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Molecular and Cellular Biology, October 2002, p. 6959-6970, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.6959-6970.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Adapter Protein ZIP Binds Grb14 and Regulates Its Inhibitory Action on Insulin Signaling by Recruiting Protein Kinase C{zeta}

Bertrand Cariou,1 Dominique Perdereau,1 Katia Cailliau,2 Edith Browaeys-Poly,2 Véronique Béréziat,1 Mireille Vasseur-Cognet,3 Jean Girard,1 and Anne-Françoise Burnol1*

Département d'Endocrinologie,1 Département de Génétique, Développement et Pathologie Moléculaire Institut Cochin, CNRS-INSERM-Université René Descartes 75674 Paris,3 Laboratoire de Biologie du Développement, UE 1033, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq Cedex, France2

Received 22 April 2002/ Returned for modification 20 May 2002/ Accepted 8 July 2002

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 C{zeta} (PKC{zeta}) interacting protein, ZIP, interacted with Grb14. Coimmunoprecipitation experiments demonstrated that ZIP bound to both Grb14 and PKC{zeta}, thereby acting as a link in the assembly of a PKC{zeta}-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. PKC{zeta} 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 PKC{zeta}-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 PKC{zeta}. Interestingly, the phosphorylation of Grb14 by PKC{zeta} 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 PKC{zeta} and the phosphorylation of Grb14, providing in vivo evidences for a regulation of Grb14-inhibitory action by ZIP and PKC{zeta}. Together, these results suggest that Grb14, ZIP, and PKC{zeta} participate in a new feedback pathway of insulin signaling.

* Corresponding author. Mailing address: Institut Cochin, CNRS-INSERM-Université René Descartes, Département d'Endocrinologie, 24 rue du Faubourg Saint-Jacques, 75674 Paris, France. Phone: 33 1 53 73 27 09. Fax: 33 1 53 73 27 03. E-mail: burnol{at}cochin.inserm.fr.

Molecular and Cellular Biology, October 2002, p. 6959-6970, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.6959-6970.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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