SPD2A_MOUSE
ID SPD2A_MOUSE Reviewed; 1124 AA.
AC O89032; E9QKJ2; Q148Q8;
DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=SH3 and PX domain-containing protein 2A;
DE AltName: Full=Five SH3 domain-containing protein;
DE AltName: Full=SH3 multiple domains protein 1;
DE AltName: Full=Tyrosine kinase substrate with five SH3 domains;
GN Name=Sh3pxd2a; Synonyms=Fish, Sh3md1, Tks5;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ALTERNATIVE SPLICING (ISOFORM 3),
RP PTM, AND TISSUE SPECIFICITY.
RX PubMed=9687503; DOI=10.1093/emboj/17.15.4346;
RA Lock P., Abram C.L., Gibson T., Courtneidge S.A.;
RT "A new method for isolating tyrosine kinase substrates used to identify
RT fish, an SH3 and PX domain-containing protein, and Src substrate.";
RL EMBO J. 17:4346-4357(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-812, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=18417249; DOI=10.1016/j.ejcb.2008.02.008;
RA Blouw B., Seals D.F., Pass I., Diaz B., Courtneidge S.A.;
RT "A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth
RT in vivo.";
RL Eur. J. Cell Biol. 87:555-567(2008).
RN [6]
RP FUNCTION, DISRUPTION PHENOTYPE, AND INTERACTION WITH CYBA.
RX PubMed=19755709; DOI=10.1126/scisignal.2000368;
RA Diaz B., Shani G., Pass I., Anderson D., Quintavalle M., Courtneidge S.A.;
RT "Tks5-dependent, nox-mediated generation of reactive oxygen species is
RT necessary for invadopodia formation.";
RL Sci. Signal. 2:RA53-RA53(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-256; SER-546; SER-643;
RP SER-764; SER-766; SER-812; THR-822; SER-993; SER-1007; SER-1008 AND
RP SER-1029, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Adapter protein involved in invadopodia and podosome
CC formation, extracellular matrix degradation and invasiveness of some
CC cancer cells. Binds matrix metalloproteinases (ADAMs), NADPH oxidases
CC (NOXs) and phosphoinositides. Acts as an organizer protein that allows
CC NOX1- or NOX3-dependent reactive oxygen species (ROS) generation and
CC ROS localization. In association with ADAM12, mediates the neurotoxic
CC effect of amyloid-beta peptide (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:18417249, ECO:0000269|PubMed:19755709}.
CC -!- SUBUNIT: Interacts with ADAM12, ADAM15 and ADAM19 (By similarity).
CC Interacts with NOXO1 (By similarity). Interacts (via SH3 domains) with
CC NOXA1; the interaction is direct (By similarity). Interacts (via N-
CC terminus) with CYBA. Interacts with FASLG (By similarity).
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell projection, podosome
CC {ECO:0000250}. Note=Cytoplasmic in normal cells and localizes to
CC podosomes in Src-transformed cells. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Additional isoforms seem to exist.;
CC Name=1;
CC IsoId=O89032-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O89032-2; Sequence=VSP_023315;
CC Name=3;
CC IsoId=O89032-3; Sequence=VSP_023314, VSP_023315;
CC -!- TISSUE SPECIFICITY: Widely expressed. Not found in the spleen and
CC testis. {ECO:0000269|PubMed:9687503}.
CC -!- DOMAIN: The PX domain is required for podosome localization because of
CC its ability to bind phosphatidylinositol 3-phosphate (PtdIns(3)P) and
CC phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) and, to a lesser
CC extent, phosphatidylinositol 4-phosphate (PtdIns(4)P),
CC phosphatidylinositol 5-phosphate (PtdIns(5)P), and phosphatidylinositol
CC 3,5-bisphosphate (PtdIns(3,5)P2). Binds to the third intramolecular SH3
CC domain (By similarity). {ECO:0000250}.
CC -!- DOMAIN: The fifth SH3 domain mediates binding with ADAM12, ADAM15 and
CC ADAM19. {ECO:0000250}.
CC -!- PTM: Tyrosine phosphorylated by SRC. Phosphorylation plays a regulatory
CC role in the protein localization. The intramolecular interaction of the
CC PX domain with the third SH3 domain maintains the protein in the
CC cytoplasm and phosphorylation disrupts this interaction, resulting in
CC the redistribution of the protein from cytoplasm to the perimembrane
CC region. Phosphorylated on serine upon DNA damage, probably by ATM or
CC ATR (By similarity). {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Shows significant decrease in total cellular
CC reactive oxygen species (ROS) and in podosome formation.
CC {ECO:0000269|PubMed:18417249, ECO:0000269|PubMed:19755709}.
CC -!- SIMILARITY: Belongs to the SH3PXD2 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAI18023.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AJ007012; CAA07416.1; -; mRNA.
