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AS160 (Akt substrate of 160 kDa), which was originally known as TBC1 domain family member 4 (TBC1D4), is a Rab GTPase-activating protein that in humans is encoded by the TBC1D4gene.
The 160 kD protein product was first discovered in a screen for novel substrates of the serine-threonine kinase Akt2, which phosphorylates AS160 at Thr-642 and Ser-588 after insulin stimulation. Insulin stimulation of fat and muscle cells results in translocation of the glucose transporter GLUT4 to the plasma membrane, and this translocation process is dependent on phosphorylation of AS160. The role of AS160 in GLUT4 translocation is mediated by its GTPase activating domain and interactions with Rab proteins in vesicle formation, increasing GLUT4 translocation when its GTPase activity is inhibited by Akt phosphorylation. Specifically, this inhibition activates RAB2A, RAB8A, RAB10 and RAB14.
AS160 also contains a calmodulin-binding domain, and this domain mediates phosphorylation-independent glucose uptake in muscle cells.
Isoforms
The TBC1D4 gene has two isoforms - a long isoform expressed almost exclusively in skeletal and cardiac muscle, and a short isoform with more widespread expression.
Pathogenic mutations
A nonsense p.Arg684Ter variant in the TBC1D4 gene has been identified in the Greenlandic Inuit population that is associated with increased risk of type II diabetes. The variant mainly affects individuals with two copies of the mutation, indicating recessive inheritance. Although the mutation does not effect the short isoform of the protein, it introduces a premature stop codon in the long isoform, resulting in the absence of the long isoform protein in muscle tissue.
Homozygous carriers of the p.Arg684Ter allele have lower concentrations of fasting plasma glucose and insulin. They also have a markedly increased risk of Type II Diabetes — individuals with two mutant genes have about 10 times the chance of contracting Type II diabetes (odds ratio = 10.3) compared to noncarriers. Approximately 3.8% of Greenlanders are homozygous for the mutation, which is estimated to be responsible for approximately 10% of Type II Diabetes cases in Greenland.
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