QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 21 September 2004
doi: 10.1242/jcs.01354

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: jcs.01354v1 117/21/5001    most recent Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de Melker, A. A. Articles by Borst, J. Search for Related Content PubMed PubMed Citation Articles by de Melker, A. A. Articles by Borst, J.

c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15

Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

^* Author for correspondence (e-mail: j.borst{at}nki.nl)

Accepted 9 June 2004

c-Cbl associates with the activated EGF receptor before endocytosis. We here reveal that the capacity of c-Cbl to promote receptor internalization depends on its ubiquitin ligase activity, which functionally connects the EGF receptor to Eps15, a mediator of clathrin-coated pit formation. EGF-induced phosphorylation of Eps15, as well as recruitment of Eps15 to the plasma membrane and its co-localization with the EGF receptor in endosomes required the ubiquitin ligase activity of c-Cbl. This suggested that ubiquitin provides a direct or indirect link between the receptor and Eps15. Indeed, EGF-induced redistribution of Eps15 to the plasma membrane and endosomes depended on its ubiquitin-interacting motif. Upon over-expression, the ubiquitin-interacting motif abrogated the capacity of c-Cbl to promote EGF receptor endocytosis and only allowed receptor internalization via a route that lacked Eps15. Our findings disclose a novel function for the c-Cbl ubiquitin ligase and identify ubiquitin as a module that directs the EGF receptor into an endocytic pathway involving Eps15.

Key words: Ubiquitin-interacting motif, EGF receptor, c-Cbl, Eps15, Endocytosis

This article has been cited by other articles:

				H. Hayashi and Y. Sugiyama Short-Chain Ubiquitination Is Associated with the Degradation Rate of a Cell-Surface-Resident Bile Salt Export Pump (BSEP/ABCB11) Mol. Pharmacol., January 1, 2009; 75(1): 143 - 150. [Abstract] [Full Text] [PDF]

				S. Chi, H. Cao, J. Chen, and M. A. McNiven Eps15 Mediates Vesicle Trafficking from the trans-Golgi Network via an Interaction with the Clathrin Adaptor AP-1 Mol. Biol. Cell, August 1, 2008; 19(8): 3564 - 3575. [Abstract] [Full Text] [PDF]

				B. Sehat, S. Andersson, L. Girnita, and O. Larsson Identification of c-Cbl as a New Ligase for Insulin-like Growth Factor-I Receptor with Distinct Roles from Mdm2 in Receptor Ubiquitination and Endocytosis Cancer Res., July 15, 2008; 68(14): 5669 - 5677. [Abstract] [Full Text] [PDF]

				I. Roxrud, C. Raiborg, N. M. Pedersen, E. Stang, and H. Stenmark An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor J. Cell Biol., March 24, 2008; 180(6): 1205 - 1218. [Abstract] [Full Text] [PDF]

				D. J. Kusner, C. R. Thompson, N. A. Melrose, S. M. Pitson, L. M. Obeid, and S. S. Iyer The Localization and Activity of Sphingosine Kinase 1 Are Coordinately Regulated with Actin Cytoskeletal Dynamics in Macrophages J. Biol. Chem., August 10, 2007; 282(32): 23147 - 23162. [Abstract] [Full Text] [PDF]

				N. Li, M. Lorinczi, K. Ireton, and L. A. Elferink Specific Grb2-mediated Interactions Regulate Clathrin-dependent Endocytosis of the cMet-tyrosine Kinase J. Biol. Chem., June 8, 2007; 282(23): 16764 - 16775. [Abstract] [Full Text] [PDF]

				F. Shen, Q. Lin, Y. Gu, C. Childress, and W. Yang Activated Cdc42-associated Kinase 1 Is a Component of EGF Receptor Signaling Complex and Regulates EGF Receptor Degradation Mol. Biol. Cell, March 1, 2007; 18(3): 732 - 742. [Abstract] [Full Text] [PDF]

				N. P. Martin, R. P. Mohney, S. Dunn, M. Das, E. Scappini, and J. P. O'Bryan Intersectin Regulates Epidermal Growth Factor Receptor Endocytosis, Ubiquitylation, and Signaling Mol. Pharmacol., November 1, 2006; 70(5): 1643 - 1653. [Abstract] [Full Text] [PDF]

				M. Mitsushima, K. Ueda, and N. Kioka Vinexin beta regulates the phosphorylation of epidermal growth factor receptor on the cell surface. Genes Cells, September 1, 2006; 11(9): 971 - 982. [Abstract] [Full Text] [PDF]

				D. P. Tan, Q.-Y. Liu, N. Koshiya, H. Gu, and D. Alkon Enhancement of long-term memory retention and short-term synaptic plasticity in cbl-b null mice PNAS, March 28, 2006; 103(13): 5125 - 5130. [Abstract] [Full Text] [PDF]

				E. Regan-Klapisz, I. Sorokina, J. Voortman, P. de Keizer, R. C. Roovers, P. Verheesen, S. Urbe, L. Fallon, E. A. Fon, A. Verkleij, et al. Ubiquilin recruits Eps15 into ubiquitin-rich cytoplasmic aggregates via a UIM-UBL interaction J. Cell Sci., October 1, 2005; 118(19): 4437 - 4450. [Abstract] [Full Text] [PDF]

				Y.-J. Jin, C. Y. Cai, X. Zhang, H.-T. Zhang, J. A. Hirst, and S. J. Burakoff HIV Nef-Mediated CD4 Down-Regulation Is Adaptor Protein Complex 2 Dependent J. Immunol., September 1, 2005; 175(5): 3157 - 3164. [Abstract] [Full Text] [PDF]

				A. A. de Melker, G. van der Horst, and J. Borst Ubiquitin Ligase Activity of c-Cbl Guides the Epidermal Growth Factor Receptor into Clathrin-coated Pits by Two Distinct Modes of Eps15 Recruitment J. Biol. Chem., December 31, 2004; 279(53): 55465 - 55473. [Abstract] [Full Text] [PDF]