DR EMBL; AC132268; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC132288; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC118022; AAI18023.1; ALT_FRAME; mRNA.
DR CCDS; CCDS29891.1; -. [O89032-1]
DR CCDS; CCDS50464.1; -. [O89032-2]
DR RefSeq; NP_001158189.1; NM_001164717.1. [O89032-2]
DR RefSeq; NP_032044.2; NM_008018.4. [O89032-1]
DR AlphaFoldDB; O89032; -.
DR SMR; O89032; -.
DR BioGRID; 199678; 5.
DR IntAct; O89032; 2.
DR MINT; O89032; -.
DR STRING; 10090.ENSMUSP00000080325; -.
DR iPTMnet; O89032; -.
DR PhosphoSitePlus; O89032; -.
DR EPD; O89032; -.
DR jPOST; O89032; -.
DR MaxQB; O89032; -.
DR PaxDb; O89032; -.
DR PeptideAtlas; O89032; -.
DR PRIDE; O89032; -.
DR ProteomicsDB; 261123; -. [O89032-1]
DR ProteomicsDB; 261124; -. [O89032-2]
DR ProteomicsDB; 261125; -. [O89032-3]
DR Antibodypedia; 46067; 180 antibodies from 32 providers.
DR DNASU; 14218; -.
DR Ensembl; ENSMUST00000081619; ENSMUSP00000080325; ENSMUSG00000053617. [O89032-1]
DR Ensembl; ENSMUST00000111800; ENSMUSP00000107430; ENSMUSG00000053617. [O89032-2]
DR GeneID; 14218; -.
DR KEGG; mmu:14218; -.
DR UCSC; uc008huy.2; mouse. [O89032-1]
DR UCSC; uc008hva.2; mouse. [O89032-2]
DR CTD; 9644; -.
DR MGI; MGI:1298393; Sh3pxd2a.
DR VEuPathDB; HostDB:ENSMUSG00000053617; -.
DR eggNOG; KOG0905; Eukaryota.
DR GeneTree; ENSGT00940000157732; -.
DR HOGENOM; CLU_013051_0_0_1; -.
DR InParanoid; O89032; -.
DR OMA; TKEECIY; -.
DR OrthoDB; 1183210at2759; -.
DR PhylomeDB; O89032; -.
DR TreeFam; TF329347; -.
DR Reactome; R-MMU-8941237; Invadopodia formation.
DR Reactome; R-MMU-9013148; CDC42 GTPase cycle.
DR BioGRID-ORCS; 14218; 1 hit in 71 CRISPR screens.
DR ChiTaRS; Sh3pxd2a; mouse.
DR PRO; PR:O89032; -.
DR Proteomes; UP000000589; Chromosome 19.
DR RNAct; O89032; protein.
DR Bgee; ENSMUSG00000053617; Expressed in molar tooth and 217 other tissues.
DR ExpressionAtlas; O89032; baseline and differential.
DR Genevisible; O89032; MM.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0002102; C:podosome; IDA:UniProtKB.
DR GO; GO:0035091; F:phosphatidylinositol binding; IMP:UniProtKB.
DR GO; GO:0043325; F:phosphatidylinositol-3,4-bisphosphate binding; IMP:UniProtKB.
DR GO; GO:0032266; F:phosphatidylinositol-3-phosphate binding; IMP:UniProtKB.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IMP:UniProtKB.
DR GO; GO:0070273; F:phosphatidylinositol-4-phosphate binding; IMP:UniProtKB.
DR GO; GO:0010314; F:phosphatidylinositol-5-phosphate binding; IMP:UniProtKB.
DR GO; GO:0002020; F:protease binding; IPI:UniProtKB.
DR GO; GO:0016176; F:superoxide-generating NADPH oxidase activator activity; IBA:GO_Central.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR GO; GO:0072675; P:osteoclast fusion; ISO:MGI.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:UniProtKB.
DR GO; GO:0042554; P:superoxide anion generation; IBA:GO_Central.
DR GO; GO:0006801; P:superoxide metabolic process; ISO:MGI.
DR CDD; cd06888; PX_FISH; 1.
DR CDD; cd12074; SH3_Tks5_1; 1.
DR CDD; cd12077; SH3_Tks5_2; 1.
DR CDD; cd12079; SH3_Tks5_3; 1.
DR CDD; cd12019; SH3_Tks5_4; 1.
DR CDD; cd12020; SH3_Tks5_5; 1.
DR Gene3D; 3.30.1520.10; -; 1.
DR InterPro; IPR001683; PX_dom.
DR InterPro; IPR036871; PX_dom_sf.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR InterPro; IPR037961; SH3PXD2_PX.
DR InterPro; IPR034917; SH3PXD2A.
DR InterPro; IPR035450; SH3PXD2A_SH3_1.
DR InterPro; IPR035452; SH3PXD2A_SH3_2.
DR InterPro; IPR035449; SH3PXD2A_SH3_3.
