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Am J Physiol Endocrinol Metab (January 24, 2006). doi:10.1152/ajpendo.00609.2005
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Submitted on December 2, 2005
Accepted on January 18, 2006

GRB10 MEDIATES INSULIN-STIMULATED DEGRADATION OF THE INSULIN RECEPTOR: A MECHANISM OF NEGATIVE REGULATION

Fresnida J Ramos1, Paul R Langlais2, Derong Hu1, Lily Q Dong3, and Feng Liu4*

1 Department of Pharmacology, Univerisity of Texas Health Science Center, San Antonio, TX, USA
2 Department of Biochemistry, Univerisity of Texas Health Science Center, San Antonio, TX, USA
3 Department of Pharmacology, Univerisity of Texas Health Science Center, San Antonio, TX, USA; Department of Cellular and Structural Biology, Univerisity of Texas Health Science Center, San Antonio, TX, USA; The Barshop Center for Longevity and Aging Studies, San Antonio, TX, USA
4 Department of Pharmacology, Univerisity of Texas Health Science Center, San Antonio, TX, USA; Department of Biochemistry, Univerisity of Texas Health Science Center, San Antonio, TX, USA; The Barshop Center for Longevity and Aging Studies, San Antonio, TX, USA

* To whom correspondence should be addressed. E-mail: liuf{at}uthscsa.edu.

Growth factor receptor bound protein 10 (Grb10) is an adapter protein that interacts with a number of tyrosine-phosphorylated growth factor receptors including the insulin receptor (IR). To investigate the role of Grb10 in insulin signaling, we generated cell lines in which the expression levels of Grb10 are either overexpressed by stable transfection or suppressed by RNAi. We found that suppressing endogenous Grb10 expression led to increased IR protein levels while overexpression of Grb10 led to reduced IR protein levels. Altering Grb10 expression levels had no effect on the mRNA levels of IR, suggesting that the modulation occurs at the protein level. Reduced IR levels were also observed in cells with prolonged insulin treatment and this reduction was inhibited in Grb10-deficient cells. The insulin-induced IR reduction was greatly reversed by MG-132, a proteasomal inhibitor, but not by chloroquine, a lysosomal inhibitor. IR underwent insulin-stimulated ubiquitination in cells and this ubiquitination was inhibited in the Grb10-suppressed cell line. Taken together, our results suggest that in addition to inhibiting IR kinase activity by directly binding to the IR, Grb10 also negatively regulates insulin signaling by mediating insulin-stimulated degradation of the receptor.




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