{"gene":"SH3PXD2A","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2014,"finding":"Homozygous gene-trap disruption of sh3pxd2a in mice causes neonatal death and complete cleft of the secondary palate, establishing an essential role for the long (PX-domain-containing) Tks5 isoform in mammalian development. Embryonic fibroblasts from homozygous mutant mice lacked only the highest molecular weight band of the Tks5 triplet, revealing a novel shorter isoform.","method":"Gene-trap mouse knockout with phenotypic analysis; protein immunoblotting of embryonic fibroblasts","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined developmental phenotype plus orthogonal protein biochemistry; single lab but multiple methods with rigorous controls","pmids":["25259869"],"is_preprint":false},{"year":2014,"finding":"A novel Tks5 isoform, Tks5β, was identified via 5'RACE on mouse fibroblasts. Tks5β is encoded by an alternative transcription start site in intron V of sh3pxd2a and lacks the PX domain (which confers phosphatidylinositol-3,4-bisphosphate binding), instead possessing a unique short N-terminal sequence encoded by newly discovered exon 6β. Tks5β is a substrate for Src tyrosine kinase and its expression is regulated through the proteasome degradation pathway.","method":"5'RACE, Src kinase substrate assay, proteasome inhibitor treatment with protein blotting","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical identification of new isoform by 5'RACE, Src kinase assay, and proteasome pathway experiment in single study with multiple orthogonal methods","pmids":["25259869"],"is_preprint":false},{"year":2007,"finding":"Genetic interaction analysis in an Alzheimer's disease case-control cohort revealed a statistically significant interaction between variants in SH3MD1 (SH3PXD2A) and ADAM12, suggesting that the FISH adapter protein (encoded by SH3MD1) may functionally interact with ADAM12 to mediate effects relevant to late-onset Alzheimer's disease pathogenesis.","method":"Genetic association and SNP interaction analysis in 1,051 AD cases and 1,269 controls","journal":"American journal of medical genetics. Part B, Neuropsychiatric genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genetic association/interaction study only; no direct biochemical or cellular mechanistic experiment performed on the protein itself","pmids":["17440933"],"is_preprint":false}],"current_model":"SH3PXD2A encodes the scaffold protein Tks5, which exists in at least two isoforms: the long form (containing a PX domain that binds phosphatidylinositol-3,4-bisphosphate) and a novel shorter isoform Tks5β (lacking the PX domain); the long isoform is essential for mammalian palatogenesis and normal development, both isoforms are substrates for Src tyrosine kinase, and Tks5β levels are regulated by proteasomal degradation."},"narrative":{"mechanistic_narrative":"SH3PXD2A encodes the scaffold protein Tks5, which is essential for mammalian development: homozygous gene-trap disruption in mice causes neonatal death and complete cleft of the secondary palate, demonstrating that the long, PX-domain-containing isoform is required for normal palatogenesis [PMID:25259869]. The locus produces at least two isoforms—the long form bearing a PX domain that binds phosphatidylinositol-3,4-bisphosphate, and a shorter Tks5β isoform identified by 5'RACE, which arises from an alternative transcription start site in intron V and replaces the PX domain with a unique N-terminal sequence encoded by a newly discovered exon 6β [PMID:25259869]. Both isoforms are substrates for Src tyrosine kinase, and Tks5β abundance is controlled by proteasomal degradation [PMID:25259869]. Beyond these isoform-defining and developmental findings, no further mechanistic detail on Tks5 effector function has been characterized in the available corpus.","teleology":[{"year":2007,"claim":"Before any biochemical characterization, a candidate link of SH3PXD2A to disease was tested by asking whether its variants interact genetically with a partner locus in neurodegeneration.","evidence":"Genetic association and SNP interaction analysis in an Alzheimer's disease case-control cohort (1,051 cases, 1,269 controls)","pmids":["17440933"],"confidence":"Low","gaps":["Statistical genetic interaction only; no biochemical or cellular interaction between the proteins demonstrated","No mechanism linking SH3PXD2A to Alzheimer's pathogenesis established","Association not independently confirmed in the corpus"]},{"year":2014,"claim":"The developmental requirement for Tks5 was unknown; genetic ablation showed the long PX-domain isoform is essential, defining a discrete in vivo function in palatogenesis.","evidence":"Gene-trap mouse knockout with phenotypic analysis plus immunoblotting of embryonic fibroblasts","pmids":["25259869"],"confidence":"High","gaps":["Molecular effector pathway through which Tks5 drives palate closure not defined","Cell types responsible for the cleft phenotype not resolved","Contribution of PI(3,4)P2 binding to the developmental role not directly tested"]},{"year":2014,"claim":"The identity and regulation of the shorter Tks5 band were unknown; 5'RACE and biochemistry defined Tks5β as a distinct, PX-domain-lacking isoform that is Src-phosphorylated and proteasomally regulated.","evidence":"5'RACE, Src kinase substrate assay, and proteasome inhibitor treatment with protein blotting in mouse fibroblasts","pmids":["25259869"],"confidence":"High","gaps":["Functional role of Tks5β versus the long isoform not established","Downstream effectors recruited by either isoform not identified","Consequence of Src phosphorylation on Tks5β activity or stability not resolved"]},{"year":null,"claim":"How Tks5 isoforms assemble effector complexes and translate Src phosphorylation and PI(3,4)P2 binding into the cellular events underlying palatogenesis remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct physical partners or substrate complexes characterized in the corpus","No structural or biophysical model of PX-domain lipid engagement","Distinct cellular functions of the long isoform versus Tks5β not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"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 in fish.","date":"2009","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19348807","citation_count":721,"is_preprint":false},{"pmid":"18482399","id":"PMC_18482399","title":"Regulation of oocyte maturation in fish.","date":"2008","source":"Development, growth & differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/18482399","citation_count":498,"is_preprint":false},{"pmid":"15939626","id":"PMC_15939626","title":"The interferon system of teleost fish.","date":"2006","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15939626","citation_count":421,"is_preprint":false},{"pmid":"12398363","id":"PMC_12398363","title":"Ammonia toxicity in fish.","date":"2002","source":"Marine pollution bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/12398363","citation_count":410,"is_preprint":false},{"pmid":"19686749","id":"PMC_19686749","title":"Perspectives on fish gonadotropins and their receptors.","date":"2009","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19686749","citation_count":344,"is_preprint":false},{"pmid":"12696592","id":"PMC_12696592","title":"Regulation of fish gonadotropins.","date":"2003","source":"International review of cytology","url":"https://pubmed.ncbi.nlm.nih.gov/12696592","citation_count":276,"is_preprint":false},{"pmid":"10898459","id":"PMC_10898459","title":"Histamine fish poisoning revisited.","date":"2000","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10898459","citation_count":273,"is_preprint":false},{"pmid":"16494227","id":"PMC_16494227","title":"Effects of microcystins on fish.","date":"2006","source":"Environmental toxicology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16494227","citation_count":259,"is_preprint":false},{"pmid":"21605591","id":"PMC_21605591","title":"The interleukins of fish.","date":"2011","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21605591","citation_count":228,"is_preprint":false},{"pmid":"11399452","id":"PMC_11399452","title":"Paradigms of growth in fish.","date":"2001","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11399452","citation_count":212,"is_preprint":false},{"pmid":"21414348","id":"PMC_21414348","title":"Chemokines in teleost fish species.","date":"2011","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21414348","citation_count":186,"is_preprint":false},{"pmid":"16403502","id":"PMC_16403502","title":"CRF and stress in fish.","date":"2006","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/16403502","citation_count":169,"is_preprint":false},{"pmid":"12653993","id":"PMC_12653993","title":"'Antifreeze' glycoproteins from polar fish.","date":"2003","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12653993","citation_count":164,"is_preprint":false},{"pmid":"27879632","id":"PMC_27879632","title":"Fish Immunoglobulins.","date":"2016","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/27879632","citation_count":158,"is_preprint":false},{"pmid":"16297386","id":"PMC_16297386","title":"Endotoxin recognition: in fish or not in fish?","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16297386","citation_count":157,"is_preprint":false},{"pmid":"31649660","id":"PMC_31649660","title":"A Comparison of the Innate and Adaptive Immune Systems in Cartilaginous Fish, Ray-Finned Fish, and Lobe-Finned Fish.