.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9687503","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19322201","id":"PMC_19322201","title":"Ubiquitin-mediated proteolysis of HuR by heat shock.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19322201","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29117863","id":"PMC_29117863","title":"RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for 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(Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16374509","id":"PMC_16374509","title":"Identification of preferred protein interactions by phage-display of the human Src homology-3 proteome.","date":"2006","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/16374509","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18417249","id":"PMC_18417249","title":"A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo.","date":"2008","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18417249","citation_count":96,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22584907","id":"PMC_22584907","title":"Tks5-dependent formation of circumferential podosomes/invadopodia mediates cell-cell fusion.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22584907","citation_count":88,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19755710","id":"PMC_19755710","title":"Novel p47(phox)-related organizers regulate localized NADPH oxidase 1 (Nox1) activity.","date":"2009","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/19755710","citation_count":86,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9455477","id":"PMC_9455477","title":"Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro.","date":"1997","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/9455477","citation_count":68,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41548,"output_tokens":1470,"usd":0.073347},"stage2":{"model":"claude-opus-4-6","input_tokens":4726,"output_tokens":1548,"usd":0.093495},"total_usd":0.417077,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":54183,"output_tokens":2925,"usd":0.103212},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6528,"output_tokens":2615,"usd":0.147023}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Homozygous disruption of sh3pxd2a by gene-trapping in mice results in neonatal death and complete cleft of the secondary palate, establishing that the full-length (PX-domain-containing) Tks5 isoform is essential for correct mammalian development. Embryonic fibroblasts from homozygous mice lack only the highest molecular weight Tks5 band, revealing that the gene-trap selectively eliminates the long isoform.\",\n      \"method\": \"Gene-trap mouse knockout; protein immunoblotting of embryonic fibroblasts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific developmental phenotype plus isoform-level protein analysis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25259869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A novel Tks5 isoform, Tks5β, was discovered from an alternative transcription start site within intron V of sh3pxd2a. Tks5β lacks the PX domain (which confers affinity for phosphatidylinositol-3,4-bisphosphate) and instead carries a unique short N-terminal sequence. Tks5β is a substrate for Src tyrosine kinase, and its expression is regulated through the proteasome degradation pathway.\",\n      \"method\": \"5' RACE on mouse fibroblasts; Src kinase in vitro phosphorylation assay; proteasome inhibitor treatment with immunoblotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — novel isoform identified by 5'RACE and validated biochemically with kinase assay and proteasome inhibition in same study\",\n      \"pmids\": [\"25259869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The SH3PXD2A gene product (FISH adapter protein) was shown to bind to and potentially regulate ADAM12 (a disintegrin and metalloprotease 12), mediating a neurotoxic effect of Aβ. Genetic interaction between variants in SH3MD1 (SH3PXD2A) and ADAM12 was detected in a case-control study of late-onset Alzheimer's disease.\",\n      \"method\": \"Genetic interaction analysis (SNP × SNP interaction in 1,051 AD cases vs. 1,269 controls); prior biochemical binding evidence cited\",\n      \"journal\": \"American journal of medical genetics. Part B, Neuropsychiatric genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic association with interaction term; the binding claim references prior evidence not directly demonstrated in this paper\",\n      \"pmids\": [\"17440933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA SH3PXD2A-AS1 inhibits trophoblast invasion and migration by recruiting CTCF to the promoters of SH3PXD2A and CCR7, thereby repressing their transcription. Upregulation of SH3PXD2A-AS1 in preeclamptic placentae suppresses SH3PXD2A expression, linking the scaffold protein's transcriptional regulation to placentation defects.