Disease relevance of TBC1D4

• Transcription levels of the gene KIAA0603/AS160 in CD3(+) cells from patients with atopic dermatitis (AD) were significantly higher than in normal individuals [1].

High impact information on TBC1D4

• We therefore examined if these signaling pathways engage AS160 to regulate GLUT4 traffic in muscle cells [2].
• Insulin-dependent phosphorylation of Akt target AS160 is required for GLUT4 translocation [2].
• Stimuli that activate c/n PKC or AMPK also elevated AS160 phosphorylation [2].
• RK-AS160 (GTPase-activating protein [GAP] inactive) or 4PRK-AS160 (GAP inactive, nonphosphorylatable) had no effect on surface GLUT4myc elicited by all stimuli [2].
• In conclusion, AS160 and filamin A may provide an important link to mediate endurance exercise-induced bioeffects in skeletal muscle [3].

Biological context of TBC1D4

• Several exercise-responsive phosphoproteins were detected by immunoblot analysis with a phospho-Akt substrate antibody. pp160 and pp300 were identified as AS160 and filamin A, respectively, with increased phosphorylation (2.0- and 4.9-fold, respectively; P < 0.05) after endurance but not resistance exercise [3].
• Introduction of a constitutive 14-3-3 binding site into AS160(4P) restored 14-3-3 binding without disrupting AS160-IRAP (insulin-responsive amino peptidase) interaction and reversed the inhibitory effect of AS160(4P) on GLUT4 translocation [4].

Anatomical context of TBC1D4

• Expression of KIAA0603 in T cells may be involved in pathogenesis of AD [1].
• These data show that the insulin-dependent association of 14-3-3 with AS160 plays an important role in GLUT4 trafficking in adipocytes [4].
• The coordinated action of phosphatidylinositol 3-kinase effectors, protein kinase Akt, atypical protein kinase C (aPKC) and Akt substrate of 160-kDa (AS160), regulates the GLUT4 cycle by affecting its translocation, fusion with the plasma membrane, internalization and sorting [5].

Associations of TBC1D4 with chemical compounds

• The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation [6].
• The KIAA0603 gene encodes a 1299 amino acid protein with two phosphotyrosine interaction domains at the N-terminal region and a TBC domain at the C-terminal region [1].
• These proteins, Tbc1d4 (also known as AS160) and now Tbc1d1, as reported in this issue of the Biochemical Journal, have been demonstrated to be Rab GAPs (GTPase-activating proteins) that link upstream to Akt (protein kinase B) and phosphoinositide 3-kinase and downstream to Rabs involved in trafficking of GLUT4 vesicles [7].
• Interaction of the Akt Substrate, AS160, with the Glucose Transporter 4 Vesicle Marker Protein, Insulin-Regulated Aminopeptidase [8].
• AS160 phosphorylation and glucose transport were positively correlated in control subjects (R(2) = 0.97, P = 0.01) but not relatives (R(2) = 0.46, P = 0.32). mRNA of key transcriptional factors and coregulators of mitochondrial biogenesis were also determined [9].

Physical interactions of TBC1D4

• In addition, we demonstrate that the IRAP-binding domain of AS160 falls within its second phosphotyrosine-binding domain and the interaction is not regulated by AS160 phosphorylation [8].
• In conclusion, the uncoupling of insulin action on Akt/AS160 signaling and glucose transport implicates defective GLUT4 trafficking as an early event in the pathogenesis of type 2 diabetes [9].

Regulatory relationships of TBC1D4

• Rabs 8A and 14 are targets of the insulin-regulated Rab-GAP AS160 regulating GLUT4 traffic in muscle cells [10].

Other interactions of TBC1D4

• PDGF and insulin increased AS160 phosphorylation in CHO-IR cells [2].
• The RabGAP (Rab GTPase-activating protein) AS160 (Akt substrate of 160 kDa) is a direct substrate of Akt and plays an essential role in the regulation of GLUT4 trafficking [4].
• These results suggest that Rab8A and possibly Rab14 may be targets of AS160 leading to GLUT4 translocation in L6 muscle cells [10].
• Nor do we know which protein substrates are responsible for mediating the effects of protein kinase B, although two recently identified proteins (AS160 and PIKfyve) may play a role [11].

Analytical, diagnostic and therapeutic context of TBC1D4

• We have used liquid chromatography tandem mass spectrometry to identify several 14-3-3 isoforms as AS160-interacting proteins [4].
• Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients [12].

References