Binding of Cbl to a phospholipase Cγ1-docking site on platelet-derived growth factor receptor β provides a dual mechanism of negative regulation

Alagarsamy Lakku Reddi, Guo Guang Ying, Lei Duan, Gengsheng Chen, Manjari Dimri, Patrice Douillard, Brian J. Druker, Mayumi Naramura, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)29336-29347
Number of pages12
JournalJournal of Biological Chemistry
Issue number40
StatePublished - Oct 5 2007


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this