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

J. Biol. Chem., Vol. 280, Issue 7, 6157-6169, February 18, 2005

This Article Full Text Full Text (PDF) Suplemental Data All Versions of this Article: 280/7/6157    most recent M410491200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hendriks, B. S. Articles by Lauffenburger, D. A. Search for Related Content PubMed PubMed Citation Articles by Hendriks, B. S. Articles by Lauffenburger, D. A. Social Bookmarking                      What's this?

Parsing ERK Activation Reveals Quantitatively Equivalent Contributions from Epidermal Growth Factor Receptor and HER2 in Human Mammary Epithelial Cells^*

Bart S. Hendriks, Gayla Orr, Alan Wells¶, H. Steven Wiley, and Douglas A. Lauffenburger||**

From the Department of Chemical Engineering and the ^||Department of Biology, Biological Engineering Division, and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, the ^¶Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and the Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352

HER2, a member of the epidermal growth factor receptor (EGFR) tyrosine kinase family, functions as an accessory EGFR signaling component and alters EGFR trafficking by heterodimerization. HER2 overexpression leads to aberrant cell behavior including enhanced proliferation and motility. Here we applied a combination of computational modeling and quantitative experimental studies of the dynamic interactions between EGFR and HER2 and their downstream activation of ERK to understand this complex signaling system. Using cells expressing different levels of HER2 relative to the EGFR, we could separate relative contributions of EGFR and HER2 to signaling amplitude and duration. Based on our model calculations, we demonstrated that, in contrast with previous suggestions in the literature, the intrinsic capabilities of EGFR and HER2 to activate ERK were quantitatively equivalent. We found that HER2-mediated effects on EGFR dimerization and trafficking were sufficient to explain the observed HER2-mediated amplification of epidermal growth factor-induced ERK signaling. Our model suggests that transient amplification of ERK activity by HER2 arises predominantly from the 2-to-1 stoichiometry of receptor kinase to bound ligand in EGFR/HER2 heterodimers compared with the 1-to-1 stoichiometry of the EGFR homodimer, but alterations in receptor trafficking yielding increased EGFR sparing cause the sustained HER2-mediated enhancement of ERK signaling.

Received for publication, September 13, 2004 , and in revised form, November 22, 2004.

^* This work was supported by National Institutes of Health Grants CA88865 and CA96504 (to D. A. L.), along with a Whitaker graduate fellowship (to B. S. H.). Part of this work was supported by Laboratory Directed Research and Development funds from the United States Department of Energy (to Pacific Northwest National Laboratory). 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 Supplemental Figs. S1-S3.

^** To whom correspondence should be addressed: Massachusetts Inst. 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:

				K. D. Rodland, N. Bollinger, D. Ippolito, L. K. Opresko, R. J. Coffey, R. Zangar, and H. S. Wiley Multiple Mechanisms Are Responsible for Transactivation of the Epidermal Growth Factor Receptor in Mammary Epithelial Cells J. Biol. Chem., November 14, 2008; 283(46): 31477 - 31487. [Abstract] [Full Text] [PDF]

				E. Behmoaram, K. Bijian, S. Jie, Y. Xu, A. Darnel, T. A. Bismar, and M. A. Alaoui-Jamali Focal Adhesion Kinase-Related Proline-Rich Tyrosine Kinase 2 and Focal Adhesion Kinase Are Co-Overexpressed in Early-Stage and Invasive ErbB-2-Positive Breast Cancer and Cooperate for Breast Cancer Cell Tumorigenesis and Invasiveness Am. J. Pathol., November 1, 2008; 173(5): 1540 - 1550. [Abstract] [Full Text] [PDF]

				R. J. Romanelli, A. P. LeBeau, C. G. Fulmer, D. A. Lazzarino, A. Hochberg, and T. L. Wood Insulin-like Growth Factor Type-I Receptor Internalization and Recycling Mediate the Sustained Phosphorylation of Akt J. Biol. Chem., August 3, 2007; 282(31): 22513 - 22524. [Abstract] [Full Text] [PDF]

				C. Tolg, S. R. Hamilton, K.-A. Nakrieko, F. Kooshesh, P. Walton, J. B. McCarthy, M. J. Bissell, and E. A. Turley Rhamm-/- fibroblasts are defective in CD44-mediated ERK1,2 motogenic signaling, leading to defective skin wound repair J. Cell Biol., December 18, 2006; 175(6): 1017 - 1028. [Abstract] [Full Text] [PDF]

				S. McLaughlin, S. O. Smith, M. J. Hayman, and D. Murray An Electrostatic Engine Model for Autoinhibition and Activation of the Epidermal Growth Factor Receptor (EGFR/ErbB) Family J. Gen. Physiol., June 27, 2005; 126(1): 41 - 53. [Abstract] [Full Text] [PDF]