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Details on Person UniProt:P43403 ZAP70
| Class:Id | ReferenceGeneProduct:68100 |
|---|---|
| _chainChangeLog | chain:1-619 added on Fri February 6 2015 |
| _displayName | UniProt:P43403 ZAP70 |
| _timestamp | 2026-02-20 21:36:21 |
| chain | chain:1-619 |
| checksum | D1E1A8EC66FA116F |
| comment | 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. Also contributes 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 phosphorylated TCR components CD3E and CD247/CD3Z through ITAM motif at the plasma membrane (PubMed:7509083). 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).CATALYTIC ACTIVITY L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+)ACTIVITY REGULATION Activated by phosphorylation at Tyr-493 in the activation loop. Inhibited by staurosporine.SUBUNIT Interacts with CD247/CD3Z; this interaction docks ZAP70 at the stimulated TCR (PubMed:1423621, PubMed:26783323, PubMed:7659156). 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:10078535, PubMed:10449770). 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).INTERACTION 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).ALTERNATIVE PRODUCTS Expressed in T- and natural killer cells. Also present in early thymocytes and pro/pre B-cells.DOMAIN Composed of 2 N-terminal SH2 domains and a C-terminal kinase domain. The tandem SH2 domains bind to the doubly phosphorylated tyrosine-based activation motif (ITAM) of CD247/CD3Z and the non-canonical phosphorylated tyrosine-based activation motif (TAM) of RHOH (By similarity). The interdomain B located between the second SH2 and the kinase domain contains 3 tyrosines (Tyr-292, Tyr-315, Tyr-319) that are phosphorylated following TCR activation. These sites have been implicated in binding to other signaling molecules including CBL or VAV1. Thus, ZAP70 can also function as a scaffold by recruiting additional factors to the stimulated TCR complex.PTM Phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation. Phosphorylation of Tyr-315 and Tyr-319 are essential for ZAP70 positive function on T-lymphocyte activation whereas Tyr-292 has a negative regulatory role. Within the C-terminal kinase domain, Tyr-492 and Tyr-493 are phosphorylated after TCR induction, Tyr-492 playing a negative regulatory role and Tyr-493 a positive. Tyr-493 is dephosphorylated by PTN22.PTM Ubiquitinated in response to T cell activation. Deubiquitinated by OTUD7B.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.ONLINE INFORMATION ZAP70 mutation db |
| description | recommendedName: Tyrosine-protein kinase ZAP-70 ecNumber evidence="19"2.7.10.2 alternativeName: 70 kDa zeta-chain associated protein alternativeName: Syk-related tyrosine kinase |
| geneName | ZAP70 SRK |
| identifier | P43403 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Adaptive immunity Alternative splicing ATP-binding Cell membrane Cytoplasm Disease variant Immunity Isopeptide bond Kinase Membrane Nucleotide-binding Phosphoprotein Proteomics identification Reference proteome Repeat SCID SH2 domain Transferase Tyrosine-protein kinase Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | ZAP70 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8991077] ENSEMBL:ENSG00000115085 ZAP70 [Homo sapiens] |
| secondaryIdentifier | ZAP70_HUMAN A6NFP4 Q6PIA4 Q8IXD6 Q9UBS6 |
| sequenceLength | 619 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:257188] UniProt:P43403-2 ZAP70 [Homo sapiens] [ReferenceIsoform:257189] UniProt:P43403-3 ZAP70 [Homo sapiens] [ReferenceIsoform:404060] UniProt:P43403-1 ZAP70 [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:202252] p-Y315,Y493-ZAP70 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:202368] p-Y493-ZAP70 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:202397] ZAP70 [cytosol] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:202313] O4'-phospho-L-tyrosine at 493 [ModifiedResidue:202409] O4'-phospho-L-tyrosine at 315 |
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No pathways have been reviewed or authored by UniProt:P43403 ZAP70 (68100)
