Affiliation:
1. Département d'Endocrinologie
2. Laboratoire de Biologie du Développement, UE 1033, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq Cedex, France
3. Département de Génétique, Développement et Pathologie Moléculaire Institut Cochin, CNRS-INSERM-Université René Descartes 75674 Paris
Abstract
ABSTRACT
Grb14 is a member of the Grb7 family of adapters and acts as a negative regulator of insulin-mediated signaling. Here we found that the protein kinase Cζ (PKCζ) interacting protein, ZIP, interacted with Grb14. Coimmunoprecipitation experiments demonstrated that ZIP bound to both Grb14 and PKCζ, thereby acting as a link in the assembly of a PKCζ-ZIP-Grb14 heterotrimeric complex. Mapping studies indicated that ZIP interacted through its ZZ zinc finger domain with the phosphorylated insulin receptor interacting region (PIR) of Grb14. PKCζ phosphorylated Grb14 under in vitro conditions and in CHO-IR cells as demonstrated by in vivo labeling experiments. Furthermore, Grb14 phosphorylation was increased under insulin stimulation, suggesting that the PKCζ-ZIP-Grb14 complex is involved in insulin signaling. The PIR of Grb14, which also interacts with the catalytic domain of the insulin receptor (IR) and inhibits its activity, was preferentially phosphorylated by PKCζ. Interestingly, the phosphorylation of Grb14 by PKCζ increased its inhibitory effect on IR tyrosine kinase activity in vitro. The role of ZIP and Grb14 in insulin signaling was further investigated in vivo in
Xenopus laevis
oocytes. In this model, ZIP potentiated the inhibitory action of Grb14 on insulin-induced oocyte maturation. Importantly, this effect required the recruitment of PKCζ and the phosphorylation of Grb14, providing in vivo evidences for a regulation of Grb14-inhibitory action by ZIP and PKCζ. Together, these results suggest that Grb14, ZIP, and PKCζ participate in a new feedback pathway of insulin signaling.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Reference72 articles.
1. Bandyopadhyay, G., M. L. Standaert, U. Kikkawa, Y. Ono, J. Moscat, and R. V. Farese. 1999. Effect of transiently expressed atypical (zeta, lambda), conventional (alpha, beta) and novel (delta, epsilon) protein kinase C isoforms on insulin-stimulated translocation of epitope-tagged GLUT4 glucose transporters in rat adipocytes: specific interchangeable effects of protein kinase C-zeta and C-lambda. Biochem. J. 337 : 461-470.
2. Bereziat, V., A. Kasus-Jacobi, D. Perdereau, B. Cariou, J. Girard, and A. F. Burnol. 2002. Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14. J. Biol. Chem. 28 : 4845-4852.
3. Berra, E., M. T. Diaz-Meco, I. Dominguez, M. M. Municio, L. Sanz, J. Lozano, R. S. Chapkin, and J. Moscat. 1993. Protein kinase C zeta isoform is critical for mitogenic signal transduction. Cell 74 : 555-563.
4. Bossenmaier, B., L. Mosthaf, H. Mischak, A. Ullrich, and H. U. Haring. 1997. Protein kinase C isoforms beta 1 and beta 2 inhibit the tyrosine kinase activity of the insulin receptor. Diabetologia 40 : 863-866.
5. Activation of Protein Kinase Cζ Induces Serine Phosphorylation of VAMP2 in the GLUT4 Compartment and Increases Glucose Transport in Skeletal Muscle
Cited by
41 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献