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

J. Biol. Chem., Vol. 283, Issue 18, 12026-12033, May 2, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/18/12026    most recent M704592200v1 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 Abdulhussein, R. Articles by Vogel, W. F. Search for Related Content PubMed PubMed Citation Articles by Abdulhussein, R. Articles by Vogel, W. F. Social Bookmarking                      What's this?

Identification of Disulfide-linked Dimers of the Receptor Tyrosine Kinase DDR1^*

Rahim Abdulhussein¹, Diana H. H. Koo², and Wolfgang F. Vogel

From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Discoidin domain receptor 1 (DDR1) is a transmembrane receptor tyrosine kinase activated by triple-helical collagen. So far six different isoforms of DDR1 have been described. Aberrant expression and signaling of DDR1 have been implicated in several human diseases linked to accelerated matrix degradation and remodeling, including tumor invasion, atherosclerosis, and lung fibrosis. Here we show that DDR1 exists as a disulfide-linked dimer in transfected as well as endogenously expressing cells. This dimer formation occurred irrespective of its kinase domain, as dimers were also found for the truncated DDR1d isoform. A deletion analysis of the extracellular domain showed that DDR1 mutants lacking the stalk region failed to form dimers, whereas deletion of the discoidin domain did not prevent dimerization. Point mutagenesis within the stalk region suggested that cysteines 303 and 348 are necessary for dimerization, collagen binding, and activation of kinase function. The identification of DDR1 dimers provides new insights into the molecular structure of receptor tyrosine kinases and suggests distinct signaling mechanisms of each receptor subfamily.

Received for publication, June 4, 2007 , and in revised form, November 28, 2007.

^* This work was supported in part by grants from the Association for International Cancer Research, the National Cancer Institute of Canada, and the Canada Research Chair Program (to W. F. V.). 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.

² Supported by the Premiers' Research Excellence Award program.

This paper is dedicated to the memory of the scientific integrity, passion, and dedication of Wolfgang Vogel who died suddenly December 5, 2007, while at the peak of his career.

¹ To whom correspondence should be addressed: Dept. of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Banting Institute, 100 College St., Rm. 110, Toronto, Ontario M5G 1L5, Canada. E-mail: rahim.abdulhussein{at}utoronto.ca.

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

This article has been cited by other articles:

				E. Adiguzel, P. J Ahmad, C. Franco, and M. P Bendeck Collagens in the progression and complications of atherosclerosis Vascular Medicine, February 1, 2009; 14(1): 73 - 89. [Abstract] [PDF]