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J. Biol. Chem., Vol. 280, Issue 18, 18504-18510, May 6, 2005

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Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Controls Endocytosis and c-CBL-mediated Ubiquitination of the Platelet-derived Growth Factor Receptor (PDGFR)^*

Yoshiharu Takayama, Petra May¶, Richard G. W. Anderson||, and Joachim Herz**

From the Departments of Molecular Genetics and ^||Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046 and the Zentrum für Neurowissenschaften, Medizinische Klinik II, Albert-Ludwigs-Universität, 79104 Freiburg, Germany

The low density lipoprotein receptor-related protein 1 (LRP1) has been implicated in intracellular signaling functions as well as in lipid metabolism. Recent in vivo and in vitro studies suggest that LRP1 is a physiological modulator of the platelet-derived growth factor (PDGF) signaling pathway. Here we show that in mouse fibroblasts LRP1 modulates PDGF-BB signaling by controlling endocytosis and ligand-induced down-regulation of the PDGF receptor (PDGFR). In LRP1-deficient fibroblasts, basal PDGFR tyrosine kinase activity was derepressed, and PDGF-BB-induced endocytosis and degradation of PDGFR were accelerated as compared with control cells. This was accompanied by rapid uptake of receptor-bound PDGF-BB into the cells and by attenuated ERK activation in response to PDGF-BB stimulation. Pulse-chase analysis indicated that the steady-state turnover rate of PDGFR was also accelerated in LRP-deficient fibroblasts. The rapid degradation of PDGFR in the LRP1-deficient fibroblasts was prevented by MG132 and chloroquine. Furthermore, the association of PDGFR with c-Cbl, a ubiquitin E3-ligase, as well as the ligand-induced ubiquitination of PDGFR were increased in LRP1-deficient fibroblasts. We show that LRP1 can directly interact with c-Cbl, suggesting a Sprouty-like role for LRP1 in regulating the access of the PDGFR to the ubiquitination machinery. Thus, LRP1 modulates PDGF signaling by controlling ubiquitination and endocytosis of the PDGFR.

Received for publication, September 7, 2004 , and in revised form, February 16, 2005.

^* This study was supported by National Institutes of Health Grants HL20948, HL63762, AR041940, and NS43408, the Perot Family Foundation, and the Humboldt Foundation. 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.

^¶ Recipient of an Emmy-Noether Fellowship from the Deutsche Forschungsgemeinschaft.

^** To whom correspondence should be addressed: Dept. of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9046; Tel.: 214-648-5633; Fax: 214-648-8804; E-mail: Joachim.Herz{at}UTSouthwestern.edu.

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