TY - JOUR
T1 - Low density lipoprotein receptor-related protein 1 (LRP1) controls endocytosis and c-CBL-mediated ubiquitination of the platelet-derived growth factor receptor β (PDGFRβ)
AU - Takayama, Yoshiharu
AU - May, Petra
AU - Anderson, Richard G W
AU - Herz, Joachim
PY - 2005/5/6
Y1 - 2005/5/6
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M410265200
DO - 10.1074/jbc.M410265200
M3 - Article
C2 - 15753096
AN - SCOPUS:23044455604
SN - 0021-9258
VL - 280
SP - 18504
EP - 18510
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 18
ER -