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J. Biol. Chem., Vol. 282, Issue 40, 29336-29347, October 5, 2007

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Binding of Cbl to a Phospholipase C1-docking Site on Platelet-derived Growth Factor Receptor Provides a Dual Mechanism of Negative Regulation^*

Alagarsamy Lakku Reddi, GuoGuang Ying, Lei Duan, Gengsheng Chen, Manjari Dimri, Patrice Douillard, Brian J. Druker^¶, Mayumi Naramura, Vimla Band^||**, and Hamid Band^**1

From the Divisions of Molecular Oncology and ^||Cancer Biology, Evanston Northwestern Healthcare Research Institute, and Department of Medicine, Feinberg School of Medicine and ^**Department of Biochemistry, Molecular Biology and Cell Biology, Weinberg College of Arts and Science, Northwestern University, Evanston, Illinois 60201, the Eucodis GmbH, Brunner Strasse 59, 1230 Vienna, Austria, and the ^¶Oregon Health and Science University Cancer Institute, Portland, Oregon 97239

Ubiquitin conjugation to receptor tyrosine kinases is a critical biochemical step in attenuating their signaling through lysosomal degradation. Our previous studies have established Cbl as an E3 ubiquitin ligase for ubiquitinylation and degradation of platelet-derived growth factor receptor (PDGFR) and PDGFR. However, the role of endogenous Cbl in PDGFR regulation and the molecular mechanisms of this regulation remain unclear. Here, we demonstrate that endogenous Cbl is essential for ligand-induced ubiquitinylation and degradation of PDGFR; this involves the Cbl TKB domain binding to PDGFR phosphotyrosine 1021, a known phospholipase C (PLC) 1 SH2 domain-binding site. Lack of Cbl or ablation of the Cbl-binding site on PDGFR impedes receptor sorting to the lysosome. Cbl-deficient cells also show more PDGF-induced PLC1 association with PDGFR and enhanced PLC-mediated cell migration. Thus, Cbl-dependent negative regulation of PDGFR involves a dual mechanism that concurrently promotes ubiquitin-dependent lysosomal sorting of the receptor and competitively reduces the recruitment of a positive mediator of receptor signaling.

Received for publication, March 1, 2007 , and in revised form, July 2, 2007.

^* This work was supported by National Institutes of Health Grants CA 99900, CA99163, CA 87986, and CA76118 (to H. B.) and CA94143, CA96844, and CA81076 (to V. B.); Department of Defense Breast Cancer Research Grants DAMD17-02-1-0303 (to H. B.) and DAMD17-02-1-0508 (to V. B.); Center for Cancer Nanotechnology Excellence Grant NCI 1U54 CA119341-01 (to H. B. and V. B.); the Jean Ruggles-Romoser Chair of Cancer Research (to H. B.); and the Duckworth Family Chair of Breast Cancer Research (to V. B.). 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 Tables S1-S3 and supplemental Figs. S1-S6.

¹ To whom correspondence should be addressed: ENH Research Institute, 1001 University Place, Evanston, IL 60201. Tel.: 224-364-7401/7424; Fax: 224-364-7402; E-mail: h-band{at}northwestern.edu.

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