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31649660","citation_count":154,"is_preprint":false},{"pmid":"20483237","id":"PMC_20483237","title":"Genomics of fish cytokines.","date":"2005","source":"Comparative biochemistry and physiology. Part D, Genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/20483237","citation_count":138,"is_preprint":false},{"pmid":"16146649","id":"PMC_16146649","title":"Antibody repertoire development in cartilaginous fish.","date":"2006","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16146649","citation_count":138,"is_preprint":false},{"pmid":"15939625","id":"PMC_15939625","title":"Cytotoxic activities of fish leucocytes.","date":"2006","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15939625","citation_count":137,"is_preprint":false},{"pmid":"9914914","id":"PMC_9914914","title":"Lymphocyte development in fish and amphibians.","date":"1998","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/9914914","citation_count":136,"is_preprint":false},{"pmid":"16110889","id":"PMC_16110889","title":"DNA vaccines for aquacultured fish.","date":"2005","source":"Revue scientifique et technique (International Office of Epizootics)","url":"https://pubmed.ncbi.nlm.nih.gov/16110889","citation_count":133,"is_preprint":false},{"pmid":"26426066","id":"PMC_26426066","title":"T Cells in Fish.","date":"2015","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/26426066","citation_count":133,"is_preprint":false},{"pmid":"7839864","id":"PMC_7839864","title":"Olfaction and gustation in fish: an overview.","date":"1994","source":"Acta physiologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/7839864","citation_count":122,"is_preprint":false},{"pmid":"24795722","id":"PMC_24795722","title":"Fish allergens at a glance: variable allergenicity of parvalbumins, the major fish allergens.","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24795722","citation_count":113,"is_preprint":false},{"pmid":"33287193","id":"PMC_33287193","title":"An Overview of Histamine and Other Biogenic Amines in Fish and Fish Products.","date":"2020","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33287193","citation_count":106,"is_preprint":false},{"pmid":"19133828","id":"PMC_19133828","title":"Pigments, patterns, and fish behavior.","date":"2008","source":"Zebrafish","url":"https://pubmed.ncbi.nlm.nih.gov/19133828","citation_count":100,"is_preprint":false},{"pmid":"22534056","id":"PMC_22534056","title":"Which fish should I eat? Perspectives influencing fish consumption choices.","date":"2012","source":"Environmental health perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/22534056","citation_count":98,"is_preprint":false},{"pmid":"28604723","id":"PMC_28604723","title":"FISH-ing for captured contacts: towards reconciling FISH and 3C.","date":"2017","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/28604723","citation_count":94,"is_preprint":false},{"pmid":"24066168","id":"PMC_24066168","title":"Turbo FISH: a method for rapid single molecule RNA FISH.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24066168","citation_count":93,"is_preprint":false},{"pmid":"26995769","id":"PMC_26995769","title":"Transcriptomic responses in the fish intestine.","date":"2016","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26995769","citation_count":91,"is_preprint":false},{"pmid":"27760553","id":"PMC_27760553","title":"Closing the loop: 3C versus DNA FISH.","date":"2016","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/27760553","citation_count":90,"is_preprint":false},{"pmid":"28599948","id":"PMC_28599948","title":"Fish pigmentation and the melanocortin system.","date":"2017","source":"Comparative biochemistry and physiology. Part A, Molecular & integrative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28599948","citation_count":88,"is_preprint":false},{"pmid":"22355456","id":"PMC_22355456","title":"Immunity to fish