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Gene Review

TBC1D4  -  TBC1 domain family, member 4

Homo sapiens

Synonyms: AS160, Akt substrate of 160 kDa, DKFZp779C0666, KIAA0603, NIDDM5, ...
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Disease relevance of TBC1D4


High impact information on TBC1D4


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


Other interactions of TBC1D4


Analytical, diagnostic and therapeutic context of TBC1D4


  1. Upregulation of the transcript level of GTPase activating protein KIAA0603 in T cells from patients with atopic dermatitis. Matsumoto, Y., Imai, Y., Lu Yoshida, N., Sugita, Y., Tanaka, T., Tsujimoto, G., Saito, H., Oshida, T. FEBS Lett. (2004) [Pubmed]
  2. The Rab GTPase-Activating Protein AS160 Integrates Akt, Protein Kinase C, and AMP-Activated Protein Kinase Signals Regulating GLUT4 Traffic. Thong, F.S., Bilan, P.J., Klip, A. Diabetes (2007) [Pubmed]
  3. Exercise-Induced Phosphorylation of the Novel Akt Substrates AS160 and Filamin A in Human Skeletal Muscle. Deshmukh, A., Coffey, V.G., Zhong, Z., Chibalin, A.V., Hawley, J.A., Zierath, J.R. Diabetes (2006) [Pubmed]
  4. A Role for 14-3-3 in Insulin-stimulated GLUT4 Translocation through Its Interaction with the RabGAP AS160. Ramm, G., Larance, M., Guilhaus, M., James, D.E. J. Biol. Chem. (2006) [Pubmed]
  5. Glucose transporter 4: cycling, compartments and controversies. Dugani, C.B., Klip, A. EMBO Rep. (2005) [Pubmed]
  6. Interleukin-1{beta}-Induced Insulin Resistance in Adipocytes through Down-Regulation of Insulin Receptor Substrate-1 Expression. Jager, J., Gr??meaux, T., Cormont, M., Le Marchand-Brustel, Y., Tanti, J.F. Endocrinology (2007) [Pubmed]
  7. Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways. Koumanov, F., Holman, G.D. Biochem. J. (2007) [Pubmed]
  8. Interaction of the Akt Substrate, AS160, with the Glucose Transporter 4 Vesicle Marker Protein, Insulin-Regulated Aminopeptidase. Peck, G.R., Ye, S., Pham, V., Fernando, R.N., Macaulay, S.L., Chai, S.Y., Albiston, A.L. Mol. Endocrinol. (2006) [Pubmed]
  9. Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients. Karlsson, H.K., Ahlsén, M., Zierath, J.R., Wallberg-Henriksson, H., Koistinen, H.A. Diabetes (2006) [Pubmed]
  10. Rabs 8A and 14 are targets of the insulin-regulated Rab-GAP AS160 regulating GLUT4 traffic in muscle cells. Ishikura, S., Bilan, P.J., Klip, A. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  11. Role of protein kinase B in insulin-regulated glucose uptake. Welsh, G.I., Hers, I., Berwick, D.C., Dell, G., Wherlock, M., Birkin, R., Leney, S., Tavaré, J.M. Biochem. Soc. Trans. (2005) [Pubmed]
  12. IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients. Bouzakri, K., Karlsson, H.K., Vestergaard, H., Madsbad, S., Christiansen, E., Zierath, J.R. Diabetes (2006) [Pubmed]
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