HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 26, 23343-23351, June 27, 2003

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 278/26/23343    most recent M300477200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend 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 Hendriks, B. S. Articles by Lauffenburger, D. Search for Related Content PubMed PubMed Citation Articles by Hendriks, B. S. Articles by Lauffenburger, D. Social Bookmarking                      What's this?

Quantitative Analysis of HER2-mediated Effects on HER2 and Epidermal Growth Factor Receptor Endocytosis

DISTRIBUTION OF HOMO- AND HETERODIMERS DEPENDS ON RELATIVE HER2 LEVELS^*,

Bart S. Hendriks , Lee K. Opresko , H. Steven Wiley  and Douglas Lauffenburger  ¶ ||

From the Department of Chemical Engineering, the ^¶Department of Biology, Biological Engineering Division, and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and the Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352

Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR) family. Many cell types express multiple EGFR family members (including EGFR, HER2, HER3, and/or HER4) that interact to form an array of homo- and heterodimers. Differential trafficking of these receptors should strongly affect signaling through this system by changing substrate access and heterodimerization efficiency. Because of the complexity of these dynamic processes, we used a quantitative and computational model to understand their integrated operation. Parameters characterizing EGFR and HER2 interactions were determined using experimental data obtained from mammary epithelial cells constructed to express different levels of HER2, enabling us to estimate receptor-specific internalization rate constants and dimer uncoupling rate constants. Significant novel results obtained from this work are as follows: first, that EGFR homodimerization and EGFR/HER2 heterodimerization occur with comparable affinities; second, that EGFR/HER2 heterodimers traffic as single entities. Furthermore, model predictions of the relationship of HER2 expression levels to consequent distribution of EGFR homodimers and EGFR/HER2 heterodimers suggest that the levels of HER2 found on normal cells are barely at the threshold necessary to drive efficient heterodimerization. Thus, altering HER2 concentrations, either overall or local, could provide an effective mechanism for regulating EGFR/HER2 heterodimerization and may explain why HER2 overexpression found in some cancers has such a profound effect on cell physiology.

Received for publication, January 16, 2003 , and in revised form, April 2, 2003.

^* This work was supported by grants from the National Institutes of Health, the National Science Foundation, a graduate fellowship from the Whitaker Foundation (to B. S. H.), and by the United States Department of Energy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains the Appendix.

^|| To whom correspondence should be addressed: Massachusetts Institute of Technology, 56-341, Cambridge, MA 02139. Tel.: 617-252-1629; Fax: 617-258-0204; E-mail: lauffen{at}mit.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. R. Kumar, T. P. Quinn, and S. L. Deutscher Evaluation of an 111In-Radiolabeled Peptide as a Targeting and Imaging Agent for ErbB-2 Receptor Expressing Breast Carcinomas Clin. Cancer Res., October 15, 2007; 13(20): 6070 - 6079. [Abstract] [Full Text] [PDF]

				S. Yang, M. A. Raymond-Stintz, W. Ying, J. Zhang, D. S. Lidke, S. L. Steinberg, L. Williams, J. M. Oliver, and B. S. Wilson Mapping ErbB receptors on breast cancer cell membranes during signal transduction J. Cell Sci., August 15, 2007; 120(16): 2763 - 2773. [Abstract] [Full Text] [PDF]

				H. Shankaran, H. S. Wiley, and H. Resat Modeling the Effects of HER/ErbB1-3 Coexpression on Receptor Dimerization and Biological Response Biophys. J., June 1, 2006; 90(11): 3993 - 4009. [Abstract] [Full Text] [PDF]

				M. I. Monine, A. M. Berezhkovskii, E. J. Joslin, H. S. Wiley, D. A. Lauffenburger, and S. Y. Shvartsman Ligand Accumulation in Autocrine Cell Cultures Biophys. J., April 1, 2005; 88(4): 2384 - 2390. [Abstract] [Full Text] [PDF]

				B. S. Hendriks, G. Orr, A. Wells, H. S. Wiley, and D. A. Lauffenburger Parsing ERK Activation Reveals Quantitatively Equivalent Contributions from Epidermal Growth Factor Receptor and HER2 in Human Mammary Epithelial Cells J. Biol. Chem., February 18, 2005; 280(7): 6157 - 6169. [Abstract] [Full Text] [PDF]

				O. Tikhomirov and G. Carpenter Ligand-induced, p38-dependent Apoptosis in Cells Expressing High Levels of Epidermal Growth Factor Receptor and ErbB-2 J. Biol. Chem., March 26, 2004; 279(13): 12988 - 12996. [Abstract] [Full Text] [PDF]

				G. E. Konecny, C. A. Wilson, and D. J. Slamon Is There a Role for Epidermal Growth Factor Receptor Inhibitors in Breast Cancer Prevention? J Natl Cancer Inst, December 17, 2003; 95(24): 1813 - 1815. [Full Text] [PDF]

				B. S. Hendriks, H. S. Wiley, and D. Lauffenburger HER2-Mediated Effects on EGFR Endosomal Sorting: Analysis of Biophysical Mechanisms Biophys. J., October 1, 2003; 85(4): 2732 - 2745. [Abstract] [Full Text] [PDF]