rhabdoviruses.","date":"2012","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/22355456","citation_count":88,"is_preprint":false},{"pmid":"21208603","id":"PMC_21208603","title":"Fish melanocortin system.","date":"2011","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21208603","citation_count":83,"is_preprint":false},{"pmid":"36287901","id":"PMC_36287901","title":"Toxic Effects of Cadmium on Fish.","date":"2022","source":"Toxics","url":"https://pubmed.ncbi.nlm.nih.gov/36287901","citation_count":81,"is_preprint":false},{"pmid":"28502661","id":"PMC_28502661","title":"An Adenosine Receptor for Olfaction in Fish.","date":"2017","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/28502661","citation_count":81,"is_preprint":false},{"pmid":"25034975","id":"PMC_25034975","title":"Gonadal development in fish.","date":"2014","source":"Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/25034975","citation_count":78,"is_preprint":false},{"pmid":"21414343","id":"PMC_21414343","title":"Heterogeneity of macrophage activation in fish.","date":"2011","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21414343","citation_count":77,"is_preprint":false},{"pmid":"24113787","id":"PMC_24113787","title":"Optimized RNA ISH, RNA FISH and protein-RNA double labeling (IF/FISH) in Drosophila ovaries.","date":"2013","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/24113787","citation_count":76,"is_preprint":false},{"pmid":"33476127","id":"PMC_33476127","title":"Demethylation of Methylmercury in Bird, Fish, and Earthworm.","date":"2021","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/33476127","citation_count":74,"is_preprint":false},{"pmid":"20596909","id":"PMC_20596909","title":"Fish germ cells.","date":"2010","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/20596909","citation_count":73,"is_preprint":false},{"pmid":"830087","id":"PMC_830087","title":"Olfaction in fish.","date":"1975","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/830087","citation_count":72,"is_preprint":false},{"pmid":"22387589","id":"PMC_22387589","title":"Maternal immunity in fish.","date":"2012","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22387589","citation_count":65,"is_preprint":false},{"pmid":"24552235","id":"PMC_24552235","title":"Strategies and hurdles using DNA vaccines to fish.","date":"2014","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/24552235","citation_count":62,"is_preprint":false},{"pmid":"8128504","id":"PMC_8128504","title":"Fish as biomarkers in immunotoxicology.","date":"1994","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/8128504","citation_count":62,"is_preprint":false},{"pmid":"8221508","id":"PMC_8221508","title":"Allergic reactions to fish.","date":"1993","source":"Clinical reviews in allergy","url":"https://pubmed.ncbi.nlm.nih.gov/8221508","citation_count":60,"is_preprint":false},{"pmid":"2258720","id":"PMC_2258720","title":"Metamorphosis and fish vision.","date":"1990","source":"Journal of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/2258720","citation_count":59,"is_preprint":false},{"pmid":"15962473","id":"PMC_15962473","title":"Update on viral vaccines for fish.","date":"2005","source":"Developments in biologicals","url":"https://pubmed.ncbi.nlm.nih.gov/15962473","citation_count":58,"is_preprint":false},{"pmid":"9029253","id":"PMC_9029253","title":"Aeromonas species in fish, fish-eggs, shrimp and freshwater.","date":"1997","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9029253","citation_count":58,"is_preprint":false},{"pmid":"18228455","id":"PMC_18228455","title":"Fluorescence in situ Hybridization (FISH).","date":"2004","source":"Current protocols in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18228455","citation_count":57,"is_preprint":false},{"pmid":"8923683","id":"PMC_8923683","title":"Experimental chemical carcinogenesis in fish.","date":"1996","source":"Toxicologic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8923683","citation_count":53,"is_preprint":false},{"pmid":"29514876","id":"PMC_29514876","title":"Adipogenesis in fish.","date":"2018","source":"The Journal of experimental biology","url":"https://pubmed.ncbi.nlm.nih.gov/29514876","citation_count":52,"is_preprint":false},{"pmid":"25941767","id":"PMC_25941767","title":"Bioactive components in fish venoms.","date":"2015","source":"Toxins","url":"https://pubmed.ncbi.nlm.nih.gov/25941767","citation_count":50,"is_preprint":false},{"pmid":"29673844","id":"PMC_29673844","title":"Nongenomic cortisol signaling in fish.","date":"2018","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29673844","citation_count":49,"is_preprint":false},{"pmid":"9339359","id":"PMC_9339359","title":"FISH probes for mouse chromosome identification.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9339359","citation_count":49,"is_preprint":false},{"pmid":"30469489","id":"PMC_30469489","title":"Fish, Fish Oils and Cardioprotection: Promise or Fish Tale?","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30469489","citation_count":48,"is_preprint":false},{"pmid":"26633533","id":"PMC_26633533","title":"Fish Peroxiredoxins and Their Role in Immunity.","date":"2015","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/26633533","citation_count":47,"is_preprint":false},{"pmid":"21547056","id":"PMC_21547056","title":"Fish stem cell cultures.","date":"2011","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21547056","citation_count":46,"is_preprint":false},{"pmid":"21261495","id":"PMC_21261495","title":"The FISH-BOL collaborators' protocol.","date":"2011","source":"Mitochondrial DNA","url":"https://pubmed.ncbi.nlm.nih.gov/21261495","citation_count":46,"is_preprint":false},{"pmid":"30550990","id":"PMC_30550990","title":"Fish antiviral tripartite motif (TRIM) proteins.","date":"2018","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30550990","citation_count":45,"is_preprint":false},{"pmid":"33553231","id":"PMC_33553231","title":"Dietary Fish, Fish Nutrients, and Immune Function: A Review.","date":"2021","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/33553231","citation_count":43,"is_preprint":false},{"pmid":"21314902","id":"PMC_21314902","title":"Taxonomy of bacterial fish pathogens.","date":"2011","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/21314902","citation_count":42,"is_preprint":false},{"pmid":"9270831","id":"PMC_9270831","title":"Immunity in fish larvae.","date":"1997","source":"Developments in biological standardization","url":"https://pubmed.ncbi.nlm.nih.gov/9270831","citation_count":41,"is_preprint":false},{"pmid":"9008419","id":"PMC_9008419","title":"FISH technology in chromosome and genome research.","date":"1997","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9008419","citation_count":41,"is_preprint":false},{"pmid":"22640622","id":"PMC_22640622","title":"Orexin system in teleost fish.","date":"2012","source":"Vitamins and hormones","url":"https://pubmed.ncbi.nlm.nih.gov/22640622","citation_count":39,"is_preprint":false},{"pmid":"16954660","id":"PMC_16954660","title":"Multicolor fluorescence in situ hybridization (FISH) applied to FISH-banding.","date":"2006","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16954660","citation_count":39,"is_preprint":false},{"pmid":"16971577","id":"PMC_16971577","title":"Fish meals, fish components, and fish protein hydrolysates as potential ingredients in pet foods.","date":"2006","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/16971577","citation_count":39,"is_preprint":false},{"pmid":"1915772","id":"PMC_1915772","title":"Transgenesis in fish.","date":"1991","source":"Experientia","url":"https://pubmed.ncbi.nlm.nih.gov/1915772","citation_count":38,"is_preprint":false},{"pmid":"32752046","id":"PMC_32752046","title":"Advances in Detecting Ciguatoxins in Fish.","date":"2020","source":"Toxins","url":"https://pubmed.ncbi.nlm.nih.gov/32752046","citation_count":38,"is_preprint":false},{"pmid":"10765980","id":"PMC_10765980","title":"Embryonic and genetic manipulation in fish.","date":"2000","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/10765980","citation_count":38,"is_preprint":false},{"pmid":"14644331","id":"PMC_14644331","title":"Formation of chromosome aberrations: insights from FISH.","date":"2003","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/14644331","citation_count":38,"is_preprint":false},{"pmid":"11298006","id":"PMC_11298006","title":"Allergens from fish and egg.","date":"2001","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/11298006","citation_count":37,"is_preprint":false},{"pmid":"32719429","id":"PMC_32719429","title":"Association of lncRNA SH3PXD2A-AS1 with preeclampsia and its function in invasion and migration of placental trophoblast cells.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32719429","citation_count":36,"is_preprint":false},{"pmid":"23544093","id":"PMC_23544093","title":"Up-regulated expression and aberrant DNA methylation of LEP and SH3PXD2A in pre-eclampsia.