Reviewed, UniProtKB/Swiss-Prot P43404 (ZAP70_MOUSE)

Names and origin

Protein names

Recommended name:
    Tyrosine-protein kinase ZAP-70
    EC=2.7.10.2
Alternative name(s):
    70 kDa zeta-associated protein
    Syk-related tyrosine kinase

Gene names

Name:	Zap70
Synonyms:	Srk, Zap-70

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	618 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Plays a role in T-cell development and lymphocyte activation. Essential for TCR-mediated IL-2 production. Isoform 1 induces TCR-mediated signal transduction, isoform 2 does not. Ref.3
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Interacts with CBL. Interacts with SHB. Interacts with FCRL3 By similarity. Interacts with CD3Z and with phosphorylated NFAM1. Interacts with SLA and SLA2 when it is phosphorylated. The association with SLA (or SLA2) and CBL probably leads to its destruction. Interacts with CBLB and DEF6. Interacts (via SH2 domains) with RHOH. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10
Subcellular location	Cytoplasm. Cell membrane. Note: After antigen stimulation, isoform 1 concentrates at the immunological synapse and isoform 2 remains cytoplasmic. Co-localizes together with RHOH in the immunological synapse. RHOH is required for its proper localization to the cell membrane and cytoskeleton fractions in the thymocytes. Ref.3 Ref.10
Tissue specificity	Isoform 1 and isoform 2 are expressed in thymus, sleen and lymph nodes. Ref.3
Developmental stage	Isoform 2 is expressed in develoing thymocytes from the CD44+CD25- stage up to mature T cells. Isoform 1 is not expressed in thymocytes at the CD44+CD25- or CD44+CD25+ stages. Ref.3
Domain	The SH2 domains bind to the phosphorylated tyrosine-based activation motif (TAM) of CD3Z and the non-canonical phosphorylated tyrosine-based activation motif (TAM) of RHOH. Ref.10
Post-translational modification	Phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation. Tyr-318 phosphorylation is essential for full activity By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily. Contains 1 protein kinase domain. Contains 2 SH2 domains.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat SH2 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	T cell receptor signaling pathway Ref.2 Inferred from mutant phenotype. Source: MGI beta selection Inferred from genetic interaction. Source: MGI negative thymic T cell selection Inferred from mutant phenotype. Source: MGI peptidyl-tyrosine phosphorylation Ref.2 Inferred from direct assay. Source: MGI positive regulation of alpha-beta T cell differentiation Ref.2 Inferred from mutant phenotype. Source: MGI positive regulation of alpha-beta T cell proliferation Inferred from genetic interaction. Source: MGI positive regulation of calcium-mediated signaling Ref.2 Inferred from mutant phenotype. Source: MGI positive thymic T cell selection Inferred from mutant phenotype. Source: MGI protein amino acid autophosphorylation Ref.2 Inferred from direct assay. Source: MGI protein kinase cascade Inferred from electronic annotation. Source: InterPro
Cellular component	cytosol Inferred from direct assay. Source: MGI immunological synapse Ref.10 Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Inferred from direct assay. Source: MGI non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC phosphotyrosine binding Ref.1 Inferred from physical interaction. Source: MGI
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P43404-1)

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: P43404-2)

Also known as: TZK;

The sequence of this isoform differs from the canonical sequence as follows:
     1-306: Missing.

