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

J. Biol. Chem., Vol. 281, Issue 31, 21710-21719, August 4, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/31/21710    most recent M602014200v1 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 Germano, S. Articles by Gaudino, G. Search for Related Content PubMed PubMed Citation Articles by Germano, S. Articles by Gaudino, G. Social Bookmarking                      What's this?

Geldanamycins Trigger a Novel Ron Degradative Pathway, Hampering Oncogenic Signaling^*

Serena Germano, Davide Barberis, Massimo M. Santoro, Lorenza Penengo¹, Ami Citri, Yosef Yarden, and Giovanni Gaudino²

From the Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy and the Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel

Ron, the tyrosine kinase receptor for macrophage-stimulating protein is responsible for proliferation and migration of cells from different tissues. Ron can acquire oncogenic potential by single point mutations in the kinase domain, and dysregulated Ron signaling has been involved in the development of different human cancers. We have previously shown that ligand-activated Ron recruits the negative regulator c-Cbl, which mediates its ubiquitylation and degradation. Here we report that Ron is ubiquitylated also by the U-box E3 ligase C-terminal Hsc70-interacting protein (CHIP), recruited via chaperone intermediates Hsp90 and Hsc70. Gene silencing shows that CHIP activity is necessary to mediate Ron degradation upon cell treatment with Hsp90 inhibitors geldanamycins. The oncogenic Ron^M1254T receptor escapes from c-Cbl negative regulation but retains a strong association with CHIP. This constitutively active mutant of Ron displays increased sensitivity to geldanamycins, enhanced physical interaction with Hsp90, and more rapid degradation rate. Cell growth and migration, as well as the transforming potential evoked by Ron^M1254T, are abrogated upon Hsp90 inhibition. These data highlight a novel mechanism for Ron degradation and propose Hsp90 antagonists like geldanamycins as suitable pharmacological agents for therapy of cancers where altered Ron signaling is involved.

Received for publication, March 2, 2006 , and in revised form, June 1, 2006.

^* This work was supported by research grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), from the Italian Department of University (COFIN-PRIN), and from the Buzzi Unicem Foundation (to G. G.). 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. 1–3.

¹ Present address: IFOM, The FIRC Institute for Molecular Oncology, Via Adamello 16, Milano 20139, Italy.

² To whom correspondence should be addressed: DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," via Bovio 6, Novara 28100, Italy. Tel.: 39-0321-375-815; Fax: 39-0321-375-821; E-mail: giovanni.gaudino{at}unipmn.it.

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

This article has been cited by other articles:

				S. Zhao, S. Ammanamanchi, M. Brattain, L. Cao, A. Thangasamy, J. Wang, and J. W. Freeman Smad4-dependent TGF-{beta} Signaling Suppresses RON Receptor Tyrosine Kinase-dependent Motility and Invasion of Pancreatic Cancer Cells J. Biol. Chem., April 25, 2008; 283(17): 11293 - 11301. [Abstract] [Full Text] [PDF]

				X. Li, L. Shen, J. Zhang, J. Su, L. Shen, X. Liu, H. Han, W. Han, and L. Yao Degradation of HER2 by Cbl-Based Chimeric Ubiquitin Ligases Cancer Res., September 15, 2007; 67(18): 8716 - 8724. [Abstract] [Full Text] [PDF]