\",\n      \"method\": \"Transcriptome profiling of preeclamptic vs. normal placentae; lncRNA knockdown/overexpression in trophoblast cells with invasion/migration assays; ChIP demonstrating CTCF recruitment to SH3PXD2A and CCR7 promoters\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP plus functional cell assays in single lab; demonstrates transcriptional regulation of SH3PXD2A via CTCF-mediated mechanism\",\n      \"pmids\": [\"32719429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SH3PXD2A is differentially expressed and shows aberrant DNA methylation (hypermethylation in a gene-body CpG island, CGI34) in preeclamptic placentae compared with controls, with the hypermethylation proposed to promote transcription efficiency, implicating SH3PXD2A in regulation of trophoblast cell invasion during placenta formation.\",\n      \"method\": \"Microarray expression profiling validated by qRT-PCR; quantitative methylation analysis (bisulfite sequencing/pyrosequencing) of 16 preeclamptic vs. 16 normal placentae\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — expression and methylation correlation without direct functional mechanistic experiment for SH3PXD2A itself\",\n      \"pmids\": [\"23544093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3PXD2A encodes Tks5, a PX-domain-containing scaffold protein and Src tyrosine kinase substrate that is essential for invadosome formation, cell migration, and matrix degradation; the gene produces at least two isoforms (the long PX-domain form and the shorter Tks5β lacking the PX domain), with the full-length isoform required for mammalian palatogenesis, while Tks5β is regulated by the proteasome and phosphorylated by Src, and the gene's expression is transcriptionally repressed by lncRNA SH3PXD2A-AS1 via CTCF recruitment to its promoter.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Fish (SH3PXD2A/Tks5) was identified as a novel Src tyrosine kinase substrate containing five SH3 domains and a PX domain; it is tyrosine-phosphorylated in Src-transformed fibroblasts and in normal cells following growth factor treatment or cytochalasin D treatment, implicating it in actin cytoskeleton signaling downstream of tyrosine kinases.\",\n      \"method\": \"Anti-phosphotyrosine antibody screening of cDNA expression libraries; in vivo phosphorylation assays in Src-transformed and growth factor-treated cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original identification paper with multiple orthogonal assays (library screen, in vivo phosphorylation, cytochalasin D treatment), foundational study\",\n      \"pmids\": [\"9687503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The PX domain of Fish (Tks5) binds 3-phosphorylated phosphatidylinositols (PI3P and PI(3,4)P2); full-length Fish is largely cytoplasmic in normal fibroblasts but dramatically relocalizes to actin-rich podosomes in Src-transformed cells, with the PX domain necessary and sufficient for this relocalization. Fish interacts with ADAM family members (ADAM12, 15, 19) via its fifth SH3 domain, and ADAM12 co-localizes with Fish at podosomes.\",\n      \"method\": \"PX domain lipid-binding assays; GFP-fusion localization imaging; phage display screen with SH3 domain; co-immunoprecipitation and co-localization in Src-transformed cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (lipid binding, live imaging, phage display, Co-IP, co-localization) in a single rigorous study\",\n      \"pmids\": [\"12615925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Tks5/Fish is required for podosome formation and function in Src-transformed cells; knockdown of Tks5/Fish abolishes podosome formation, gelatin degradation, and matrigel invasion. Co-expression of Tks5/Fish and Src in epithelial cells is sufficient to induce podosomes. Tks5/Fish expression is detected in podosomes of invasive cancer cells and in human breast cancer and melanoma samples.\",\n      \"method\": \"siRNA knockdown with invasion and gelatin degradation assays; co-expression experiments; immunolocalization in cancer cell lines and tumor samples\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with specific cellular phenotypes (podosome loss, invasion, degradation) replicated across multiple cancer cell lines\",\n      \"pmids\": [\"15710328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tks5 is required for tumor growth in vivo; Src-transformed NIH-3T3 cells with stable Tks5 knockdown form significantly smaller subcutaneous tumors with reduced vascularization. Tail vein injection produced smaller lung metastases but no difference in lesion number, suggesting podosomes mediate tumor growth and angiogenesis but not extravasation.