Isoform 3 (identifier: P43404-3)

Also known as: TZK-2;

The sequence of this isoform differs from the canonical sequence as follows:
     1-309: Missing.
     310-360: DTSVYESPYS...VRQGVYRMRK → MAYGRVSGVS...MLSVASHLGR

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 618	618	Tyrosine-protein kinase ZAP-70		PRO_0000088169
Regions
	Domain	10 – 102	93	SH2 1
	Domain	163 – 254	92	SH2 2
	Domain	337 – 597	261	Protein kinase
	Nucleotide binding	343 – 351	9	ATP By similarity
Sites
	Active site	460	1	Proton acceptor By similarity
	Binding site	368	1	ATP By similarity
Amino acid modifications
	Modified residue	248	1	Phosphotyrosine By similarity
	Modified residue	287	1	Phosphoserine By similarity
	Modified residue	314	1	Phosphotyrosine By similarity
	Modified residue	318	1	Phosphotyrosine By similarity
	Modified residue	491	1	Phosphotyrosine; by autocatalysis By similarity
Natural variations
	Alternative sequence	1 – 309	309	Missing in isoform 3.		VSP_031160
	Alternative sequence	1 – 306	306	Missing in isoform 2.		VSP_031159
	Alternative sequence	310 – 360	51	DTSVY…YRMRK → MAYGRVSGVSELSRVLYVPF PPPPFLSNPGVHDTRMYTQH AMLSVASHLGR in isoform 3.		VSP_031161
	Natural variant	464	1	R → C in ST; causes an absence of mature T cells due to thymocyte development being arrested at the CD4+CD8+ stage. Ref.2
Experimental info
	Sequence conflict	124	1	C → R in AAB36538. Ref.2
	Sequence conflict	526 – 529	4	VTMW → GHHV in BAC67015. Ref.4
	Sequence conflict	546	1	E → Q in AAA19250. Ref.1
	Sequence conflict	599	1	L → P in AAA19250. Ref.1
	Sequence conflict	599	1	L → P in AAB36538. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 5, 2008. Version 2. Checksum: A560AE692D045EBD	FASTA	618	70,058
	10 20 30 40 50 60 MPDPAAHLPF FYGSISRAEA EEHLKLAGMA DGLFLLRQCL RSLGGYVLSL VHDVRFHHFP 70 80 90 100 110 120 IERQLNGTYA IAGGKAHCGP AELCQFYSQD PDGLPCNLRK PCNRPPGLEP QPGVFDCLRD 130 140 150 160 170 180 AMVCDYVRQT WKLEGDALEQ AIISQAPQVE KLIATTAHER MPWYHSSLTR EEAERKLYSG 190 200 210 220 230 240 QQTDGKFLLR PRKEQGTYAL SLVYGKTVYH YLISQDKAGK YCIPEGTKFD TLWQLVEYLK 250 260 270 280 290 300 LKADGLIYRL KEVCPNSSAS AAVAAPTLPA HPSTFTQPQR RVDTLNSDGY TPEPARLASS 310 320 330 340 350 360 TDKPRPMPMD TSVYESPYSD PEELKDKKLF LKRENLLVAD IELGCGNFGS VRQGVYRMRK 370 380 390 400 410 420 KQIDVAIKVL KQGTEKADKD EMMREAQIMH QLDNPYIVRL IGVCQAEALM LVMEMAGGGP 430 440 450 460 470 480 LHKFLLGKKE EIPVSNVAEL LHQVAMGMKY LEEKNFVHRD LAARNVLLVN RHYAKISDFG 490 500 510 520 530 540 LSKALGADDS YYTARSAGKW PLKWYAPECI NFRKFSSRSD VWSYGVTMWE AFSYGQKPYK 550 560 570 580 590 600 KMKGPEVLDF IKQGKRMECP PECPPEMYAL MSDCWIYKWE DRPDFLTVEQ RMRNYYYSLA 610 SRAEGPPQCE QVAEAACG
	Isoform 2 (TZK). Checksum: 12CCA3AA2C3B1CF2	FASTA	312	35,883
	10 20 30 40 50 60 MPMDTSVYES PYSDPEELKD KKLFLKRENL LVADIELGCG NFGSVRQGVY RMRKKQIDVA 70 80 90 100 110 120 IKVLKQGTEK ADKDEMMREA QIMHQLDNPY IVRLIGVCQA EALMLVMEMA GGGPLHKFLL 130 140 150 160 170 180 GKKEEIPVSN VAELLHQVAM GMKYLEEKNF VHRDLAARNV LLVNRHYAKI SDFGLSKALG 190 200 210 220 230 240 ADDSYYTARS AGKWPLKWYA PECINFRKFS SRSDVWSYGV TMWEAFSYGQ KPYKKMKGPE 250 260 270 280 290 300 VLDFIKQGKR MECPPECPPE MYALMSDCWI YKWEDRPDFL TVEQRMRNYY YSLASRAEGP 310 PQCEQVAEAA CG
	Isoform 3 (TZK-2). Checksum: D1A230395CA2AFE4	FASTA	309	35,255
	10 20 30 40 50 60 MAYGRVSGVS ELSRVLYVPF PPPPFLSNPG VHDTRMYTQH AMLSVASHLG RKQIDVAIKV 70 80 90 100 110 120 LKQGTEKADK DEMMREAQIM HQLDNPYIVR LIGVCQAEAL MLVMEMAGGG PLHKFLLGKK 130 140 150 160 170 180 EEIPVSNVAE LLHQVAMGMK YLEEKNFVHR DLAARNVLLV NRHYAKISDF GLSKALGADD 190 200 210 220 230 240 SYYTARSAGK WPLKWYAPEC INFRKFSSRS DVWSYGVTMW EAFSYGQKPY KKMKGPEVLD 250 260 270 280 290 300 FIKQGKRMEC PPECPPEMYA LMSDCWIYKW EDRPDFLTVE QRMRNYYYSL ASRAEGPPQC EQVAEAACG

