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  7. Tyrosine-protein kinase ZAP-70

Tchem Tyrosine-protein kinase ZAP-70

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).

This gene encodes an enzyme belonging to the protein tyrosine kinase family, and it plays a role in T-cell development and lymphocyte activation. This enzyme, which is phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with the Src family kinases, Lck and Fyn. This enzyme is also essential for thymocyte development. Mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T-cells. Two transcript variants that encode different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

 Comments

Property Summary

Ligand Count 17
NCBI Gene PubMed Count 276
PubMed Score 798.23
PubTator Score 1050.46

Knowledge Summary

Patent (114,997)

TINX Plot

  Disease (6)

Disease Target Count P-value
ovarian cancer 8520 9.6e-04
osteosarcoma 7950 2.2e-03
interstitial cystitis 2312 2.9e-03
cutaneous lupus erythematosus 1057 3.5e-02
Disease Target Count Z-score Confidence
Carcinoma 11493 0.0 0.9
Kidney cancer 2613 0.0 0.5
Disease Target Count
CD8 Deficiency, Familial 2

Expression

  Differential Expression (4)

Disease log2 FC p
cutaneous lupus erythematosus 1.100 3.5e-02
interstitial cystitis 1.700 2.9e-03
osteosarcoma -1.330 2.2e-03
ovarian cancer -1.100 9.6e-04

Synonym

Accession P43403 A6NFP4 Q6PIA4 Q8IXD6 Q9UBS6
Symbols SRK
STD
TZK
STCD
IMD48
ADMIO2
ZAP-70

Gene

ZAP70

PDB

3ZNI   4A4B   4A4C   1FBV   2CBL   2Y1N   1M61   1U59   2OQ1   2OZO   4K2R   4XZ0   4XZ1  

  Ortholog (1)

Species Source Disease
Chimp OMA EggNOG

 UniProt Keyword (23)

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 GO Function (4)

 GO Component (7)

 GO Process (22)

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 Compartment GO Term (35)

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 OMIM Phenotype (2)

 MGI Phenotype (7)

 GWAS Trait (2)

 HCA RNA Cell Line (37)

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Pathway (35)

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Ligand (17)

Structure of CHEMBL112518

CHEMBL112518
pIC50 7.59

Structure of CHEMBL3642587

CHEMBL3642587
pIC50 7.62

Structure of CHEMBL475251

CHEMBL475251
pKd 7.68

Structure of CHEMBL3262622

CHEMBL3262622
pIC50 7.75

Structure of CHEMBL603469

CHEMBL603469
pKd 7.80

Structure of CHEMBL3262616

CHEMBL3262616
pIC50 7.85

Structure of CHEMBL325912

CHEMBL325912
pIC50 7.96

Structure of CHEMBL573483

CHEMBL573483
pIC50 8.00

Structure of CHEMBL575048

CHEMBL575048
pIC50 8.00

Structure of CHEMBL3642579

CHEMBL3642579
pIC50 8.05

Structure of CHEMBL388978

CHEMBL388978
pIC50 8.06

Structure of CHEMBL112346

CHEMBL112346
pIC50 8.10

Structure of CHEMBL3642588

CHEMBL3642588
pIC50 8.10

Structure of CHEMBL3642590

CHEMBL3642590
pIC50 8.10

Structure of CHEMBL3415583

CHEMBL3415583
pIC50 8.28

Structure of CHEMBL3642585

CHEMBL3642585
pIC50 8.70

Structure of CHEMBL3642578

CHEMBL3642578
pIC50 9.00

Gene RIF (194)

AA Sequence 

MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQLNGTYA      1 - 70
IAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVRDYVRQTWKLEGEALEQ     71 - 140
AIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTDGKFLLRPRKEQGTYALSLIYGKTVYH    141 - 210
YLISQDKAGKYCIPEGTKFDTLWQLVEYLKLKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHP    211 - 280
QRRIDTLNSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFG    281 - 350
SVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGG    351 - 420
PLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDFGLSKALGADD    421 - 490
SYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPYKKMKGPEVMAFIEQGKRMEC    491 - 560
PPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGSTQKAEAACA               561 - 619
//

Text Mined References (293)

PMID Year Title