\",\n      \"method\": \"Stable shRNA knockdown; subcutaneous and tail vein injection tumor models in mice; histological analysis of vascularization\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined tumor growth and vascularization phenotypes\",\n      \"pmids\": [\"18417249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Tks5 functions as a p47(phox)-related organizer that selectively supports NADPH oxidase 1 (Nox1) and Nox3 activity (but not Nox2 or Nox4) in reconstituted cellular systems, interacting with the NoxA1 activator protein through an SH3 domain-mediated interaction. Tks5 recruits Nox1 to invadopodia, linking localized ROS production to invadopodium formation.\",\n      \"method\": \"Reconstituted Nox activity assays; Co-IP with NoxA1; immunolocalization at invadopodia; siRNA knockdown of Tks4/Tks5\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution assays combined with Co-IP and loss-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"19755710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tks5 is required for osteoclast fusion downstream of PI3K and Src; Tks5 expression is induced during osteoclastogenesis and is necessary for circumferential podosome formation and cell-cell fusion without affecting differentiation. Tyrosine phosphorylation of Tks5 by Src is required for proper podosome organization and multinucleation. Tks5 also mediates circumferential invadopodia formation in melanoma cells enabling melanoma-osteoclast hybrid cell formation.\",\n      \"method\": \"shRNA knockdown during osteoclastogenesis; Src−/− osteoclast analysis; phosphorylation assays; co-culture fusion assays; live imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (KO, KD, phosphorylation assays, co-culture) with defined mechanistic pathway placement\",\n      \"pmids\": [\"22584907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tks5 is not required for invadopodium precursor initiation but is essential for precursor stabilization; the PX domain of Tks5 interacts with PI(3,4)P2 locally accumulated at the invadopodium core, and Tks5 arrives after the initial cortactin/N-WASP/cofilin/actin core. SHIP2 (a 5'-inositol phosphatase) arrives coincident with PI(3,4)P2 accumulation and regulates mature invadopodium formation and matrix degradation.\",\n      \"method\": \"High-resolution spatiotemporal live-cell imaging; siRNA knockdown of Tks5 and SHIP2; SHIP2 overexpression; PI(3,4)P2 and PI(3,4,5)P3 biosensor imaging\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — high-resolution live imaging combined with KD and lipid biosensors precisely defining timing of Tks5 function\",\n      \"pmids\": [\"24206842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Homozygous disruption of sh3pxd2a in mice by gene-trapping results in neonatal death and complete cleft of the secondary palate. Gene-trap mice lack only the highest molecular weight Tks5 isoform, revealing the existence of a second alternative isoform Tks5β, which lacks the PX domain and instead has a unique N-terminal sequence encoded by a newly discovered exon 6β. Tks5β is a Src substrate and its levels are regulated by the proteasome.\",\n      \"method\": \"Gene-trap mouse mutant analysis; 5'RACE on mouse fibroblasts; protein analysis by Western blot; Src phosphorylation assays; proteasome inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic loss-of-function with defined developmental phenotype plus biochemical characterization of novel isoform\",\n      \"pmids\": [\"25259869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TKS5 expression is upregulated in rheumatoid arthritis (RA) T cells, enabling them to form tissue-invasive podosome-like membrane structures. This upregulation is driven by reduced glycolytic flux (low ATP and pyruvate), which triggers fatty acid biosynthesis and lipid droplet formation. Restoring pyruvate or inhibiting fatty acid synthesis corrects T cell tissue invasiveness in vivo.\",\n      \"method\": \"Gene expression analysis in RA T cells; metabolic manipulation (pyruvate restoration, fatty acid synthesis inhibition); in vivo mouse arthritis model; TKS5 knockdown/overexpression\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement with multiple orthogonal interventions and in vivo validation\",\n      \"pmids\": [\"28737753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SH3PXD2A (as KIAA0303) was identified and partially sequenced from human brain cDNA libraries as a large protein-coding gene, providing the first sequence information for the locus.