References

[1]	"Interactions of p59fyn and ZAP-70 with T-cell receptor activation motifs: defining the nature of a signalling motif." Gauen L.K.T., Zhu Y., Letourner F., Hu Q., Bolen J.B., Matis L.A., Klausner R.D., Shaw A.S. Mol. Cell. Biol. 14:3729-3741(1994) [PubMed: 8196616] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Thymus.
[2]	"A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development." Wiest D.L., Ashe J.M., Howcroft T.K., Lee H.-M., Kemper D.M., Negishi I., Singer D.S., Singer A., Abe R. Immunity 6:663-671(1997) [PubMed: 9208839] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ST CYS-464. Strain: C57BL/6. Tissue: Thymocyte.
[3]	"Identification of a novel isoform of ZAP-70, truncated ZAP kinase." Kuroyama H., Ikeda T., Kasai M., Yamasaki S., Tatsumi M., Utsuyama M., Saito T., Hirokawa K. Biochem. Biophys. Res. Commun. 315:935-941(2004) [PubMed: 14985102] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE. Strain: C57BL/6. Tissue: Thymus.
[4]	"Mouse TZK-2." Ikeda T., Kuroyama H. Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
[5]	"Src-like adaptor protein (SLAP) is a negative regulator of T cell receptor signaling." Sosinowski T., Pandey A., Dixit V.M., Weiss A. J. Exp. Med. 191:463-474(2000) [PubMed: 10662792] [Abstract] Cited for: INTERACTION WITH SLA.
[6]	"Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b." Bachmaier K., Krawczyk C., Kozieradzki I., Kong Y.-Y., Sasaki T., Oliveira-dos-Santos A., Mariathasan S., Bouchard D., Wakeham A., Itie A., Le J., Ohashi P.S., Sarosi I., Nishina H., Lipkowitz S., Penninger J.M. Nature 403:211-216(2000) [PubMed: 10646608] [Abstract] Cited for: INTERACTION WITH CBLB.
[7]	"A novel Src homology 2 domain-containing molecule, Src-like adapter protein-2 (SLAP-2), which negatively regulates T cell receptor signaling." Pandey A., Ibarrola N., Kratchmarova I., Fernandez M.M., Constantinescu S.N., Ohara O., Sawasdikosol S., Lodish H.F., Mann M. J. Biol. Chem. 277:19131-19138(2002) [PubMed: 11891219] [Abstract] Cited for: INTERACTION WITH SLA2.
[8]	"SWAP-70-like adapter of T cells, an adapter protein that regulates early TCR-initiated signaling in Th2 lineage cells." Tanaka Y., Bi K., Kitamura R., Hong S., Altman Y., Matsumoto A., Tabata H., Lebedeva S., Bushway P.J., Altman A. Immunity 18:403-414(2003) [PubMed: 12648457] [Abstract] Cited for: INTERACTION WITH DEF6.
