Browse ZAP70

Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Basic function annotation.
> Subcellular Location, Domain and Function
> Gene Ontology
> KEGG and Reactome Pathway
> Subcellular Location, Domain and Function
 
Subcellular Location Cytoplasm Cell membrane Peripheral membrane protein 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).
Domain PF07714 Protein tyrosine kinase
PF00017 SH2 domain
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).

> Gene Ontology
 
Biological Process GO:0002250 adaptive immune response
GO:0002263 cell activation involved in immune response
GO:0002274 myeloid leukocyte activation
GO:0002275 myeloid cell activation involved in immune response
GO:0002279 mast cell activation involved in immune response
GO:0002281 macrophage activation involved in immune response
GO:0002283 neutrophil activation involved in immune response
GO:0002366 leukocyte activation involved in immune response
GO:0002429 immune response-activating cell surface receptor signaling pathway
GO:0002443 leukocyte mediated immunity
GO:0002444 myeloid leukocyte mediated immunity
GO:0002448 mast cell mediated immunity
GO:0002521 leukocyte differentiation
GO:0002694 regulation of leukocyte activation
GO:0002696 positive regulation of leukocyte activation
GO:0002697 regulation of immune effector process
GO:0002699 positive regulation of immune effector process
GO:0002703 regulation of leukocyte mediated immunity
GO:0002705 positive regulation of leukocyte mediated immunity
GO:0002757 immune response-activating signal transduction
GO:0002764 immune response-regulating signaling pathway
GO:0002768 immune response-regulating cell surface receptor signaling pathway
GO:0002886 regulation of myeloid leukocyte mediated immunity
GO:0002888 positive regulation of myeloid leukocyte mediated immunity
GO:0006887 exocytosis
GO:0007159 leukocyte cell-cell adhesion
GO:0007596 blood coagulation
GO:0007599 hemostasis
GO:0010543 regulation of platelet activation
GO:0017157 regulation of exocytosis
GO:0018108 peptidyl-tyrosine phosphorylation
GO:0018212 peptidyl-tyrosine modification
GO:0019722 calcium-mediated signaling
GO:0019932 second-messenger-mediated signaling
GO:0022407 regulation of cell-cell adhesion
GO:0022409 positive regulation of cell-cell adhesion
GO:0030098 lymphocyte differentiation
GO:0030168 platelet activation
GO:0030183 B cell differentiation
GO:0030193 regulation of blood coagulation
GO:0030217 T cell differentiation
GO:0032386 regulation of intracellular transport
GO:0032388 positive regulation of intracellular transport
GO:0032418 lysosome localization
GO:0032943 mononuclear cell proliferation
GO:0032944 regulation of mononuclear cell proliferation
GO:0032946 positive regulation of mononuclear cell proliferation
GO:0033003 regulation of mast cell activation
GO:0033005 positive regulation of mast cell activation
GO:0033006 regulation of mast cell activation involved in immune response
GO:0033008 positive regulation of mast cell activation involved in immune response
GO:0033077 T cell differentiation in thymus
GO:0033627 cell adhesion mediated by integrin
GO:0033628 regulation of cell adhesion mediated by integrin
GO:0033630 positive regulation of cell adhesion mediated by integrin
GO:0034109 homotypic cell-cell adhesion
GO:0034110 regulation of homotypic cell-cell adhesion
GO:0036230 granulocyte activation
GO:0038083 peptidyl-tyrosine autophosphorylation
GO:0042098 T cell proliferation
GO:0042102 positive regulation of T cell proliferation
GO:0042110 T cell activation
GO:0042113 B cell activation
GO:0042116 macrophage activation
GO:0042119 neutrophil activation
GO:0042129 regulation of T cell proliferation
GO:0043299 leukocyte degranulation
GO:0043300 regulation of leukocyte degranulation
GO:0043302 positive regulation of leukocyte degranulation
GO:0043303 mast cell degranulation
GO:0043304 regulation of mast cell degranulation
GO:0043306 positive regulation of mast cell degranulation
GO:0043366 beta selection
GO:0043368 positive T cell selection
GO:0043383 negative T cell selection
GO:0045055 regulated exocytosis
GO:0045058 T cell selection
GO:0045059 positive thymic T cell selection
GO:0045060 negative thymic T cell selection
GO:0045061 thymic T cell selection
GO:0045576 mast cell activation
GO:0045577 regulation of B cell differentiation
GO:0045579 positive regulation of B cell differentiation
GO:0045580 regulation of T cell differentiation
GO:0045582 positive regulation of T cell differentiation
GO:0045619 regulation of lymphocyte differentiation
GO:0045621 positive regulation of lymphocyte differentiation
GO:0045785 positive regulation of cell adhesion
GO:0045921 positive regulation of exocytosis
GO:0046631 alpha-beta T cell activation
GO:0046632 alpha-beta T cell differentiation
GO:0046633 alpha-beta T cell proliferation
GO:0046634 regulation of alpha-beta T cell activation
GO:0046635 positive regulation of alpha-beta T cell activation
GO:0046637 regulation of alpha-beta T cell differentiation
GO:0046638 positive regulation of alpha-beta T cell differentiation
GO:0046640 regulation of alpha-beta T cell proliferation
GO:0046641 positive regulation of alpha-beta T cell proliferation
GO:0046651 lymphocyte proliferation
GO:0046777 protein autophosphorylation
GO:0050670 regulation of lymphocyte proliferation
GO:0050671 positive regulation of lymphocyte proliferation
GO:0050817 coagulation
GO:0050818 regulation of coagulation
GO:0050848 regulation of calcium-mediated signaling
GO:0050850 positive regulation of calcium-mediated signaling
GO:0050851 antigen receptor-mediated signaling pathway
GO:0050852 T cell receptor signaling pathway
GO:0050853 B cell receptor signaling pathway
GO:0050863 regulation of T cell activation
GO:0050864 regulation of B cell activation
GO:0050865 regulation of cell activation
GO:0050867 positive regulation of cell activation
GO:0050870 positive regulation of T cell activation
GO:0050871 positive regulation of B cell activation
GO:0050878 regulation of body fluid levels
GO:0050900 leukocyte migration
GO:0051047 positive regulation of secretion
GO:0051249 regulation of lymphocyte activation
GO:0051251 positive regulation of lymphocyte activation
GO:0051640 organelle localization
GO:0051656 establishment of organelle localization
GO:0060627 regulation of vesicle-mediated transport
GO:0061041 regulation of wound healing
GO:0070486 leukocyte aggregation
GO:0070489 T cell aggregation
GO:0070527 platelet aggregation
GO:0070661 leukocyte proliferation
GO:0070663 regulation of leukocyte proliferation
GO:0070665 positive regulation of leukocyte proliferation
GO:0071593 lymphocyte aggregation
GO:0071594 thymocyte aggregation
GO:0072676 lymphocyte migration
GO:0072678 T cell migration
GO:0090330 regulation of platelet aggregation
GO:1900046 regulation of hemostasis
GO:1902105 regulation of leukocyte differentiation
GO:1902107 positive regulation of leukocyte differentiation
GO:1903034 regulation of response to wounding
GO:1903037 regulation of leukocyte cell-cell adhesion
GO:1903039 positive regulation of leukocyte cell-cell adhesion
GO:1903305 regulation of regulated secretory pathway
GO:1903307 positive regulation of regulated secretory pathway
GO:1903532 positive regulation of secretion by cell
GO:1903706 regulation of hemopoiesis
GO:1903708 positive regulation of hemopoiesis
Molecular Function GO:0001784 phosphotyrosine binding
GO:0004713 protein tyrosine kinase activity
GO:0004715 non-membrane spanning protein tyrosine kinase activity
GO:0045309 protein phosphorylated amino acid binding
GO:0051219 phosphoprotein binding
Cellular Component GO:0001772 immunological synapse
GO:0009898 cytoplasmic side of plasma membrane
GO:0019897 extrinsic component of plasma membrane
GO:0019898 extrinsic component of membrane
GO:0031234 extrinsic component of cytoplasmic side of plasma membrane
GO:0042101 T cell receptor complex
GO:0043235 receptor complex
GO:0045121 membrane raft
GO:0098552 side of membrane
GO:0098562 cytoplasmic side of membrane
GO:0098589 membrane region
GO:0098802 plasma membrane receptor complex
GO:0098857 membrane microdomain
> KEGG and Reactome Pathway
 
