ID SPD2A_HUMAN Reviewed; 1133 AA. AC Q5TCZ1; O43302; Q5TCZ2; Q5TDQ8; DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot. DT 21-DEC-2004, sequence version 1. DT 10-FEB-2009, entry version 43. DE RecName: Full=SH3 and PX domain-containing protein 2A; DE AltName: Full=SH3 multiple domains protein 1; DE AltName: Full=Five SH3 domain-containing protein; DE AltName: Full=Adaptor protein TKS5; GN Name=SH3PXD2A; Synonyms=FISH, KIAA0418, SH3MD1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX MEDLINE=98116655; PubMed=9455477; DOI=10.1093/dnares/4.5.307; RA Ishikawa K., Nagase T., Nakajima D., Seki N., Ohira M., Miyajima N., RA Tanaka A., Kotani H., Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. VIII. RT 78 new cDNA clones from brain which code for large proteins in RT vitro."; RL DNA Res. 4:307-313(1997). RN [2] RP SEQUENCE REVISION. RA Okazaki N., Kikuno R.F., Nagase T., Ohara O., Koga H.; RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [4] RP FUNCTION, SUBCELLULAR LOCATION, DOMAINS, INTERACTION WITH ADAM12; RP ADAM15 AND ADAM19, AND MUTAGENESIS OF ARG-42 AND ARG-93. RX PubMed=12615925; DOI=10.1074/jbc.M300267200; RA Abram C.L., Seals D.F., Pass I., Salinsky D., Maurer L., Roth T.M., RA Courtneidge S.A.; RT "The adaptor protein fish associates with members of the ADAMs family RT and localizes to podosomes of Src-transformed cells."; RL J. Biol. Chem. 278:16844-16851(2003). RN [5] RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, AND TISSUE SPECIFICITY. RX PubMed=15710328; DOI=10.1016/j.ccr.2005.01.006; RA Seals D.F., Azucena E.F. Jr., Pass I., Tesfay L., Gordon R., RA Woodrow M., Resau J.H., Courtneidge S.A.; RT "The adaptor protein Tks5/Fish is required for podosome formation and RT function, and for the protease-driven invasion of cancer cells."; RL Cancer Cell 7:155-165(2005). RN [6] RP FUNCTION, INTERACTION WITH ADAM12, AND PTM. RX PubMed=15710903; DOI=10.1073/pnas.0408237102; RA Malinin N.L., Wright S., Seubert P., Schenk D., Griswold-Prenner I.; RT "Amyloid-beta neurotoxicity is mediated by FISH adapter protein and RT ADAM12 metalloprotease activity."; RL Proc. Natl. Acad. Sci. U.S.A. 102:3058-3063(2005). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-769 AND SER-1038, AND RP MASS SPECTROMETRY. RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-406; SER-421; SER-547; RP SER-567; SER-593; SER-644; SER-724; THR-731; SER-1002; SER-1016; RP SER-1017 AND SER-1038, AND MASS SPECTROMETRY. RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [9] RP STRUCTURE BY NMR OF 168-325 AND 1072-1133. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the SH3 domains from human KIAA0418 protein."; RL Submitted (AUG-2007) to the PDB data bank. CC -!- FUNCTION: Required for podosome formation, degradation of the CC extracellular matrix, and for the invasiveness of some cancer CC cells. Binds phosphatidylinositol 3-phosphate (PtdIns(3)P) and CC phosphatidylinositol 3,4-biphosphate (PtdIns(3,4)P2). In CC association with ADAM12, mediates the neurotoxic effect of beta- CC amyloid peptide. CC -!