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MBC in Press, published online ahead of print October 6, 2004
Mol. Biol. Cell 10.1091/mbc.E04-06-0446

A more recent version of this article appeared on December 1, 2004
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Submitted on June 3, 2004
Revised on September 15, 2004
Accepted on September 17, 2004

Regulation of EGF Receptor Degradation by Heterotrimeric G{alpha}s Protein

Bin Zheng,* Christine Lavoie,* Ting-Dong Tang, Phuong Ma, Timo Meerloo, Anthony Beas, and Marilyn G. Farquhar{dagger}

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651

Monitoring Editor: Juan S. Bonifacino

Heterotrimeric G proteins have been implicated in the regulation of membrane trafficking, but the mechanisms involved are not well understood. Here we report that overexpression of the stimulatory G protein subunit (G{alpha}s) promotes ligand-dependent degradation of epidermal growth factor (EGF) receptors and Texas Red-EGF, and knock-down of G{alpha}s expression by RNA interference (RNAi) delays receptor degradation. We also show that G{alpha}s and its GTPase activating protein (GAP), RGS-PX1, interact with Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), a critical component of the endosomal sorting machinery. G{alpha}s coimmunoprecipitates with Hrs and binds Hrs in pull-down assays. By immunofluorescence, exogenously expressed G{alpha}s colocalizes with myc-Hrs and GFP-RGS-PX1 on early endosomes, and expression of either Hrs or RGS-PX1 increases the localization of G{alpha}s on endosomes. Furthermore, knockdown of both Hrs and G{alpha}s by double RNAi causes greater inhibition of EGF receptor degradation than knock-down of either protein alone, suggesting that G{alpha}s and Hrs have cooperative effects on regulating EGF receptor degradation. These observations define a novel regulatory role for G{alpha}s in EGF receptor degradation and provide mechanistic insights into the function of G{alpha}s in endocytic sorting.

*These authors contributed equally to this work.

{dagger}Corresponding author. E-mail: mfarquhar{at}ucsd.edu






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