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

J. Biol. Chem., Vol. 280, Issue 1, 383-388, January 7, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/1/383    most recent M402645200v1 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 Google Scholar Google Scholar Articles by Pankonin, M. S. Articles by Loeb, J. A. Search for Related Content PubMed PubMed Citation Articles by Pankonin, M. S. Articles by Loeb, J. A. Social Bookmarking                      What's this?

Specific Structural Features of Heparan Sulfate Proteoglycans Potentiate Neuregulin-1 Signaling^*

Mark S. Pankonin, John T. Gallagher, and Jeffrey A. Loeb¶||

From the ^¶Department of Neurology, Wayne State University, Detroit, Michigan 48201, Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, and Department of Medical Oncology, University of Manchester, Cancer Research UK, Christie, Hospital NHS Trust, Manchester M204BX, United Kingdom

Neuregulins are a family of growth and differentiation factors that act through activation of cell-surface erbB receptor tyrosine kinases and have essential functions both during development and on the growth of cancer cells. One alternatively spliced neuregulin-1 form has a distinct heparin-binding immunoglobulin-like domain that enables it to adhere to heparan sulfate proteoglycans at key locations during development and substantially potentiates its activity. We examined the structural specificity needed for neuregulin-1-heparin interactions using a gel mobility shift assay together with an assay that measures the ability of specific oligosaccharides to block erbB receptor phosphorylation in L6 muscle cells. Whereas the N-sulfate group of heparin was most important, the 2-O-sulfate and 6-O-sulfate groups also contributed to neuregulin-1 binding in these two assays. Optimal binding to neuregulin-1 required eight or more heparin disaccharides; however, as few as two disaccharides were still able to bind neuregulin-1 to a lesser extent. The physiological importance of this specificity was shown both by chemical and siRNA treatment of cultured muscle cells. Pretreatment of muscle cells with chlorate that blocks all sulfation or with an siRNA that selectively blocks N-sulfation significantly reduced erbB receptor activation by neuregulin-1 but had no effect on the activity of neuregulin-1 that lacks the heparin-binding domain. These results suggest that the regulation of glycosaminoglycan sulfation is an important biological mechanism that can modulate both the localization and potentiation of neuregulin-1 signaling.

Received for publication, March 9, 2004 , and in revised form, November 1, 2004.

^* This work was supported by grants from NSF IBN-0092623, National Institutes of Health (NIH) IBN-0092623 (to J. A. L.), The Children's Research Center of Michigan (to J. A. L.), and the NIH NS 43943 (to M. S. P.). 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.

^|| To whom correspondence should be addressed: Dept. of Neurology and Center for Molecular Medicine and Genetics, Elliman 3122, 421 E. Canfield Ave., Detroit, MI 48201. Tel.: 313-577-9827; Fax: 313-577-7552; E-mail: jloeb{at}med.wayne.edu.

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