\",\n      \"method\": \"cDNA library screening and in vitro transcription/translation\",\n      \"journal\": \"DNA research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — initial sequence identification only, no functional characterization\",\n      \"pmids\": [\"9455477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Phage display screening of the complete human SH3 proteome identified SH3 domains of Fish (SH3PXD2A) among those with preferred binding to ADAM15, providing an unbiased confirmation that Fish SH3 domains mediate specific nanomolar-affinity interactions with ADAM family members.\",\n      \"method\": \"Phage display of 296 human SH3 domains against ADAM15 ligand\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteome-wide phage display, but single method\",\n      \"pmids\": [\"16374509\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3PXD2A encodes the scaffold protein Tks5/Fish, a Src tyrosine kinase substrate with a PX domain (binding PI(3,4)P2) and five SH3 domains; upon Src activation, Tks5 relocalizes via its PX domain to invadopodia/podosomes where it is required for their stabilization and maturation (but not initiation), recruits Nox1 for localized ROS production, interacts with ADAM family metalloproteinases, drives extracellular matrix degradation and cancer cell invasion, mediates osteoclast fusion and tumor growth/angiogenesis in vivo, and is essential for secondary palate formation in mice, with its activity regulated by Src-mediated tyrosine phosphorylation and by cellular metabolic state.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SH3PXD2A encodes Tks5, a PX-domain-containing scaffold protein and Src tyrosine kinase substrate that functions in cell invasion and migration. The gene produces at least two isoforms: a full-length form whose PX domain mediates phosphoinositide binding, and a shorter Tks5β isoform—initiated from an alternative transcription start site within intron V—that lacks the PX domain, is phosphorylated by Src, and is regulated by proteasomal degradation [PMID:25259869]. Homozygous disruption of the full-length isoform in mice causes complete cleft of the secondary palate and neonatal lethality, establishing an essential role in mammalian palatogenesis [PMID:25259869]. Transcription of SH3PXD2A is repressed by the antisense lncRNA SH3PXD2A-AS1 through recruitment of CTCF to its promoter, and loss of SH3PXD2A expression in trophoblasts impairs invasion and migration, linking the gene to placentation [PMID:32719429].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"An early study raised the possibility that SH3PXD2A participates in ADAM12-mediated signaling relevant to neurodegeneration, but the biochemical interaction was not directly demonstrated in the study itself.\",\n      \"evidence\": \"SNP × SNP genetic interaction analysis in a late-onset Alzheimer's disease case-control cohort (1,051 cases vs. 1,269 controls)\",\n      \"pmids\": [\"17440933\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"The SH3PXD2A–ADAM12 physical interaction was referenced but not directly demonstrated in this study\",\n        \"Genetic interaction has not been replicated in independent cohorts\",\n        \"No functional cell-based or biochemical validation of the proposed neurotoxic mechanism\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Differential expression and gene-body hypermethylation of SH3PXD2A in preeclamptic placentae first implicated it in trophoblast biology, though the study did not establish a causal mechanism.\",\n      \"evidence\": \"Microarray expression profiling with qRT-PCR validation and bisulfite/pyrosequencing methylation analysis of preeclamptic versus normal placentae\",\n      \"pmids\": [\"23544093\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Correlative methylation and expression data without functional perturbation of SH3PXD2A in trophoblasts\",\n        \"Causality between gene-body methylation and transcription not established\",\n        \"No mechanistic link to invadosome or migration function tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery of the Tks5β isoform and the essential developmental role of the full-length isoform resolved the gene's isoform architecture and established that the PX-domain-containing form is required for palatogenesis in vivo.\",\n      \"evidence\": \"Gene-trap mouse knockout eliminating the long isoform (cleft palate and neonatal lethality); 5' RACE identifying Tks5β; Src kinase phosphorylation assay and proteasome inhibitor treatment in embryonic fibroblasts\",\n      \"pmids\": [\"25259869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which Tks5 directs palatal shelf fusion is unknown\",\n        \"Whether Tks5β has a distinct in vivo function has not been tested\",\n        \"Invadosome/podosome formation was not directly assessed in the palatal tissue\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of CTCF-mediated transcriptional repression of SH3PXD2A by lncRNA SH3PXD2A-AS1 established a regulatory axis controlling trophoblast invasion, providing a mechanistic link between SH3PXD2A expression and placentation defects.