InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Zap70

Summary

InnateDB Protein

IDBP-145091.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

Zap70

Protein Name

zeta-chain (TCR) associated protein kinase

Synonyms

mrtle; mur; Srk; ZAP-70;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000027291

InnateDB Gene

IDBG-145089 (Zap70)

Protein Structure

UniProt Annotation

Function

Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). {ECO:0000269PubMed:12705855, ECO:0000269PubMed:14985102, ECO:0000269PubMed:17606633, ECO:0000269PubMed:7630421}.

Subcellular Localization

Cytoplasm. Cell membrane; Peripheral membrane protein. Note=In quiescent T-lymphocytes, ZAP70 is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD3Z. Colocalizes together with RHOH in the immunological synapse. RHOH is required for its proper localization to the cell membrane and cytoskeleton fractions in the thymocytes.

Disease Associations

Tissue Specificity

Isoform 1 and isoform 2 are expressed in thymus, spleen and lymph nodes. {ECO:0000269PubMed:14985102}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 21 experimentally validated interaction(s) in this database.
They are also associated with 53 interaction(s) predicted by orthology.

Experimentally validated
Total	21 [view]
Protein-Protein	21 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	53 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0001784	phosphotyrosine binding
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004715	non-membrane spanning protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups

Biological Process

GO:0006468	protein phosphorylation
GO:0006955	immune response
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0035556	intracellular signal transduction
GO:0043366	beta selection
GO:0045059	positive thymic T cell selection
GO:0045060	negative thymic T cell selection
GO:0045061	thymic T cell selection
GO:0045582	positive regulation of T cell differentiation
GO:0046638	positive regulation of alpha-beta T cell differentiation
GO:0046641	positive regulation of alpha-beta T cell proliferation
GO:0046777	protein autophosphorylation
GO:0050850	positive regulation of calcium-mediated signaling
GO:0050852	T cell receptor signaling pathway

Cellular Component

GO:0001772	immunological synapse
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0005911	cell-cell junction
GO:0042101	T cell receptor complex
GO:0045121	membrane raft

Protein Structure and Domains

PDB ID

MGI:99613

InterPro

IPR000719 Protein kinase domain
IPR000980 SH2 domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine- /dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR012234 Tyrosine-protein kinase, non-receptor SYK/ZAP-70
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF00017
PF14633
PF07714

PRINTS

PR00401
PR00109

PIRSF

PIRSF000604

SMART

SM00252
SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References