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Q5TCZ1 (SPD2A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 98. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
SH3 and PX domain-containing protein 2A
Alternative name(s):
Adapter protein TKS5
Five SH3 domain-containing protein
SH3 multiple domains protein 1
Tyrosine kinase substrate with five SH3 domains
Gene names
Name:SH3PXD2A
Synonyms:FISH, KIAA0418, SH3MD1, TKS5
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1133 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Adapter protein involved in invadopodia and podosome formation, extracellular matrix degradation and invasiveness of some cancer cells. 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 beta-amyloid peptide. Ref.5 Ref.6 Ref.7 Ref.12 Ref.14

Subunit structure

Interacts (via N-terminus) with CYBA By similarity. Interacts with ADAM12, ADAM15 and ADAM19. Interacts with NOXO1. Interacts (via SH3 domains) with NOXA1. Interacts with FASLG. Ref.5 Ref.7 Ref.11 Ref.12 Ref.14

Subcellular location

Cytoplasm. Cell projectionpodosome. Note: Cytoplasmic in normal cells and localizes to podosomes in SRC-transformed cells. Ref.5 Ref.6 Ref.9

Tissue specificity

Found in several cancer cell lines, particularly invasive breast carcinomas and melanomas. Ref.6

Domain

The PX domain is required for podosome localization because of its ability to bind phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) and, to a lesser extent, phosphatidylinositol 4-phosphate (PtdIns4P), phosphatidylinositol 5-phosphate (PtdIns5P), and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Binds to the third intramolecular SH3 domain By similarity. Ref.5 Ref.6

The fifth SH3 domain mediates binding with ADAM12, ADAM15 and ADAM19. Ref.5 Ref.6

Post-translational modification

Tyrosine phosphorylated by SRC. Phosphorylation plays a regulatory role in the protein localization. The intramolecular interaction of the PX domain with the third SH3 domain maintains the protein in the cytoplasm and phosphorylation disrupts this interaction, resulting in the redistribution of the protein from cytoplasm to the perimembrane region. Phosphorylated on serine upon DNA damage, probably by ATM or ATR.

Sequence similarities

Belongs to the SH3PXD2 family.

Contains 1 PX (phox homology) domain.

Contains 5 SH3 domains.

Sequence caution

The sequence BAA24848.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ADAM15Q134442EBI-2483234,EBI-77818
Dnm1P215752EBI-7014859,EBI-80070From a different organism.
SOS1Q078895EBI-7014859,EBI-297487

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q5TCZ1-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q5TCZ1-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-165: Missing.
     240-267: Missing.
Isoform 3 (identifier: Q5TCZ1-3)

The sequence of this isoform differs from the canonical sequence as follows:
     240-267: Missing.
Note: Gene prediction based on similarity to mouse ortholog and partial transcript data.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 11331133SH3 and PX domain-containing protein 2A
PRO_0000278488

Regions

Domain4 – 128125PX
Domain166 – 22560SH3 1
Domain266 – 32560SH3 2
Domain448 – 50760SH3 3
Domain840 – 89960SH3 4
Domain1071 – 113363SH3 5
Coiled coil917 – 94630 Potential
Compositional bias634 – 72491Ser-rich

Amino acid modifications

Modified residue4211Phosphoserine Ref.10
Modified residue5471Phosphoserine Ref.10
Modified residue5671Phosphoserine Ref.10
Modified residue5931Phosphoserine Ref.10
Modified residue6441Phosphoserine Ref.10
Modified residue7311Phosphothreonine Ref.10
Modified residue8191Phosphoserine By similarity
Modified residue10021Phosphoserine Ref.10 Ref.13
Modified residue10161Phosphoserine Ref.10
Modified residue10171Phosphoserine Ref.10
Modified residue10381Phosphoserine Ref.10

Natural variations

Alternative sequence1 – 165165Missing in isoform 2.
VSP_023312
Alternative sequence240 – 26728Missing in isoform 2 and isoform 3.
VSP_023313
Natural variant6591K → Q.
Corresponds to variant rs11818820 [ dbSNP | Ensembl ].
VAR_030781
Natural variant10351R → Q.
Corresponds to variant rs3781365 [ dbSNP | Ensembl ].
VAR_030782
Natural variant10731L → P.
Corresponds to variant rs12764700 [ dbSNP | Ensembl ].
VAR_056993

Experimental info

Mutagenesis421R → A: Loss of binding to (PtdIns(3)P) and (PtdIns(3,4)P2). Ref.5
Mutagenesis931R → A: Loss of binding to (PtdIns(3)P) and (PtdIns(3,4)P2). Ref.5

Secondary structure

............................................ 1133
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified December 21, 2004. Version 1.
Checksum: D485F49E9192359C

FASTA1,133125,289
        10         20         30         40         50         60 
MLAYCVQDAT VVDVEKRRNP SKHYVYIINV TWSDSTSQTI YRRYSKFFDL QMQLLDKFPI 

        70         80         90        100        110        120 
EGGQKDPKQR IIPFLPGKIL FRRSHIRDVA VKRLKPIDEY CRALVRLPPH ISQCDEVFRF 