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23544093","citation_count":35,"is_preprint":false},{"pmid":"17581674","id":"PMC_17581674","title":"Fish hemoglobins.","date":"2007","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/17581674","citation_count":34,"is_preprint":false},{"pmid":"26528989","id":"PMC_26528989","title":"Fish Synucleins: An Update.","date":"2015","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/26528989","citation_count":33,"is_preprint":false},{"pmid":"16861230","id":"PMC_16861230","title":"Ribonucleases and angiogenins from fish.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16861230","citation_count":32,"is_preprint":false},{"pmid":"25259869","id":"PMC_25259869","title":"Genetic disruption of the sh3pxd2a gene reveals an essential role in mouse development and the existence of a novel isoform of tks5.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25259869","citation_count":31,"is_preprint":false},{"pmid":"29734178","id":"PMC_29734178","title":"Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29734178","citation_count":31,"is_preprint":false},{"pmid":"7535028","id":"PMC_7535028","title":"Fish oil, atherogenesis, and thrombogenesis.","date":"1995","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/7535028","citation_count":31,"is_preprint":false},{"pmid":"26537383","id":"PMC_26537383","title":"Antibody Repertoires in Fish.","date":"2015","source":"Results and problems in cell differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/26537383","citation_count":29,"is_preprint":false},{"pmid":"33716662","id":"PMC_33716662","title":"Integration of Nutrient Sensing in Fish Hypothalamus.","date":"2021","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33716662","citation_count":28,"is_preprint":false},{"pmid":"16954655","id":"PMC_16954655","title":"Multiplex-FISH (M-FISH): technique, developments and applications.","date":"2006","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16954655","citation_count":28,"is_preprint":false},{"pmid":"24393605","id":"PMC_24393605","title":"Impacts of moonlight on fish reproduction.","date":"2014","source":"Marine genomics","url":"https://pubmed.ncbi.nlm.nih.gov/24393605","citation_count":26,"is_preprint":false},{"pmid":"17206385","id":"PMC_17206385","title":"Heme, an iron supply for vibrios pathogenic for fish.","date":"2007","source":"Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17206385","citation_count":26,"is_preprint":false},{"pmid":"38735599","id":"PMC_38735599","title":"Immunotoxicity of microplastics in fish.","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38735599","citation_count":25,"is_preprint":false},{"pmid":"31827520","id":"PMC_31827520","title":"Occurrence of Fungi and Mycotoxins in Fish Feeds and Their Impact on Fish Health.","date":"2019","source":"International journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31827520","citation_count":25,"is_preprint":false},{"pmid":"24345395","id":"PMC_24345395","title":"RNA detection in situ with FISH-STICs.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24345395","citation_count":25,"is_preprint":false},{"pmid":"1366668","id":"PMC_1366668","title":"Transgenic fish.","date":"1990","source":"Trends in biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/1366668","citation_count":24,"is_preprint":false},{"pmid":"30521091","id":"PMC_30521091","title":"The inner ear proteome of fish.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/30521091","citation_count":24,"is_preprint":false},{"pmid":"17440933","id":"PMC_17440933","title":"Interaction between the ADAM12 and SH3MD1 genes may confer susceptibility to late-onset Alzheimer's disease.","date":"2007","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17440933","citation_count":23,"is_preprint":false},{"pmid":"21490440","id":"PMC_21490440","title":"Nevus versus melanoma: to FISH, or not to FISH.","date":"2011","source":"Advances in anatomic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21490440","citation_count":23,"is_preprint":false},{"pmid":"33994260","id":"PMC_33994260","title":"STAT3/SH3PXD2A-AS1/miR-125b/STAT3 positive feedback loop affects psoriasis pathogenesis via regulating human keratinocyte proliferation.","date":"2021","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/33994260","citation_count":22,"is_preprint":false},{"pmid":"11581523","id":"PMC_11581523","title":"Trangenic fish as models in environmental toxicology.","date":"2001","source":"ILAR