\",\n      \"evidence\": \"lncRNA knockdown/overexpression in trophoblast cell lines with invasion and migration assays; ChIP demonstrating CTCF recruitment to the SH3PXD2A promoter\",\n      \"pmids\": [\"32719429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings from a single lab; not independently replicated\",\n        \"Whether CTCF-mediated repression operates in vivo in placental tissue has not been confirmed\",\n        \"Downstream effectors of SH3PXD2A in trophoblast invasion (e.g., matrix metalloprotease recruitment) are not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise molecular mechanism by which Tks5 scaffolding drives invadosome formation and matrix degradation, the distinct physiological roles of Tks5β versus the full-length isoform, and the structural basis for PX-domain-dependent membrane targeting remain to be defined by direct experimentation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of Tks5 or its PX domain–PI(3,4)P2 interaction from the timeline literature\",\n        \"Invadosome-related scaffolding partners have not been mapped in a systematic manner within these studies\",\n        \"In vivo functions beyond palatogenesis and trophoblast invasion are unexplored in these discoveries\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SRC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SH3PXD2A (Tks5/Fish) is a multi-domain scaffold protein that functions as a critical organizer of invadopodia and podosomes, coupling Src tyrosine kinase signaling to invasive cell migration, extracellular matrix degradation, and cell–cell fusion. Identified as a Src substrate with a PX domain and five SH3 domains, Tks5 is recruited to invadopodium precursors via PX domain binding to PI(3,4)P₂, where it stabilizes nascent structures rather than initiating them, and scaffolds NADPH oxidase 1 (Nox1) for localized ROS production and ADAM family metalloproteinases for matrix remodeling [PMID:12615925, PMID:24206842, PMID:19755710]. Tks5 is required for tumor growth and vascularization in vivo, for osteoclast fusion downstream of PI3K/Src, and its expression in rheumatoid arthritis T cells—driven by altered glycolytic metabolism—confers tissue-invasive capacity [PMID:18417249, PMID:22584907, PMID:28737753]. Homozygous disruption of Sh3pxd2a in mice causes neonatal lethality with complete cleft of the secondary palate [PMID:25259869].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying Tks5 as a novel Src substrate with five SH3 domains and a PX domain established it as a potential signaling scaffold linking tyrosine kinase signaling to actin cytoskeleton remodeling.\",\n      \"evidence\": \"Anti-phosphotyrosine cDNA library screen with in vivo phosphorylation assays in Src-transformed and growth factor-treated fibroblasts\",\n      \"pmids\": [\"9687503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular function of the protein was unknown\", \"PX domain lipid specificity was uncharacterized\", \"SH3 domain interaction partners were unidentified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that the PX domain binds PI(3,4)P₂ and mediates relocalization to podosomes in Src-transformed cells, and that SH3 domains interact with ADAM metalloproteinases, revealed how Tks5 is spatially targeted and linked to proteolytic effectors.\",\n      \"evidence\": \"PX domain lipid-binding assays, GFP-fusion imaging, phage display screen, co-immunoprecipitation and co-localization in Src-transformed fibroblasts\",\n      \"pmids\": [\"12615925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tks5 is functionally required for podosome formation was untested\", \"In vivo relevance was unknown\", \"Other SH3 domain partners beyond ADAMs were uncharacterized\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Loss-of-function experiments established that Tks5 is required for podosome formation, gelatin degradation, and Matrigel invasion, transforming its status from a Src substrate to a necessary functional component of the invasive machinery.\",\n      \"evidence\": \"siRNA knockdown with invasion and degradation assays in Src-transformed and cancer cell lines; immunolocalization in human tumors\",\n      \"pmids\": [\"15710328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tks5 is needed for initiation versus stabilization of podosomes was unclear\", \"In vivo tumor growth contribution was untested\", \"Non-cancer physiological roles were unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"In vivo tumor xenograft studies showed Tks5 knockdown reduces tumor growth and vascularization but not metastatic seeding, positioning Tks5-dependent podosomes as mediators of tumor growth and angiogenesis rather than extravasation.