InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ZAP70

Summary

InnateDB Protein

IDBP-383238.5

Last Modified

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

Gene Symbol

ZAP70

Protein Name

zeta-chain (TCR) associated protein kinase 70kDa

Synonyms

SRK; STCD; STD; TZK; ZAP-70;

Species

Homo sapiens

Ensembl Protein

ENSP00000400475

InnateDB Gene

IDBG-62509 (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 CD247/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-CD247/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:11353765, ECO:0000269PubMed:1423621, ECO:0000269PubMed:20135127, ECO:0000269PubMed:8124727, ECO:0000269PubMed:8702662, ECO:0000269PubMed:9489702}.

Subcellular Localization

Cytoplasm {ECO:0000269PubMed:9813084}. Cell membrane {ECO:0000269PubMed:9813084}; Peripheral membrane protein {ECO:0000269PubMed:9813084}. Note=In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/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 (By similarity). {ECO:0000250}.

Disease Associations

Selective T-cell defect (STCD) [MIM:269840]: A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T-cells. {ECO:0000269PubMed:11123350, ECO:0000269PubMed:11412303, ECO:0000269PubMed:18509675, ECO:0000269PubMed:8124727, ECO:0000269PubMed:8202713}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells. {ECO:0000269PubMed:1423621, ECO:0000269PubMed:16467082, ECO:0000269PubMed:9378960}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 86 experimentally validated interaction(s) in this database.
They are also associated with 15 interaction(s) predicted by orthology.

Experimentally validated
Total	86 [view]
Protein-Protein	85 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	15 [view]

Gene Ontology

Molecular Function

Accession	GO Term
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:0002250	adaptive immune response
GO:0006468	protein phosphorylation
GO:0006955	immune response
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0030217	T cell differentiation
GO:0035556	intracellular signal transduction
GO:0042110	T cell activation
GO:0042113	B cell activation
GO:0045059	positive thymic T cell selection
GO:0045582	positive regulation of T cell differentiation
GO:0050852	T cell receptor signaling pathway
GO:0070489	T cell aggregation
GO:0072678	T cell migration

Cellular Component

GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0042101	T cell receptor complex
GO:0045121	membrane raft

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714

PRINTS

PR00109

PIRSF

SMART

SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt