Binding of Cbl to a Phospholipase Cγ1-docking Site on Platelet-derived Growth Factor Receptor β Provides a Dual Mechanism of Negative Regulation
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)...
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Published in | The Journal of biological chemistry Vol. 282; no. 40; pp. 29336 - 29347 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
05.10.2007
American Society for Biochemistry and Molecular Biology |
Online Access | Get full text |
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Summary: | 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) α and PDGFRβ. 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 PDGFRβ; this involves the Cbl TKB domain binding to PDGFRβ phosphotyrosine 1021, a known phospholipase C (PLC) γ1 SH2 domain-binding site. Lack of Cbl or ablation of the Cbl-binding site on PDGFRβ impedes receptor sorting to the lysosome. Cbl-deficient cells also show more PDGF-induced PLCγ1 association with PDGFRβ and enhanced PLC-mediated cell migration. Thus, Cbl-dependent negative regulation of PDGFRβ 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. |
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Bibliography: | http://www.jbc.org/ |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M701797200 |