[9]	"NFAM1, an immunoreceptor tyrosine-based activation motif-bearing molecule that regulates B cell development and signaling." Ohtsuka M., Arase H., Takeuchi A., Yamasaki S., Shiina R., Suenaga T., Sakurai D., Yokosuka T., Arase N., Iwashima M., Kitamura T., Moriya H., Saito T. Proc. Natl. Acad. Sci. U.S.A. 101:8126-8131(2004) [PubMed: 15143214] [Abstract] Cited for: INTERACTION WITH NFAM1.
[10]	"RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development." Gu Y., Chae H.-D., Siefring J.E., Jasti A.C., Hildeman D.A., Williams D.A. Nat. Immunol. 7:1182-1190(2006) [PubMed: 17028588] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH RHOH, DOMAIN.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U04379 mRNA. Translation: AAA19250.1. U77667 mRNA. Translation: AAB36538.1. AB083210 mRNA. Translation: BAC43746.1. AB084383 mRNA. Translation: BAC67015.1.
IPI	IPI00331216. IPI00403592. IPI00885341.
PIR	I48914.
UniGene	Mm.8038
3D structure databases
SMR	P43404. Positions 2-605.
ModBase	Search...
Protein-protein interaction databases
STRING	P43404.
PTM databases
PhosphoSite	P43404.
Proteomic databases
PRIDE	P43404.
Genome annotation databases
Ensembl	ENSMUST00000027291; ENSMUSP00000027291; ENSMUSG00000026117; Mus musculus. [Genome view] ENSMUST00000070299; ENSMUSP00000068307; ENSMUSG00000026117; Mus musculus. [Genome view]
Organism-specific databases
MGI	MGI:99613. Zap70.
Phylogenomic databases
eggNOG	roNOG04941.
HOGENOM	HBG714705.
HOVERGEN	P43404.
InParanoid	P43404.
Enzyme and pathway databases
BRENDA	2.7.10.2. 244.
Gene expression databases
ArrayExpress	P43404.
Bgee	P43404.
CleanEx	MM_ZAP70.
Genevestigator	P43404.
GermOnline	ENSMUSG00000026117. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR000980. SH2. IPR012234. Tyr_kinase_non-rcpt_SYK/ZAP70. IPR020686. Tyr_kinase_non-rcpt_ZAP-70. IPR020635. Tyr_Pkinase_cat_dom. IPR020685. Tyr_prot_kinase. IPR008266. Tyr_prot_kinase_AS. [Graphical view]
Gene3D	G3DSA:3.30.505.10. SH2. 2 hits.
PANTHER	PTHR23256:SF98. Tyr_kinase_non-rcpt_ZAP-70. 1 hit. PTHR23256. Tyr_prot_kinase. 1 hit.
Pfam	PF00017. SH2. 2 hits. [Graphical view]
PIRSF	PIRSF000604. TyrPK_SYK. 1 hit.
PRINTS	PR00401. SH2DOMAIN.
SMART	SM00252. SH2. 2 hits. SM00219. TyrKc. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. PS50001. SH2. 2 hits. [Graphical view]
ProtoNet	Search...
Other Resources
SOURCE	Search...

Entry information

Entry name

ZAP70_MOUSE

Accession

Primary (citable) accession number: P43404
Secondary accession number(s): P97455, Q80VV2, Q8CHJ3

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	February 5, 2008
Last modified:	February 9, 2010
This is version 95 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)