TBC1 domain family member 4; Akt substrate of 160 kD (AS160, TBC1D4, KIAA0603)
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Function
- GTPase activating protein for Rab family proteins
- phosphorylated by AKT1, insulin-induced
- isoform 2 promotes insulin-induced glucose transporter SLC2A4/GLUT4 translocation at the plasma membrane, thus increasing glucose uptake
- insulin-stimulated phosphorylation required for GLUT4 translocation
- has no effect on GLUT4 internalization
- physiologic hyperinsulinemia increases phosphorylation in skeletal muscle
- insulin-stimulated phosphorylation is reduced by 40% in type 2 diabetic patients
- subcellular redistribution from low density microsomes to the cytosol with insulin treatment
Structure
- contains 2 PID domains
- contains 1 Rab-GAP TBC domain
Compartment
- cytoplasm
- isoform 2 shows a cytoplasmic perinuclear localization in a myoblastic cell line in resting & insulin-stimulated cells
Alternative splicing
named isoforms=5
Expression
- widely expressed
- isoform 2 with highest expreession in most tissues
- expressed in adrenal, thyroid gland, lung, kidney, colon, brain & adipose tissue > skeletal muscle
- isoform 1 is highly expressed in skeletal muscle & heart
- not detectable in the liver or adipose tissue
- expressed in pancreatic islets, including beta cells (at protein level).
- expressed in heart, skeletal muscle, immune tissues (spleen, lymph node, leukocytes)
Pathology
- expression is decreased by twofold in pancreatic islets in type 2 diabetes patients compared to control subjects
- defects in TBC1D4 associated with NIDDM5 (diabetes mellitus, non-insulin-dependent, 5)[2]
- up-regulated in T-cells from patients with atopic dermatitis