Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

ZAP70 (P43403) - Overview - Molecular Target Synopsis

Protein


ZAP70, Tyrosine-protein kinase ZAP-70
Enzyme Classification 2.7.10.2
UniProt P43403

Also Known as ZAP70_HUMAN, ZAP70, SRK

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). Interacts with CD247/CD3Z; this interaction docks ZAP70 at the stimulated TCR (PubMed:1423621, PubMed:7659156, PubMed:26783323). Interacts with NFAM1 (PubMed:15143214). Interacts with adapter protein SLA; this interaction negatively regulates T-cell receptor signaling (PubMed:10449770). Interacts with FCRL3 (PubMed:12051764, PubMed:19843936). Interacts with VAV1 (PubMed:9151714). Interacts with CBL; this interaction promotes ubiquitination, internalization and subsequent degradation of CD247/CD3Z (PubMed:10449770, PubMed:10078535). Identified in a complex with CBL and UBE2L3 (PubMed:10966114). Interacts with SHB (PubMed:12084069). Interacts with adapter protein SLA2; this interaction negatively regulates T-cell receptor signaling. Interacts with CBLB. Interacts (via SH2 domains) with RHOH; this interaction regulates ZAP70 subcellular localization. Interacts with DEF6 (By similarity). Interacts (ubiquitinated form) with OTUD7B and UBASH3B (PubMed:26903241).

5O76
6 RESIDUE FRAGMENT OF
TYROSINE PROTEIN KINASE ZAP70 PEPTIDE
IN THE STRUCTURE OF
STRUCTURE OF PHOSPHOY371 C-CBL IN COMPLEX WITH ZAP70-PEPTIDE AND UBV.PCBL UBIQUITIN VARIANT
RCSB/PDB
Inspect Structure
See all 3D Structures for ZAP70

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: ZAP70 is active in the following subcellular-locations: cell membrane, cytoplasm.
GO terms: ZAP70 is active in the following subcellular-locations: cell-cell junction, cytoplasm, cytosol, immunological synapse, plasma membrane, T cell receptor complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project ZAP70 has gain in 2 cell-lines, loss in 0 cell-lines and no signal in 1003 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MOLT_4, CCRF_CEM, SR

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: Jurkat, Clone E6-1, DU4475, SR

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, NHLF, HSMM

(see details)

RNA Interference


ZAP70 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: MFM223, OE19. (see details)

3D Structures


For ZAP70 there are:
14 structures (19 chains) solved
5 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


ZAP70 has been screened with 1229 compounds (1949 bioactivities), 103 compounds have bioactivities that show binding affinity of <= 500nM (132 bioactivities). (see details)