DR InterPro; IPR035453; SH3PXD2A_SH3_4.
DR InterPro; IPR035454; SH3PXD2A_SH3_5.
DR PANTHER; PTHR15706:SF22; PTHR15706:SF22; 1.
DR Pfam; PF00787; PX; 1.
DR Pfam; PF00018; SH3_1; 4.
DR SMART; SM00312; PX; 1.
DR SMART; SM00326; SH3; 5.
DR SUPFAM; SSF50044; SSF50044; 5.
DR SUPFAM; SSF64268; SSF64268; 1.
DR PROSITE; PS50195; PX; 1.
DR PROSITE; PS50002; SH3; 5.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell junction; Cell projection; Coiled coil;
KW Cytoplasm; Phosphoprotein; Reference proteome; Repeat; SH3 domain.
FT CHAIN 1..1124
FT /note="SH3 and PX domain-containing protein 2A"
FT /id="PRO_0000278489"
FT DOMAIN 4..128
FT /note="PX"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00147"
FT DOMAIN 166..225
FT /note="SH3 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 266..325
FT /note="SH3 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 447..506
FT /note="SH3 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 833..892
FT /note="SH3 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 1063..1124
FT /note="SH3 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT REGION 414..443
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 504..672
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 692..830
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 886..952
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1020..1050
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 907..937
FT /evidence="ECO:0000255"
FT COMPBIAS 571..585
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 631..671
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 692..716
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 720..737
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 759..780
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 890..905
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 906..922
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 256
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 405
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5TCZ1"
FT MOD_RES 420
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5TCZ1"
FT MOD_RES 546
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 566
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5TCZ1"
FT MOD_RES 592
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5TCZ1"
FT MOD_RES 643
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 728
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q5TCZ1"
FT MOD_RES 764
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 766
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 812
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 822
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 993
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 1007
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 1008
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 1029
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT VAR_SEQ 143..157
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_023314"
FT VAR_SEQ 240..267
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_023315"
FT CONFLICT 867
FT /note="E -> V (in Ref. 1; CAA07416)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1124 AA; 124201 MW; 2A06118D1CE7C567 CRC64;
MLAYCVQDAT VVDVEKRRSP SKHYVYIINV TWSDSTSQTI YRRYSKFFDL QMQLLDKFPI
EGGQKDPKQR IIPFLPGKIL FRRSHIRDVA VKRLKPIDEY CRALVRLPPH ISQCDEVFRF
FEARPEDVNP PKEDYGSSKR KSVWLSSWAE SPKKDVTGAD TNAEPMILEQ YVVVSNYKKQ
ENSELSLQAG EVVDVIEKNE SGWWFVSTSE EQGWVPATYL EAQNGTRDDS DINTSKTGEV
SKRRKAHLRR LDRRWTLGGM VNRQHSREEK YVTVQPYTSQ SKDEIGFEKG VTVEVIRKNL
EGWWYIRYLG KEGWAPASYL KKAKDDLPTR KKNLAGPVEI IGNIMEISNL LNKKASGDKE
APAEGEGSEA PITKKEISLP ILCNASNGSA LAIPERTTSK LAQGSPAVAR IAPQRAQISS
PNLRTRPPPR RESSLGFQLP KPPEPPSVEV EYYTIAEFQS CISDGISFRG GQKAEVIDKN
SGGWWYVQIG EKEGWAPASY IDKRKKPNLS RRTSTLTRPK VPPPAPPSKP KEAEENPVGA
CESQGSPLKV KYEEPEYDVP AFGFDSEPEM NEEPSGDRGS GDKHPAQPRR ISPASSLQRA
HFKVGESSED VALEEETIYE NEGFRPYTED TLSARGSSGD SDSPGSSSLS LAVKNSPKSD
SPKSSSLLKL KAEKNAQAEL GKNQSNISFS SSVTISTTCS SSSSSSSLSK NNGDLKPRSA
SDAGIRDTPK VGTKKDPDVK AGLASCARAK PSVRPKPVLN RAESQSQEKM DISSLRRQLR
PTGQLRGGLK GSRSEDSELP PQMASEGSRR GSADIIPLTA TTPPCVPKKE WEGQGATYVT
CSAYQKVQDS EISFPEGAEV HVLEKAESGW WYVRFGELEG WAPSHYLVAE ENQQPDTASK
EGDTGKSSQN EGKSDSLEKI EKRVQALNTV NQSKRATPPI PSKPPGGFGK TSGTVAVKMR
NGVRQVAVRP QSVFVSPPPK DNNLSCALRR NESLTATDSL RGVRRNSSFS TARSAAAEAK
GRLAERAASQ GSESPLLPTQ RKGIPVSPVR PKPIEKSQFI HNNLKDVYIS IADYEGDEET
AGFQEGVSME VLEKNPNGWW YCQILDEVKP FKGWVPSNYL EKKN