journal","url":"https://pubmed.ncbi.nlm.nih.gov/11581523","citation_count":21,"is_preprint":false},{"pmid":"21461816","id":"PMC_21461816","title":"CO-FISH, COD-FISH, ReD-FISH, SKY-FISH.","date":"2011","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/21461816","citation_count":20,"is_preprint":false},{"pmid":"31965296","id":"PMC_31965296","title":"FISH and chips: a review of microfluidic platforms for FISH analysis.","date":"2020","source":"Medical microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31965296","citation_count":20,"is_preprint":false},{"pmid":"11217460","id":"PMC_11217460","title":"Fish, amphibian, and reptile analgesia.","date":"2001","source":"The veterinary clinics of North America. Exotic animal practice","url":"https://pubmed.ncbi.nlm.nih.gov/11217460","citation_count":20,"is_preprint":false},{"pmid":"33363355","id":"PMC_33363355","title":"Megalocytiviruses in ornamental fish: A review.","date":"2020","source":"Veterinary world","url":"https://pubmed.ncbi.nlm.nih.gov/33363355","citation_count":19,"is_preprint":false},{"pmid":"10796622","id":"PMC_10796622","title":"Polyunsaturated fatty acid (fish or evening primrose oil) for schizophrenia.","date":"2000","source":"The Cochrane database of systematic reviews","url":"https://pubmed.ncbi.nlm.nih.gov/10796622","citation_count":19,"is_preprint":false},{"pmid":"18228456","id":"PMC_18228456","title":"Multi-color FISH techniques.","date":"2004","source":"Current protocols in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18228456","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43978,"output_tokens":1203,"usd":0.07499,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7398,"output_tokens":1576,"usd":0.038195,"stage2_stop_reason":"end_turn"},"total_usd":0.113185,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about SH3PXD2A (also known as FISH, KIAA0418, SH3MD1) - the human/mammalian scaffold protein Tks5, not the many papers about actual fish biology or FISH (fluorescence in situ hybridization) technique.\n\nRelevant papers:\n- PMID 25259869: Direct study of sh3pxd2a gene disruption in mice, discovering a novel Tks5β isoform\n- PMID 17440933: Studies SH3MD1 (alias for SH3PXD2A) interaction with ADAM12\n- PMID 23544093: Expression/methylation study of SH3PXD2A in preeclampsia - mostly correlative, but mentions trophoblast invasion role\n- PMID 32719429: lncRNA SH3PXD2A-AS1 - this is the antisense lncRNA, NOT the protein - EXCLUDE\n- PMID 29734178: lncRNA SH3PXD2A-AS1 - EXCLUDE\n- PMID 33994260: lncRNA SH3PXD2A-AS1 - EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Homozygous gene-trap disruption of sh3pxd2a in mice causes neonatal death and complete cleft of the secondary palate, establishing an essential role for the long (PX-domain-containing) Tks5 isoform in mammalian development. Embryonic fibroblasts from homozygous mutant mice lacked only the highest molecular weight band of the Tks5 triplet, revealing a novel shorter isoform.\",\n      \"method\": \"Gene-trap mouse knockout with phenotypic analysis; protein immunoblotting of embryonic fibroblasts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined developmental phenotype plus orthogonal protein biochemistry; single lab but multiple methods with rigorous controls\",\n      \"pmids\": [\"25259869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A novel Tks5 isoform, Tks5β, was identified via 5'RACE on mouse fibroblasts. Tks5β is encoded by an alternative transcription start site in intron V of sh3pxd2a and lacks the PX domain (which confers phosphatidylinositol-3,4-bisphosphate binding), instead possessing a unique short N-terminal sequence encoded by newly discovered exon 6β. Tks5β is a substrate for Src tyrosine kinase and its expression is regulated through the proteasome degradation pathway.\",\n      \"method\": \"5'RACE, Src kinase substrate assay, proteasome inhibitor treatment with protein blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical identification of new isoform by 5'RACE, Src kinase assay, and proteasome pathway experiment in single study with multiple orthogonal methods\",\n      \"pmids\": [\"25259869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Genetic interaction analysis in an Alzheimer's disease case-control cohort revealed a statistically significant interaction between variants in SH3MD1 (SH3PXD2A) and ADAM12, suggesting that the FISH adapter protein (encoded by SH3MD1) may functionally interact with ADAM12 to mediate effects relevant to late-onset Alzheimer's disease pathogenesis.