Cyclin G-associated kinase (GAK)

Cyclin G-associated kinase (GAK) is a multifunctional serine/threonine kinase that is a member of the numb-associated kinase (NAK) family and encoded by the GAK gene in humans[1][2][3][5]. It serves as a critical regulator of clathrin-mediated vesicle trafficking by acting as a cofactor for heat shock cognate 70 (Hsc70) in the uncoating of clathrin-coated vesicles—a process essential for receptor recycling and intracellular signaling[4][5][7]. GAK phosphorylates the μ chain of clathrin adaptor proteins AP1 and AP2 and mediates vesicle trafficking not only at the plasma membrane but also at the trans-Golgi network[7]. In addition to its cytoplasmic role, GAK is crucial for mitotic progression through regulation of centrosome maturation and spindle assembly, and its loss leads to severe defects in embryonic and adult tissue viability[5][7]. GAK is also associated with disease: risk variants near its gene locus are linked to Parkinson’s disease, and its inhibition is a key safety concern in kinase inhibitor therapy, especially in lung cancer treatment with EGFR inhibitors such as gefitinib[2][5].

Other names

GAKDnaJ homolog subfamily C member 26DNAJC26Auxilin-22.7.11.1 (Enzyme Commission number)

Kinase inhibition (ATP-competitive inhibition) Inhibition of clathrin-mediated endocytosis by blocking vesicle uncoating and signaling protein trafficking