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

J. Biol. Chem., Vol. 282, Issue 23, 16764-16775, June 8, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/23/16764    most recent M610835200v1 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 Li, N. Articles by Elferink, L. A. Search for Related Content PubMed PubMed Citation Articles by Li, N. Articles by Elferink, L. A. Social Bookmarking                      What's this?

Specific Grb2-mediated Interactions Regulate Clathrin-dependent Endocytosis of the cMet-tyrosine Kinase^*

Ning Li, Marta Lorinczi, Keith Ireton, and Lisa A. Elferink^¶1

From the Department of Neuroscience and Cell Biology, ^¶Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1074 and Department of Molecular Biology and Microbiology, Biomolecular Science Center, University of Central Florida, Orlando, Florida 32826-3227

Lysosomal degradation of the receptor-tyrosine kinase cMet requires receptor ubiquitination by the E3 ubiquitin ligase Cbl followed by clathrin-dependent internalization. A role for Cbl as an adaptor for cMet internalization has been previously reported. However, the requirement for Cbl ubiquitin ligase activity in this process and its mode of recruitment to cMet has yet to be determined. Cbl can directly bind cMet at phosphotyrosine 1003 or indirectly via Grb2 to phosphotyrosine 1356 in the multisubstrate binding domain of cMet. The direct binding of Cbl with cMet is critical for receptor degradation and not receptor internalization. Here we show a strict requirement for Grb2 and the ubiquitin ligase activity of Cbl for cMet endocytosis. Receptor internalization was impaired by small interfering RNA depletion of Grb2, overexpression of dominant negative Grb2 mutants, and point mutations in the cMet multisubstrate docking site that inhibits the direct association of Grb2 with cMet. The requirement for Grb2 was specific and did not involve the multiadaptor Gab1. cMet internalization was impaired in cells expressing an ubiquitin ligase-deficient Cbl mutant or conjugation-deficient ubiquitin but was unaffected in cells expressing a Cbl mutant that is unable to bind cMet directly. Expression of a Cbl-Grb2 chimera rescued impaired cMet endocytosis in cells depleted of endogenous Grb2. These results indicate that the ubiquitin ligase activity of Cbl is critical for clathrin-dependent cMet internalization and suggest a role for Grb2 as an intermediary linking Cbl ubiquitin ligase activity to this process.

Received for publication, November 22, 2006 , and in revised form, April 18, 2007.

^* This work was supported by National Science Foundation Grant IBN-343739 and National Institutes of Health Grants CA-112605 and CA-119075 (to L. A. E.), Canadian Institutes of Health Research Grant MT-15497, and a Canadian Institutes of Health Research New Investigator award (to K. I.). 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–S8.

¹ To whom correspondence should be addressed: Dept. of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1074. Tel.: 409-772-2775; Fax: 409-747-1938; E-mail: laelferi{at}utmb.edu.

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

This article has been cited by other articles:

				S. Goldoni, A. Humphries, A. Nystrom, S. Sattar, R. T. Owens, D. J. McQuillan, K. Ireton, and R. V. Iozzo Decorin is a novel antagonistic ligand of the Met receptor J. Cell Biol., May 18, 2009; 185(4): 743 - 754. [Abstract] [Full Text] [PDF]

				C. A. Parachoniak and M. Park Distinct Recruitment of Eps15 via Its Coiled-coil Domain Is Required For Efficient Down-regulation of the Met Receptor Tyrosine Kinase J. Biol. Chem., March 27, 2009; 284(13): 8382 - 8394. [Abstract] [Full Text] [PDF]

				X. Gao, M. Lorinczi, K. S. Hill, N. C. Brooks, H. Dokainish, K. Ireton, and L. A. Elferink Met Receptor Tyrosine Kinase Degradation Is Altered in Response to the Leucine-rich Repeat of the Listeria Invasion Protein Internalin B J. Biol. Chem., January 9, 2009; 284(2): 774 - 783. [Abstract] [Full Text] [PDF]

				I. Seiden-Long, R. Navab, W. Shih, M. Li, J. Chow, C. Q. Zhu, N. Radulovich, C. Saucier, and M.-S. Tsao Gab1 but not Grb2 mediates tumor progression in Met overexpressing colorectal cancer cells Carcinogenesis, March 1, 2008; 29(3): 647 - 655. [Abstract] [Full Text] [PDF]