NDLI: Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Controls Endocytosis and c-CBL-mediated Ubiquitination of the Platelet-derived Growth Factor Receptor β (PDGFRβ)

Content Provider	Journal of Biological Chemistry (JBC)
Author	Takayama, Yoshiharu May, Petra Anderson, Richard G. W. Herz, Joachim
Abstract	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 β (PDGFRβ). In LRP1-deficient fibroblasts, basal PDGFRβ tyrosine kinase activity was derepressed, and PDGF-BB-induced endocytosis and degradation of PDGFRβ 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 PDGFRβ was also accelerated in LRP-deficient fibroblasts. The rapid degradation of PDGFRβ in the LRP1-deficient fibroblasts was prevented by MG132 and chloroquine. Furthermore, the association of PDGFRβ with c-Cbl, a ubiquitin E3-ligase, as well as the ligand-induced ubiquitination of PDGFRβ 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 PDGFRβ to the ubiquitination machinery. Thus, LRP1 modulates PDGF signaling by controlling ubiquitination and endocytosis of the PDGFRβ.
Related Links	http://www.jbc.org/content/280/18/18504.abstract
Ending Page	18510
Starting Page	18504
Page Count	7
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	18
Volume Number	280
DOI	10.1074/jbc.M410265200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2005-05-06
Access Restriction	Open
Subject Keyword	Mechanisms of Signal Transduction
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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