QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 15, Issue 12, 5538-5550, December 2004

This Article Full Text Full Text (PDF) All Versions of this Article: E04-06-0446v1 15/12/5538    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, B. Articles by Farquhar, M. G. Search for Related Content PubMed PubMed Citation Articles by Zheng, B. Articles by Farquhar, M. G.

Regulation of Epidermal Growth Factor Receptor Degradation by Heterotrimeric Gs Protein

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

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

Submitted June 3, 2004; Revised September 15, 2004; Accepted September 17, 2004
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 (Gs) promotes ligand-dependent degradation of epidermal growth factor (EGF) receptors and Texas Red EGF, and knock-down of Gs expression by RNA interference (RNAi) delays receptor degradation. We also show that Gs 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. Gs coimmunoprecipitates with Hrs and binds Hrs in pull-down assays. By immunofluorescence, exogenously expressed Gs colocalizes with myc-Hrs and GFP-RGS-PX1 on early endosomes, and expression of either Hrs or RGS-PX1 increases the localization of Gs on endosomes. Furthermore, knock-down of both Hrs and Gs by double RNAi causes greater inhibition of EGF receptor degradation than knock-down of either protein alone, suggesting that Gs and Hrs have cooperative effects on regulating EGF receptor degradation. These observations define a novel regulatory role for Gs in EGF receptor degradation and provide mechanistic insights into the function of Gs in endocytic sorting.

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.

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

This article has been cited by other articles:

				P. Ghosh, M. Garcia-Marcos, S. J. Bornheimer, and M. G. Farquhar Activation of G{alpha}i3 triggers cell migration via regulation of GIV J. Cell Biol., July 28, 2008; 182(2): 381 - 393. [Abstract] [Full Text] [PDF]

				C. M. Peres, D. M. Aronoff, C. H. Serezani, N. Flamand, L. H. Faccioli, and M. Peters-Golden Specific Leukotriene Receptors Couple to Distinct G Proteins to Effect Stimulation of Alveolar Macrophage Host Defense Functions J. Immunol., October 15, 2007; 179(8): 5454 - 5461. [Abstract] [Full Text] [PDF]

				C. Kong, X. Su, P.-I Chen, and P. D. Stahl Rin1 Interacts with Signal-transducing Adaptor Molecule (STAM) and Mediates Epidermal Growth Factor Receptor Trafficking and Degradation J. Biol. Chem., May 18, 2007; 282(20): 15294 - 15301. [Abstract] [Full Text] [PDF]

				T. Stasyk, N. Schiefermeier, S. Skvortsov, H. Zwierzina, J. Peranen, G. K. Bonn, and L. A. Huber Identification of Endosomal Epidermal Growth Factor Receptor Signaling Targets by Functional Organelle Proteomics Mol. Cell. Proteomics, May 1, 2007; 6(5): 908 - 922. [Abstract] [Full Text] [PDF]

				D. E. Nethery, S. Ghosh, S. C. Erzurum, and J. A. Kern Inactivation of neuregulin-1 by nitration Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L287 - L293. [Abstract] [Full Text] [PDF]

				J. Ren, Y. Kee, J. M. Huibregtse, and R. C. Piper Hse1, a Component of the Yeast Hrs-STAM Ubiquitin-sorting Complex, Associates with Ubiquitin Peptidases and a Ligase to Control Sorting Efficiency into Multivesicular Bodies Mol. Biol. Cell, January 1, 2007; 18(1): 324 - 335. [Abstract] [Full Text] [PDF]

				B. Zheng, T. Tang, N. Tang, K. Kudlicka, K. Ohtsubo, P. Ma, J. D. Marth, M. G. Farquhar, and E. Lehtonen Essential role of RGS-PX1/sorting nexin 13 in mouse development and regulation of endocytosis dynamics PNAS, November 7, 2006; 103(45): 16776 - 16781. [Abstract] [Full Text] [PDF]

				H. Le-Niculescu, I. Niesman, T. Fischer, L. DeVries, and M. G. Farquhar Identification and Characterization of GIV, a Novel G{alpha}i/s -interacting Protein Found on COPI, Endoplasmic Reticulum-Golgi Transport Vesicles J. Biol. Chem., June 10, 2005; 280(23): 22012 - 22020. [Abstract] [Full Text] [PDF]

				J. A. Allen, J. Z. Yu, R. J. Donati, and M. M. Rasenick {beta}-Adrenergic Receptor Stimulation Promotes G{alpha}s Internalization through Lipid Rafts: A Study in Living Cells Mol. Pharmacol., May 1, 2005; 67(5): 1493 - 1504. [Abstract] [Full Text] [PDF]