ZAP70 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the ZAP70 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | ZAP70 |
|---|---|
| Full Name | Zeta-chain (TCR) associated protein kinase 70kDa |
| Gene Type | Protein coding |
| Chromosomal Location | 2q12.1 |
| NCBI Gene ID | 7535 ncbi.nlm.nih.gov/gene/7535 |
| Ensembl ID | ENSG00000115085 |
| UniProt ID | P43403 |
| OMIM ID | 176947 |
| HGNC ID | 12858 |
| Aliases | SRK, STD, ZAP-70, ImD35 |
Description
The ZAP70 gene encodes a tyrosine kinase that is essential for T cell receptor (TCR) signaling. It is primarily expressed in T cells and natural killer (NK) cells. Upon TCR engagement, ZAP70 is recruited to the phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3-zeta chain, where it becomes activated and phosphorylates downstream adaptor proteins, leading to T cell activation, proliferation, and differentiation. Mutations in ZAP70 cause a form of severe combined immunodeficiency (SCID) characterized by CD8+ T cell deficiency. Additionally, ZAP70 expression is used as a prognostic marker in chronic lymphocytic leukemia (CLL).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Severe combined immunodeficiency (SCID) due to ZAP70 deficiency | Loss-of-function mutations in ZAP70 impair TCR signaling, leading to defective T cell development and function, particularly affecting CD8+ T cells. | OMIM #176947; ClinVar |
| Chronic lymphocytic leukemia (CLL) | High ZAP70 expression in CLL cells correlates with unmutated immunoglobulin heavy-chain variable (IGHV) genes and poor prognosis, though the exact mechanism is not fully understood. | Multiple studies; ClinVar |
| Autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease) | ZAP70 polymorphisms may influence T cell reactivity and contribute to autoimmunity. | GWAS studies; ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Spleen | 12.6 | Medium |
| Lymph node | 11.2 | Medium |
| Blood | 10.5 | Medium |
| Bone marrow | 8.3 | Low |
| Thymus | 7.9 | Low |
| Lung | 1.2 | Not detected |
| Liver | 0.8 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Jurkat (T cell leukemia) | 15.3 | High expression; used as model for TCR signaling |
| MOLT-4 (T cell leukemia) | 14.1 | High expression |
| K-562 (CML) | 2.5 | Low expression |
| HeLa (cervical carcinoma) | 0.9 | Not detected |
| A549 (lung carcinoma) | 0.5 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1624C>T (p.Arg542Ter) | Nonsense | Rare | Loss-of-function; causes SCID |
| c.1422_1423del (p.Glu474AspfsTer26) | Frameshift | Rare | Loss-of-function; causes SCID |
| c.979G>A (p.Asp327Asn) | Missense | Rare | Loss-of-function; impairs kinase activity |
| c.1045C>T (p.Arg349Trp) | Missense | Rare | Loss-of-function; impairs kinase activity |
| c.1558C>T (p.Arg520Trp) | Missense | Rare | Loss-of-function; impairs kinase activity |
Mutation functional classification
Loss of Function (LOF)
Most ZAP70 mutations are loss-of-function, leading to SCID. These mutations impair kinase activity, protein stability, or recruitment to the TCR complex.
Gain of Function (GOF)
Gain-of-function mutations are rare and not well-documented. Some somatic mutations in CLL may lead to increased signaling, but evidence is limited.
Dominant Negative (DN)
Dominant-negative effects have been suggested for some missense mutations that retain binding but lack kinase activity, interfering with wild-type function.
View complete mutation data：
Gene Ontology (GO)
| • protein tyrosine kinase activity | • ATP binding |
| • T cell receptor signaling pathway | • signal transduction |
| • immune response | • cell proliferation |
| • apoptotic process | • positive regulation of T cell activation |
Pathways
• T cell receptor signaling pathway (KEGG hsa04660)
• Natural killer cell mediated cytotoxicity (KEGG hsa04650)
• PD-1 signaling
• Fc epsilon RI signaling pathway
Protein Summary
ZAP70 is a 70 kDa cytoplasmic tyrosine kinase composed of two SH2 domains and a C-terminal kinase domain. It is critical for T cell activation. Upon TCR stimulation, ZAP70 binds to phosphorylated ITAMs on CD3-zeta via its SH2 domains, becomes phosphorylated by Lck, and then phosphorylates downstream substrates such as LAT and SLP-76, leading to calcium mobilization, transcription factor activation, and cytoskeletal reorganization. ZAP70 also plays a role in B cell development and NK cell function. Its expression is tightly regulated in T cells, and aberrant expression in CLL is a prognostic biomarker.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ZAP70 Knockout HEK293 Cell Line | EDJ-KQ605 | Human | 7535 | Details Get a Quote |
| ZAP70 Knockout HeLa Cell Line | EDJ-KQ54762 | Human | 7535 | Details Get a Quote |
| ZAP70 Knockout A-549 Cell Line | EDJ-KQ63256 | Human | 7535 | Details Get a Quote |
| ZAP70 Knockout HCT 116 Cell Line | EDJ-KQ71721 | Human | 7535 | Details Get a Quote |
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