Low density lipoprotein receptor-related protein 1 (LRP1) controls endocytosis and c-CBL-mediated ubiquitination of the platelet-derived growth factor receptor β (PDGFRβ)

Yoshiharu Takayama, Petra May, Richard G W Anderson, Joachim Herz

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Abstract

The low density lipoproiein 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-incluced 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.

Original languageEnglish (US)
Pages (from-to)18504-18510
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number18
DOIs
StatePublished - May 6 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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