- SUBUNIT: Interacts with ADAM12, ADAM15 and ADAM19. CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell projection, podosome. CC Note=Cytoplasmic in normal cells and localizes to podosomes in CC SRC-transformed cells. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q5TCZ1-1; Sequence=Displayed; CC Name=2; CC IsoId=Q5TCZ1-2; Sequence=VSP_023312, VSP_023313; CC -!- TISSUE SPECIFICITY: Found in several cancer cell lines, CC particularly invasive breast carcinomas and melanomas. CC -!- DOMAIN: The PX domain is required for podosome localization, and CC for binding phosphatidylinositol 3-phosphate (PtdIns(3)P) and CC phosphatidylinositol 3,4-biphosphate (PtdIns(3,4)P2). CC -!- DOMAIN: The fifth SH3 domain mediates binding with ADAM12, ADAM15 CC and ADAM19. CC -!- PTM: Tyrosine phosphorylated by SRC. Phosphorylation plays a CC regulatory role in the protein localization. The intramolecular CC interaction of the PX domain with the third SH3 domain maintains CC the protein in the cytoplasm and phosphorylation disrupts this CC interaction, resulting in the redistribution of the protein from CC cytoplasm to the perimembrane region. Phosphorylated on serine CC upon DNA damage, probably by ATM or ATR. CC -!- SIMILARITY: Belongs to the SH3PXD2 family. CC -!- SIMILARITY: Contains 1 PX (phox homology) domain. CC -!- SIMILARITY: Contains 5 SH3 domains. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB007878; BAA24848.2; ALT_INIT; mRNA. DR EMBL; AL121929; CAI13961.1; -; Genomic_DNA. DR EMBL; AL133355; CAI13961.1; JOINED; Genomic_DNA. DR EMBL; AL121929; CAI13962.1; -; Genomic_DNA. DR EMBL; AL133355; CAI13962.1; JOINED; Genomic_DNA. DR EMBL; AL121929; CAI13963.1; -; Genomic_DNA. DR EMBL; AL133355; CAI15351.1; -; Genomic_DNA. DR EMBL; AL121929; CAI15351.1; JOINED; Genomic_DNA. DR EMBL; AL133355; CAI15352.1; -; Genomic_DNA. DR EMBL; AL121929; CAI15352.1; JOINED; Genomic_DNA. DR IPI; IPI00456943; -. DR IPI; IPI00640092; -. DR PIR; T00056; T00056. DR UniGene; Hs.702124; -. DR PDB; 2DNU; NMR; -; A=268-325. DR PDB; 2EGA; NMR; -; A=168-224. DR PDB; 2EGC; NMR; -; A=1072-1133. DR PDB; 2EKH; NMR; -; A=842-908. DR PDBsum; 2DNU; -. DR PDBsum; 2EGA; -. DR PDBsum; 2EGC; -. DR PDBsum; 2EKH; -. DR PhosphoSite; Q5TCZ1; -. DR PRIDE; Q5TCZ1; -. DR Ensembl; ENSG00000107957; Homo sapiens. DR KEGG; hsa:9644; -. DR GeneCards; GC10M105345; -. DR HGNC; HGNC:23664; SH3PXD2A. DR HOVERGEN; Q5TCZ1; -. DR NextBio; 36199; -. DR ArrayExpress; Q5TCZ1; -. DR Bgee; Q5TCZ1; -. DR CleanEx; HS_SH3PXD2A; -. DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW. DR GO; GO:0035091; F:phosphoinositide binding; IEA:InterPro. DR GO; GO:0005515; F:protein binding; IEA:InterPro. DR GO; GO:0007154; P:cell communication; IEA:InterPro. DR InterPro; IPR001683; PX. DR InterPro; IPR001452; SH3. DR Gene3D; G3DSA:3.30.1520.10; PX; 1. DR Pfam; PF00787; PX; 1. DR Pfam; PF00018; SH3_1; 5. DR PRINTS; PR00452; SH3DOMAIN. DR ProDom; PD000066; SH3; 5. DR SMART; SM00312; PX; 1. DR SMART; SM00326; SH3; 5. DR PROSITE; PS50195; PX; 1. DR PROSITE; PS50002; SH3; 5. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell projection; Coiled coil; KW Cytoplasm; Phosphoprotein; Polymorphism; Repeat; SH3 domain. FT CHAIN 1 1133 SH3 and PX domain-containing protein 2A. FT /FTId=PRO_0000278488. FT DOMAIN 4 128 PX. FT DOMAIN 166 225 SH3 1. FT DOMAIN 266 325 SH3 2. FT DOMAIN 448 507 SH3 3. FT DOMAIN 840 899 SH3 4. FT DOMAIN 1071 1133 SH3 5. FT COILED 917 946 Potential. FT COMPBIAS 634 724 Ser-rich. FT MOD_RES 406 406 Phosphoserine. FT MOD_RES 421 421 Phosphoserine. FT MOD_RES 547 547 Phosphoserine. FT MOD_RES 567 567 Phosphoserine. FT MOD_RES 593 593 Phosphoserine. FT MOD_RES 644 644 Phosphoserine. FT MOD_RES 724 724 Phosphoserine. FT MOD_RES 731 731 Phosphothreonine. FT MOD_RES 769 769 Phosphoserine. FT MOD_RES 1002 1002 Phosphoserine. FT MOD_RES 1016 1016 Phosphoserine. FT MOD_RES 1017 1017 Phosphoserine. FT MOD_RES 1038 1038 Phosphoserine. FT VAR_SEQ 1 165 Missing (in isoform 2). FT /FTId=VSP_023312. FT VAR_SEQ 240 267 Missing (in isoform 2). FT /FTId=VSP_023313. FT VARIANT 659 659 K -> Q (in dbSNP:rs11818820). FT /FTId=VAR_030781. FT VARIANT 1035 1035 R -> Q (in dbSNP:rs3781365). FT /FTId=VAR_030782. FT MUTAGEN 42 42 R->A: Loss of binding to (PtdIns(3)P) and FT (PtdIns(3,4)P2). FT MUTAGEN 93 93 R->A: Loss of binding to (PtdIns(3)P) and FT (PtdIns(3,4)P2). FT STRAND 268 272 FT STRAND 292 295 FT STRAND 300 308 FT STRAND 311 316 FT HELIX 317 319 FT STRAND 843 847 FT STRAND 866 872 FT STRAND 876 882 FT STRAND 885 890 FT TURN 891 893 SQ SEQUENCE 1133 AA; 125289 MW; D485F49E9192359C CRC64; MLAYCVQDAT VVDVEKRRNP SKHYVYIINV TWSDSTSQTI YRRYSKFFDL QMQLLDKFPI EGGQKDPKQR IIPFLPGKIL FRRSHIRDVA VKRLKPIDEY CRALVRLPPH ISQCDEVFRF FEARPEDVNP PKEDYGSSKR KSVWLSSWAE SPKKDVTGAD ATAEPMILEQ YVVVSNYKKQ ENSELSLQAG EVVDVIEKNE SGWWFVSTSE EQGWVPATYL EAQNGTRDDS DINTSKTGEV SKRRKAHLRR LDRRWTLGGM VNRQHSREEK YVTVQPYTSQ SKDEIGFEKG VTVEVIRKNL EGWWYIRYLG KEGWAPASYL KKAKDDLPTR KKNLAGPVEI IGNIMEISNL LNKKASGDKE TPPAEGEGHE APIAKKEISL PILCNASNGS AVGVPDRTVS RLAQGSPAVA RIAPQRAQIS SPNLRTRPPP RRESSLGFQL PKPPEPPSVE VEYYTIAEFQ SCISDGISFR GGQKAEVIDK NSGGWWYVQI GEKEGWAPAS YIDKRKKPNL SRRTSTLTRP KVPPPAPPSK PKEAEEGPTG ASESQDSPRK LKYEEPEYDI PAFGFDSEPE LSEEPVEDRA SGERRPAQPH RPSPASSLQR ARFKVGESSE DVALEEETIY ENEGFRPYAE DTLSARGSSG DSDSPGSSSL SLTRKNSPKS GSPKSSSLLK LKAEKNAQAE MGKNHSSASF SSSITINTTC CSSSSSSSSS LSKTSGDLKP RSASDAGIRG TPKVRAKKDA DANAGLTSCP RAKPSVRPKP FLNRAESQSQ EKMDISTLRR QLRPTGQLRG GLKGSKSEDS ELPPQTASEA PSEGSRRSSS DLITLPATTP PCPTKKEWEG PATSYMTCSA YQKVQDSEIS FPAGVEVQVL EKQESGWWYV RFGELEGWAP SHYLVLDENE QPDPSGKELD TVPAKGRQNE GKSDSLEKIE RRVQALNTVN QSKKATPPIP SKPPGGFGKT SGTPAVKMRN GVRQVAVRPQ SVFVSPPPKD NNLSCALRRN ESLTATDGLR GVRRNSSFST ARSAAAEAKG RLAERAASQG SDSPLLPAQR NSIPVSPVRP KPIEKSQFIH NNLKDVYVSI ADYEGDEETA GFQEGVSMEV LERNPNGWWY CQILDGVKPF KGWVPSNYLE KKN //