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

Vol. 15, Issue 7, 3464-3474, July 2004

This Article Full Text Full Text (PDF) All Versions of this Article: E03-10-0753v1 15/7/3464    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 Bennasroune, A. Articles by Hubert, P. Search for Related Content PubMed PubMed Citation Articles by Bennasroune, A. Articles by Hubert, P.

Transmembrane Peptides as Inhibitors of ErbB Receptor Signaling

Amar Bennasroune ^*, Maria Fickova , Anne Gardin ^* , Sylvie Dirrig-Grosch ^*, Dominique Aunis ^*, Gérard Crémel ^*, and Pierre Hubert ^* 

^* Institut National de la Santé et de la Recherche Médicale Unit 575, and Université Louis Pasteur, 67084 Strasbourg, France; Institute of Experimental Endocrinology, Slovak Academy of Sciences, 833 06 Bratislava, Slovak Republic

Submitted October 22, 2003; Revised April 23, 2004; Accepted May 3, 2004
Monitoring Editor: Guido Guidotti

Receptor tyrosine kinases have a single transmembrane (TM) segment that is usually assumed to play a passive role in ligand-induced dimerization and activation of the receptor. However, mutations within some of these receptors, and recent studies with the epidermal growth factor (EGF) and ErbB2 receptors have indicated that interactions between TM domains do contribute to stabilization of ligand-independent and/or ligand-induced receptor dimerization and activation. One consequence of the importance of these interactions is that short hydrophobic peptides corresponding to these domains should act as specific inhibitors. To test this hypothesis, we constructed expression vectors encoding short fusion peptides encompassing native or mutated TM domains of the EGF, ErbB2, and insulin receptors. In human cell lines overexpressing the wild-type EGF receptor or ErbB2, we observed that the peptides are expressed at the cell surface and that they inhibit specifically the autophosphorylation and signaling pathway of their cognate receptor. Identical results were obtained with peptides chemically synthesized. Mechanism of action involves inhibition of dimerization of the receptors as shown by the lack of effects of mutant nondimerizing sequences, completed by density centrifugation and covalent cross-linking experiments. Our findings stress the role of TM domain interactions in ErbB receptor function, and possibly for other single-spanning membrane proteins.

Abbreviations used: EGF(R), epidermal growth factor (receptor); ET, extracellular tag; RTK, receptor tyrosine kinase; TM, transmembrane.

Present address: Novartis Pharma AG, Clinical Pharmacology Department, Lichtstrasse 35, CH-4056 Basel, Switzerland.

Corresponding author. E-mail address: hubert{at}neurochem.u-strasbg.fr.

This article has been cited by other articles:

				D. Dell'Era Dosch and K. Ballmer-Hofer Transmembrane domain-mediated orientation of receptor monomers in active VEGFR-2 dimers FASEB J, January 1, 2010; 24(1): 32 - 38. [Abstract] [Full Text] [PDF]

				C. Finger, C. Escher, and D. Schneider The Single Transmembrane Domains of Human Receptor Tyrosine Kinases Encode Self-Interactions Sci. Signal., September 22, 2009; 2(89): ra56 - ra56. [Abstract] [Full Text] [PDF]

				R. Muller, A. Bleckmann, and R. Simon The Receptor Kinase CORYNE of Arabidopsis Transmits the Stem Cell-Limiting Signal CLAVATA3 Independently of CLAVATA1 PLANT CELL, April 1, 2008; 20(4): 934 - 946. [Abstract] [Full Text] [PDF]

				E. V. Bocharov, K. S. Mineev, P. E. Volynsky, Y. S. Ermolyuk, E. N. Tkach, A. G. Sobol, V. V. Chupin, M. P. Kirpichnikov, R. G. Efremov, and A. S. Arseniev Spatial Structure of the Dimeric Transmembrane Domain of the Growth Factor Receptor ErbB2 Presumably Corresponding to the Receptor Active State J. Biol. Chem., March 14, 2008; 283(11): 6950 - 6956. [Abstract] [Full Text] [PDF]

				L. Roth, C. Nasarre, S. Dirrig-Grosch, D. Aunis, G. Cremel, P. Hubert, and D. Bagnard Transmembrane Domain Interactions Control Biological Functions of Neuropilin-1 Mol. Biol. Cell, February 1, 2008; 19(2): 646 - 654. [Abstract] [Full Text] [PDF]

				J. W. B. de Groot, T. P. Links, J. T. M. Plukker, C. J. M. Lips, and R. M. W. Hofstra RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors Endocr. Rev., August 1, 2006; 27(5): 535 - 560. [Abstract] [Full Text] [PDF]

				V. T. Marchesi An alternative interpretation of the amyloid A{beta} hypothesis with regard to the pathogenesis of Alzheimer's disease PNAS, June 28, 2005; 102(26): 9093 - 9098. [Abstract] [Full Text] [PDF]

				L. K. Fritz-Laylin, N. Krishnamurthy, M. Tor, K. V. Sjolander, and J. D.G. Jones Phylogenomic Analysis of the Receptor-Like Proteins of Rice and Arabidopsis Plant Physiology, June 1, 2005; 138(2): 611 - 623. [Abstract] [Full Text] [PDF]