\",\n      \"evidence\": \"Stable shRNA knockdown; subcutaneous and tail vein injection models in mice with histological analysis\",\n      \"pmids\": [\"18417249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking podosomes to vascularization was unresolved\", \"Whether effects are cell-autonomous was not fully addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reconstitution experiments revealed Tks5 as a p47phox-related organizer of Nox1/Nox3 NADPH oxidases, recruiting Nox1 to invadopodia for localized ROS production, thereby connecting the scaffold to redox signaling at invasive structures.\",\n      \"evidence\": \"Reconstituted Nox activity assays, co-immunoprecipitation with NoxA1, immunolocalization at invadopodia, siRNA knockdown\",\n      \"pmids\": [\"19755710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ROS production mechanistically promotes invadopodium maturation was unresolved\", \"Relative contributions of Nox-organizing versus ADAM-recruiting functions were unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that Tks5 is induced during osteoclastogenesis and is required for circumferential podosome organization and multinucleation—dependent on Src-mediated tyrosine phosphorylation—extended its physiological role beyond cancer to bone homeostasis and cell fusion.\",\n      \"evidence\": \"shRNA knockdown during osteoclastogenesis, Src−/− osteoclast analysis, phosphorylation assays, co-culture fusion assays, live imaging\",\n      \"pmids\": [\"22584907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of phosphorylated tyrosine residues critical for function was not fully mapped\", \"Whether Tks5 mediates other physiological fusion events was unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"High-resolution live imaging resolved the temporal order of invadopodium assembly, showing Tks5 arrives after the initial cortactin/N-WASP/actin core and is dispensable for precursor initiation but essential for PI(3,4)P₂-dependent stabilization and maturation.\",\n      \"evidence\": \"Spatiotemporal live-cell imaging with PI(3,4)P₂ biosensors, siRNA knockdown of Tks5 and SHIP2\",\n      \"pmids\": [\"24206842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PX domain–PI(3,4)P₂ interaction at invadopodia was unresolved\", \"Downstream effectors recruited by stabilized Tks5 remain incompletely defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Gene-trap disruption of Sh3pxd2a in mice established an essential developmental role, with homozygous loss causing neonatal lethality and complete secondary palate clefting, and revealed a PX-domain-lacking isoform (Tks5β) regulated by the proteasome.\",\n      \"evidence\": \"Gene-trap mouse model with phenotypic analysis; 5'RACE; Western blot; proteasome inhibitor treatment\",\n      \"pmids\": [\"25259869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether palate defect is podosome-dependent was untested\", \"Function of the Tks5β isoform in vivo was not determined\", \"Whether SH3PXD2A mutations cause human craniofacial disorders was unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that altered glycolytic metabolism in rheumatoid arthritis T cells upregulates Tks5 to drive tissue-invasive podosome formation linked metabolic reprogramming to the invasive scaffold, revealing a non-cancer pathological context for Tks5 function.\",\n      \"evidence\": \"Gene expression analysis in RA T cells; metabolic interventions (pyruvate, fatty acid synthesis inhibitors); in vivo arthritis model; Tks5 knockdown/overexpression\",\n      \"pmids\": [\"28737753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional or post-transcriptional mechanism connecting lipid droplets to Tks5 expression was not fully elucidated\", \"Whether Tks5 contributes to other autoimmune tissue-invasive phenotypes was untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of Tks5 scaffold assembly at invadopodia, the specific tyrosine residues controlling its function, the in vivo role of the Tks5β isoform, and whether SH3PXD2A mutations contribute to human craniofacial or skeletal disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of Tks5 or its domain complexes\", \"Functional significance of individual SH3 domains beyond the fifth is poorly defined\", \"Human genetic disease association not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SRC\", \"ADAM12\", \"ADAM15\", \"ADAM19\", \"NOXA1\", \"NOX1\", \"SHIP2\"],\n    \"other_free_text\": []\n  }\n}\n```"}