TBC1 domain family member 4 (TBC1D4)

TBC1 domain family member 4 (TBC1D4), commonly known as AS160 (Akt substrate of 160 kDa), is a Rab GTPase–activating protein that plays a critical role in the regulation of glucose uptake into cells. It acts downstream of the serine-threonine kinase Akt and is phosphorylated following insulin stimulation, particularly at residues Thr642 and Ser588. This phosphorylation event inhibits its GAP activity, which allows activation of Rab proteins involved in vesicle trafficking—specifically RAB2A, RAB8A, RAB10, and RAB14—leading to translocation of the glucose transporter GLUT4 from intracellular compartments to the plasma membrane. This process increases cellular glucose uptake after insulin stimulation. AS160 contains several functional domains including two phosphotyrosine-binding domains (PTB), a calmodulin-binding domain, multiple AKT phosphomotifs, and a Rab-GTPase domain. There are two main isoforms: one predominantly expressed in skeletal and cardiac muscle; another with broader tissue distribution. Pathogenic mutations—such as p.Arg684Ter found among Greenlandic Inuit—are associated with significantly increased risk for type II diabetes due to impaired GLUT4 translocation and reduced muscle glucose uptake capacity. In addition to its established roles in adipose tissue and skeletal muscle, AS160 also functions within pancreatic β-cells where it modulates insulin secretion dynamics and cell survival under metabolic stress conditions. Currently there are no approved drugs that directly target AS160/TBC1D4; however, it remains an important node within the insulin signaling network relevant for metabolic disease research.

Other names

AS160Akt substrate of 160 kDaNIDDM5KIAA0603DKFZp779C0666OTTHUMP00000040818RP11-159J2.1RP11-159J2.3