KEGG hsa04014 Ras signaling pathway
hsa04064 NF-kappa B signaling pathway
hsa04650 Natural killer cell mediated cytotoxicity
hsa04660 T cell receptor signaling pathway
Reactome R-HSA-1280218: Adaptive Immune System
R-HSA-202433: Generation of second messenger molecules
R-HSA-168256: Immune System
R-HSA-202403: TCR signaling
R-HSA-202430: Translocation of ZAP-70 to Immunological synapse
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Literatures that report relations between ZAP70 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.
> Text Mining
 
  Literatures describing the relation between ZAP70 and anti-tumor immunity in human cancer.
PMID Cancer type Relation to immunity Evidence sentences
19278954LeukemiaPromote immunityThis combination activated phospho-ZAP70 and phospho-ERK1/2 signaling in TCRVgamma9(+) cells and strongly enhanced their ADCC activity.
18687687LeukemiaPromote immunityThe zeta chain-associated 70-kDa protein (ZAP-70) of tyrosine kinase plays a critical role in T cell receptor-mediated signal transduction and the immune response. A high level of ZAP-70 expression is observed in leukemia, which suggests ZAP-70 as a logical target for immunomodulatory therapies. Overall, these results strongly indicated that ZAP-70 activity was inhibited specifically by EGCG, which contributed to suppressing the CD3-mediated T cell-induced pathways in leukemia cells.
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.
> High-throughput Screening
  Statistical results of ZAP70 in screening data sets for detecting immune reponses.
PMID Screening System Cancer Type Cell Line Data Set Statistical Results Relation to immunity
29301958CRISPR-Cas9 melanomaB16F10Pmel-1 T cell NA/NSNA/NS
29301958CRISPR-Cas9 melanomaB16F10OT-1 T cell NA/NSNA/NS
28783722CRISPR-Cas9 melanomaMel6242CT-CRISPR NA/NSNA/NS
28723893CRISPR-Cas9 melanomaB16GVAX+Anti-PD1 NA/NSNA/NS
28723893CRISPR-Cas9 melanomaB16GVAX NA/NSNA/NS
25691366RNAiBreast cancerMCF7Luc-CTL assay NA/NSNA/NS
24476824shRNAmelanomaB16Primary screen NA/NSNA/NS
24476824shRNAmelanomaB16Secondary screen NA/NSNA/NS
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets.
> Expression difference between responders and non-responders
> Mutation difference between responders and non-responders
> Expression difference between responders and non-responders
 