\",\n      \"method\": \"Genetic association and SNP interaction analysis in 1,051 AD cases and 1,269 controls\",\n      \"journal\": \"American journal of medical genetics. Part B, Neuropsychiatric genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genetic association/interaction study only; no direct biochemical or cellular mechanistic experiment performed on the protein itself\",\n      \"pmids\": [\"17440933\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3PXD2A encodes the scaffold protein Tks5, which exists in at least two isoforms: the long form (containing a PX domain that binds phosphatidylinositol-3,4-bisphosphate) and a novel shorter isoform Tks5β (lacking the PX domain); the long isoform is essential for mammalian palatogenesis and normal development, both isoforms are substrates for Src tyrosine kinase, and Tks5β levels are regulated by proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SH3PXD2A encodes the scaffold protein Tks5, which is essential for mammalian development: homozygous gene-trap disruption in mice causes neonatal death and complete cleft of the secondary palate, demonstrating that the long, PX-domain-containing isoform is required for normal palatogenesis [#0]. The locus produces at least two isoforms—the long form bearing a PX domain that binds phosphatidylinositol-3,4-bisphosphate, and a shorter Tks5\\u03b2 isoform identified by 5'RACE, which arises from an alternative transcription start site in intron V and replaces the PX domain with a unique N-terminal sequence encoded by a newly discovered exon 6\\u03b2 [#0, #1]. Both isoforms are substrates for Src tyrosine kinase, and Tks5\\u03b2 abundance is controlled by proteasomal degradation [#1]. Beyond these isoform-defining and developmental findings, no further mechanistic detail on Tks5 effector function has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Before any biochemical characterization, a candidate link of SH3PXD2A to disease was tested by asking whether its variants interact genetically with a partner locus in neurodegeneration.\",\n      \"evidence\": \"Genetic association and SNP interaction analysis in an Alzheimer's disease case-control cohort (1,051 cases, 1,269 controls)\",\n      \"pmids\": [\"17440933\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Statistical genetic interaction only; no biochemical or cellular interaction between the proteins demonstrated\",\n        \"No mechanism linking SH3PXD2A to Alzheimer's pathogenesis established\",\n        \"Association not independently confirmed in the corpus\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The developmental requirement for Tks5 was unknown; genetic ablation showed the long PX-domain isoform is essential, defining a discrete in vivo function in palatogenesis.\",\n      \"evidence\": \"Gene-trap mouse knockout with phenotypic analysis plus immunoblotting of embryonic fibroblasts\",\n      \"pmids\": [\"25259869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular effector pathway through which Tks5 drives palate closure not defined\",\n        \"Cell types responsible for the cleft phenotype not resolved\",\n        \"Contribution of PI(3,4)P2 binding to the developmental role not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The identity and regulation of the shorter Tks5 band were unknown; 5'RACE and biochemistry defined Tks5\\u03b2 as a distinct, PX-domain-lacking isoform that is Src-phosphorylated and proteasomally regulated.\",\n      \"evidence\": \"5'RACE, Src kinase substrate assay, and proteasome inhibitor treatment with protein blotting in mouse fibroblasts\",\n      \"pmids\": [\"25259869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional role of Tks5\\u03b2 versus the long isoform not established\",\n        \"Downstream effectors recruited by either isoform not identified\",\n        \"Consequence of Src phosphorylation on Tks5\\u03b2 activity or stability not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Tks5 isoforms assemble effector complexes and translate Src phosphorylation and PI(3,4)P2 binding into the cellular events underlying palatogenesis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct physical partners or substrate complexes characterized in the corpus\",\n        \"No structural or biophysical model of PX-domain lipid engagement\",\n        \"Distinct cellular functions of the long isoform versus Tks5\\u03b2 not separated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}