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Mol. Biol. Cell 15 (12): 5538-5550

Copyright © 2004 by The American Society for Cell Biology.

Regulation of Epidermal Growth Factor 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

Received for publication June 3, 2004. Revision received September 15, 2004. Accepted for publication September 17, 2004.

Monitoring Editor: Juan S. Bonifacino

Abstract: 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 hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), 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, knock-down 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.

Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E04–06–0446. Article and publication date are available at–06–0446.

Abbreviations used: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ESCRT, endosomal sorting complexes required for transport; GAP, GTPase activating protein; GPCR, G protein-coupled receptor; Hrs, hepatocyte growth factor-regulated tyrosine kinase substrate; MVB, multivesicular body; PFA, paraformaldehyde; PX, phoX domain; RGS, regulator of G protein signaling; RNAi, RNA interference; siRNA, small-interfering RNA; SNX, sorting nexin.

* These authors contributed equally to this work.

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

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