       130        140        150        160        170        180 
FEARPEDVNP PKEDYGSSKR KSVWLSSWAE SPKKDVTGAD ATAEPMILEQ YVVVSNYKKQ 

       190        200        210        220        230        240 
ENSELSLQAG EVVDVIEKNE SGWWFVSTSE EQGWVPATYL EAQNGTRDDS DINTSKTGEV 

       250        260        270        280        290        300 
SKRRKAHLRR LDRRWTLGGM VNRQHSREEK YVTVQPYTSQ SKDEIGFEKG VTVEVIRKNL 

       310        320        330        340        350        360 
EGWWYIRYLG KEGWAPASYL KKAKDDLPTR KKNLAGPVEI IGNIMEISNL LNKKASGDKE 

       370        380        390        400        410        420 
TPPAEGEGHE APIAKKEISL PILCNASNGS AVGVPDRTVS RLAQGSPAVA RIAPQRAQIS 

       430        440        450        460        470        480 
SPNLRTRPPP RRESSLGFQL PKPPEPPSVE VEYYTIAEFQ SCISDGISFR GGQKAEVIDK 

       490        500        510        520        530        540 
NSGGWWYVQI GEKEGWAPAS YIDKRKKPNL SRRTSTLTRP KVPPPAPPSK PKEAEEGPTG 

       550        560        570        580        590        600 
ASESQDSPRK LKYEEPEYDI PAFGFDSEPE LSEEPVEDRA SGERRPAQPH RPSPASSLQR 

       610        620        630        640        650        660 
ARFKVGESSE DVALEEETIY ENEGFRPYAE DTLSARGSSG DSDSPGSSSL SLTRKNSPKS 

       670        680        690        700        710        720 
GSPKSSSLLK LKAEKNAQAE MGKNHSSASF SSSITINTTC CSSSSSSSSS LSKTSGDLKP 

       730        740        750        760        770        780 
RSASDAGIRG TPKVRAKKDA DANAGLTSCP RAKPSVRPKP FLNRAESQSQ EKMDISTLRR 

       790        800        810        820        830        840 
QLRPTGQLRG GLKGSKSEDS ELPPQTASEA PSEGSRRSSS DLITLPATTP PCPTKKEWEG 

       850        860        870        880        890        900 
PATSYMTCSA YQKVQDSEIS FPAGVEVQVL EKQESGWWYV RFGELEGWAP SHYLVLDENE 

       910        920        930        940        950        960 
QPDPSGKELD TVPAKGRQNE GKSDSLEKIE RRVQALNTVN QSKKATPPIP SKPPGGFGKT 

       970        980        990       1000       1010       1020 
SGTPAVKMRN GVRQVAVRPQ SVFVSPPPKD NNLSCALRRN ESLTATDGLR GVRRNSSFST 

      1030       1040       1050       1060       1070       1080 
ARSAAAEAKG RLAERAASQG SDSPLLPAQR NSIPVSPVRP KPIEKSQFIH NNLKDVYVSI 

      1090       1100       1110       1120       1130 
ADYEGDEETA GFQEGVSMEV LERNPNGWWY CQILDGVKPF KGWVPSNYLE KKN 

« Hide

Isoform 2 [UniParc].

Checksum: 1CA24D7BC03B8AC3
Show »

FASTA940102,618
Isoform 3 [UniParc].

Checksum: 384ECB9785EE3FAB
Show »

FASTA1,105121,836

References

« Hide 'large scale' references
[1]"Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro."
Ishikawa K., Nagase T., Nakajima D., Seki N., Ohira M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 4:307-313(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Brain.
[2]Okazaki N., Kikuno R.F., Nagase T., Ohara O., Koga H.
Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: SEQUENCE REVISION.
[3]"The DNA sequence and comparative analysis of human chromosome 10."
Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. expand/collapse author list , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.
Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells."
Abram C.L., Seals D.F., Pass I., Salinsky D., Maurer L., Roth T.M., Courtneidge S.A.
J. Biol. Chem. 278:16844-16851(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, DOMAIN, INTERACTION WITH ADAM12; ADAM15 AND ADAM19, MUTAGENESIS OF ARG-42 AND ARG-93.
[6]"The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells."
Seals D.F., Azucena E.F. Jr., Pass I., Tesfay L., Gordon R., Woodrow M., Resau J.H., Courtneidge S.A.
Cancer Cell 7:155-165(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, DOMAIN, TISSUE SPECIFICITY.
[7]"Amyloid-beta neurotoxicity is mediated by FISH adapter protein and ADAM12 metalloprotease activity."
Malinin N.L., Wright S., Seubert P., Schenk D., Griswold-Prenner I.
Proc. Natl. Acad. Sci. U.S.A. 102:3058-3063(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH ADAM12, PTM.
[8]"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage."
Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.
Science 316:1160-1166(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic kidney.
[9]"A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo."
Blouw B., Seals D.F., Pass I., Diaz B., Courtneidge S.A.
Eur. J. Cell Biol. 87:555-567(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[10]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-421; SER-547; SER-567; SER-593; SER-644; THR-731; SER-1002; SER-1016; SER-1017 AND SER-1038, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[11]"Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening."
Voss M., Lettau M., Janssen O.
BMC Immunol. 10:53-53(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FASLG.
[12]"Novel p47(phox)-related organizers regulate localized NADPH oxidase 1 (Nox1) activity."
Gianni D., Diaz B., Taulet N., Fowler B., Courtneidge S.A., Bokoch G.M.
Sci. Signal. 2:RA54-RA54(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH NOXA1.
[13]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1002, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[14]"Direct interaction between Tks proteins and the N-terminal proline-rich region (PRR) of NoxA1 mediates Nox1-dependent ROS generation."
Gianni D., Dermardirossian C., Bokoch G.M.
Eur. J. Cell Biol. 90:164-171(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH NOXA1 AND NOXO1.
[15]"Solution structure of the SH3 domains from human KIAA0418 protein."
RIKEN structural genomics initiative (RSGI)
Submitted (AUG-2007) to the PDB data bank
Cited for: STRUCTURE BY NMR OF 168-325 AND 1072-1133.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB007878 mRNA. Translation: BAA24848.2. Different initiation.
AL121929, AL133355 Genomic DNA. Translation: CAI13961.1.
AL121929, AL133355 Genomic DNA. Translation: CAI13962.1.
AL121929 Genomic DNA. Translation: CAI13963.1.
AL133355, AL121929 Genomic DNA. Translation: CAI15351.1.
AL133355, AL121929 Genomic DNA. Translation: CAI15352.1.
CH471066 Genomic DNA. Translation: EAW49623.1.
CH471066 Genomic DNA. Translation: EAW49624.1.
PIRT00056.
RefSeqNP_055446.2. NM_014631.2.
XP_005270351.1. XM_005270294.2.
UniGeneHs.678727.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2DNUNMR-A268-325[»]
2EGANMR-A168-224[»]
2EGCNMR-A1072-1133[»]
2EKHNMR-A842-908[»]
ProteinModelPortalQ5TCZ1.
SMRQ5TCZ1. Positions 6-126, 162-329, 448-506, 842-908, 1072-1133.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid115002. 11 interactions.
IntActQ5TCZ1. 12 interactions.
MINTMINT-2792114.
STRING9606.ENSP00000348215.

PTM databases

PhosphoSiteQ5TCZ1.

Polymorphism databases

DMDM74746151.

Proteomic databases

PaxDbQ5TCZ1.
PRIDEQ5TCZ1.

Protocols and materials databases

DNASU9644.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000355946; ENSP00000348215; ENSG00000107957. [Q5TCZ1-3]
ENST00000369774; ENSP00000358789; ENSG00000107957. [Q5TCZ1-1]
GeneID9644.
KEGGhsa:9644.
UCSCuc001kxj.1. human. [Q5TCZ1-3]
uc009xxn.1. human. [Q5TCZ1-2]
uc010qqu.1. human. [Q5TCZ1-1]

Organism-specific databases

CTD9644.
GeneCardsGC10M105345.
HGNCHGNC:23664. SH3PXD2A.
HPAHPA037922.
HPA037923.
neXtProtNX_Q5TCZ1.
PharmGKBPA134956816.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG148927.
HOGENOMHOG000154376.
HOVERGENHBG089589.
InParanoidQ5TCZ1.
OMALESGWWY.
OrthoDBEOG7H4DSQ.
PhylomeDBQ5TCZ1.
TreeFamTF329347.

Gene expression databases

ArrayExpressQ5TCZ1.
BgeeQ5TCZ1.
CleanExHS_SH3PXD2A.
GenevestigatorQ5TCZ1.

Family and domain databases

Gene3D3.30.1520.10. 1 hit.
InterProIPR001683. Phox.
IPR001452. SH3_domain.
[Graphical view]
PfamPF00787. PX. 1 hit.
PF00018. SH3_1. 4 hits.
[Graphical view]
SMARTSM00312. PX. 1 hit.
SM00326. SH3. 5 hits.
[Graphical view]
SUPFAMSSF50044. SSF50044. 5 hits.
SSF64268. SSF64268. 1 hit.
PROSITEPS50195. PX. 1 hit.
PS50002. SH3. 5 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSSH3PXD2A. human.
EvolutionaryTraceQ5TCZ1.
GeneWikiSH3PXD2A.
GenomeRNAi9644.
NextBio36199.
PROQ5TCZ1.

Entry information

Entry nameSPD2A_HUMAN
AccessionPrimary (citable) accession number: Q5TCZ1
Secondary accession number(s): D3DR98 expand/collapse secondary AC list , O43302, Q5TCZ2, Q5TDQ8
Entry history
Integrated into UniProtKB/Swiss-Prot: February 20, 2007
Last sequence update: December 21, 2004
Last modified: April 16, 2014
This is version 98 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 10

Human chromosome 10: entries, gene names and cross-references to MIM