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Molecular and Cellular Biology, March 2009, p. 1459-1471, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.00754-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

ClipR-59 Interacts with Akt and Regulates Akt Cellular Compartmentalization{triangledown}

Jixin Ding and Keyong Du*

Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111

Received 9 May 2008/ Returned for modification 7 July 2008/ Accepted 30 December 2008

Akt is activated on the plasma membrane and its substrates are distributed throughout various cellular compartments. To phosphorylate its substrates, Akt needs to be recruited to specific intracellular compartments. Thus, regulation of Akt cellular compartmentalization constitutes an important mechanism to specify Akt signaling. Here, we report the identification of ClipR-59 as an Akt interaction protein. We show that the interaction of ClipR-59 with Akt is mediated by the CAP-Gly domain of ClipR-59 and kinase domain of Akt and is regulated by Akt phosphorylation. We demonstrate that ClipR-59 regulates the Akt membrane association through its interaction with Akt and membrane localization and, by modulating Akt cellular compartmentalization, differentially modulates phosphorylation of Akt substrates in adipocytes. Finally, we provide evidence that one of the Akt substrates whose phosphorylation is upregulated by ClipR-59 is AS160, a negative regulator of adipocyte glucose transport. Accordingly, ectopic expression of ClipR-59 enhances, whereas knockdown of ClipR-59 suppresses, adipocyte glucose transport. We suggest that ClipR-59 functions as a scaffold protein that interacts with phospho-Akt and recruits active Akt on the membrane and may play an important role in adipocyte glucose transport.

* Corresponding author. Mailing address: Molecular Oncology Research Institutes, Tufts Medical Center, Boston, MA 02111. Phone: (617) 636-6476. Fax: (617) 636-6127. E-mail: kdu{at}tufts-nemc.org

{triangledown} Published ahead of print on 12 January 2009.

Molecular and Cellular Biology, March 2009, p. 1459-1471, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.00754-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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