GAK (cyclin G-associated kinase) is a ubiquitously expressed 150-kDa protein that serves as the primary auxilin homolog for clathrin-coated vesicle uncoating in non-neuronal cells. It associates with cyclin G and CDK5, and its expression oscillates during the cell cycle, peaking at G1 phase. GAK contains three key functional domains: an N-terminal serine/threonine kinase domain, a tensin-like domain, a clathrin-binding domain, and a C-terminal J-domain that stimulates the Hsc70 ATPase. In clathrin-mediated endocytosis, GAK acts as a J-domain cofactor that enables Hsc70-dependent uncoating of clathrin-coated vesicles at the plasma membrane and trans-Golgi network 1. The clathrin-binding domain alone can induce clathrin polymerization, while combined with the J-domain it supports full uncoating activity 2. GAK also phosphorylates the medium chains of adaptor proteins AP-1 and AP-2 and binds their appendage domains, linking kinase function to endocytic machinery. Overexpression of GAK impairs receptor-mediated endocytosis by sequestering clathrin into cytoplasmic aggregates 3. GAK is associated with multiple disease phenotypes including cancer, Alzheimer disease, and various hematologic and skeletal abnormalities, though the molecular mechanisms linking GAK dysfunction to these conditions remain largely undefined.