GAK (Cyclin G Associated Kinase)
A key regulator of clathrin-mediated endocytosis and cell cycle progression
Gene Information Card
| Symbol | GAK |
|---|---|
| Full Name | Cyclin G Associated Kinase |
| Gene Type | Protein coding |
| Chromosomal Location | 4p16.3 |
| NCBI Gene ID | 2580 ncbi.nlm.nih.gov/gene/2580 |
| Ensembl ID | ENSG00000178950 |
| UniProt ID | O14976 |
| OMIM ID | 602052 |
| HGNC ID | 4113 |
| Aliases | AUX1, DNAJC26, FLJ10671, FLJ22579, FLJ31874, MGC99654 |
Description
The GAK gene encodes cyclin G associated kinase, a serine/threonine kinase that plays a critical role in clathrin-mediated endocytosis by acting as a co-chaperone for Hsc70. GAK is also involved in cell cycle regulation through its interaction with cyclin G and CDK5. Mutations in GAK have been associated with Parkinson disease and cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Parkinson disease 17 (PARK17) | Impaired clathrin-mediated endocytosis due to GAK loss-of-function variants leads to defective synaptic vesicle recycling and dopaminergic neuron degeneration. | ClinVar, OMIM |
| Breast cancer | GAK overexpression promotes cell proliferation and migration; knockdown reduces tumor growth in vitro. | COSMIC, NCBI |
| Lung cancer | Somatic mutations in GAK (e.g., missense, nonsense) are found in lung adenocarcinoma, potentially affecting endocytic trafficking. | COSMIC |
| Hepatocellular carcinoma | GAK upregulation correlates with poor prognosis; silencing GAK induces apoptosis in liver cancer cell lines. | NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Testis | 10.8 | Medium |
| Lung | 8.2 | Low |
| Liver | 6.1 | Low |
| Heart | 5.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 14.3 | High expression |
| HeLa | 11.2 | Medium expression |
| A549 | 9.7 | Medium expression |
| MCF7 | 8.5 | Low expression |
| HepG2 | 7.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1195C>T (p.Arg399Trp) | Missense | 0.001% (gnomAD) | Impaired kinase activity; associated with Parkinson disease |
| c.1558G>A (p.Val520Met) | Missense | 0.0005% (gnomAD) | Reduced clathrin binding; risk factor for Parkinson disease |
| c.1720C>T (p.Arg574*) | Nonsense | <0.0001% | Loss of function; found in lung cancer (COSMIC) |
| c.2023_2024insA (p.Thr675Asnfs*2) | Frameshift | <0.0001% | Loss of function; observed in breast cancer (COSMIC) |
Mutation functional classification
Loss of Function (LOF)
Missense and nonsense mutations in the kinase domain or J-domain impair GAK's ability to uncoat clathrin-coated vesicles, leading to defective endocytosis and synaptic dysfunction.
Gain of Function (GOF)
Not well characterized; overexpression in cancer suggests possible oncogenic gain-of-function through enhanced cell cycle progression.
Dominant Negative (DN)
Some missense variants (e.g., p.Arg399Trp) may act in a dominant-negative manner by competing with wild-type GAK for binding partners, disrupting endocytosis.
View complete mutation data：
Gene Ontology (GO)
| • clathrin-coated vesicle uncoating | • protein phosphorylation |
| • cell cycle | • kinase activity |
| • ATP binding | • chaperone cofactor-dependent protein refolding |
Pathways
• Clathrin-mediated endocytosis (KEGG hsa04144)
• Endocytosis (Reactome R-HSA-199991)
• Cell cycle (Reactome R-HSA-1640170)
Protein Summary
GAK (cyclin G associated kinase) is a 160 kDa protein containing an N-terminal serine/threonine kinase domain, a central J-domain (DnaJ) that recruits Hsc70, and a C-terminal clathrin-binding domain. It functions as an auxilin-like co-chaperone essential for uncoating clathrin-coated vesicles during endocytosis. GAK also phosphorylates cyclin G and interacts with CDK5, linking endocytosis to cell cycle control. The protein is ubiquitously expressed, with highest levels in brain and testis.
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