Points in the above scatter plot represent the expression difference of ZAP70 in various data sets.
No PMID Cancer type Group Drug # Res # NRes Log2 (Fold Change) P value Anno
126997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)1412-0.5490.382
226997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)65-0.0130.992
326997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)87-0.9360.36
428552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 9160.7430.223
528552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 590.460.768
628552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 471.1120.616
729033130MelanomaallAnti-PD-1 (nivolumab) 26230.4480.51
829033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 15110.9660.347
929033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 1112-0.2220.847
1029301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 481.6850.108
1129301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 2001
1229301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 281.2760.383
1329443960Urothelial cancerallAnti-PD-L1 (atezolizumab) 68230-0.0910.664
> Mutation difference between responders and non-responders
 
Points in the above scatter plot represent the mutation difference of ZAP70 in various data sets.
No PMID Cancer type Group Drug # Res # NRes % Mut/Res % Mut/NRes % Diff (R vs NR) Pval Anno
125765070Non-small cell lung cancer (NSCLC)allAnti-PD-1 (pembrolizumab) 14170001
225765070Non-small cell lung cancer (NSCLC)smokingAnti-PD-1 (pembrolizumab) 1030001
325765070Non-small cell lung cancer (NSCLC)non-smokingAnti-PD-1 (pembrolizumab) 4140001
426359337MelanomaallAnti-CTLA-4 (ipilimumab) 27733.75.5-1.81
526359337MelanomaBRAFiAnti-CTLA-4 (ipilimumab) 01407.1-7.11
626359337Melanomanon-BRAFiAnti-CTLA-4 (ipilimumab) 27593.75.1-1.41
726997480MelanomaallAnti-PD-1 (pembrolizumab and nivolumab)211705.9-5.90.447
826997480MelanomaMAPKiAnti-PD-1 (pembrolizumab and nivolumab)860001
926997480Melanomanon-MAPKiAnti-PD-1 (pembrolizumab and nivolumab)131109.1-9.10.458
1028552987Urothelial cancerallAnti-PD-L1 (atezolizumab) 91611.1011.10.36
1128552987Urothelial cancersmokingAnti-PD-L1 (atezolizumab) 590001
1228552987Urothelial cancernon-smokingAnti-PD-L1 (atezolizumab) 47250250.364
1329033130MelanomaallAnti-PD-1 (nivolumab) 38275.33.71.61
1429033130MelanomaNIV3-PROGAnti-PD-1 (nivolumab) 22134.57.7-3.21
1529033130MelanomaNIV3-NAIVEAnti-PD-1 (nivolumab) 16146.206.21
1629301960Clear cell renal cell carcinoma (ccRCC)allAnti-PD-1 (nivolumab) 11139.109.10.458
1729301960Clear cell renal cell carcinoma (ccRCC)VEGFRiAnti-PD-1 (nivolumab) 6116.7016.71
1829301960Clear cell renal cell carcinoma (ccRCC)non-VEGFRiAnti-PD-1 (nivolumab) 5120001
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of ZAP70. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.
> Lymphocyte
 
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of ZAP70. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by ZAP70.
> Immunoinhibitor
> Immunostimulator
> MHC molecule
> Immunoinhibitor
 
> Immunostimulator
 
> MHC molecule
 
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of ZAP70. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene.
> Chemokine
> Receptor
> Chemokine
 
> Receptor
 
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Distribution of ZAP70 expression across immune and molecular subtypes.
> Immune subtype
> Molecular subtype
> Immune subtype
 
> Molecular subtype
 
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Associations between ZAP70 and clinical features.
> Overall survival analysis
> Cancer stage
> Tumor grade
> Overall survival
 
> Stage
 
> Grade
 
Summary
SymbolZAP70
Namezeta-chain (TCR) associated protein kinase 70kDa
Aliases ZAP-70; zeta-chain (TCR) associated protein kinase (70 kD); STCD; TZK; 70 kDa zeta-associated protein; 70 kD ......
Chromosomal Location2q11-q13
External Links HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content Drugs targeting ZAP70 collected from DrugBank database.
> Drugs from DrugBank database
 

  Details on drugs targeting ZAP70.
ID Name Drug Type Targets #Targets
DB02010StaurosporineSmall MoleculeCDK2, CHRM1, CSK, GSK3B, ITK, LCK, MAPKAPK2, PDPK1, PIK3CG, PIM1, ......13