Binding of Cbl to a Phospholipase Cγ1-docking Site on Platelet-derived Growth Factor Receptor β Provides a Dual Mechanism of Negative Regulation

• Published in: The Journal of biological chemistry 2007-10, Vol.282 (40), p.29336-29347
• Main Authors: Reddi, Alagarsamy Lakku, Ying, GuoGuang, Duan, Lei, Chen, Gengsheng, Dimri, Manjari, Douillard, Patrice, Druker, Brian J., Naramura, Mayumi, Band, Vimla, Band, Hamid
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M701797200

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.