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, GuoGuang Ying, Lei Duan, Gengsheng Chen, Manjari Dimri, Patrice Douillard, Brian Druker, Mayumi Naramura, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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
Volume282
Issue number40
DOIs
StatePublished - Oct 5 2007

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Platelet-Derived Growth Factor Receptors
Type C Phospholipases
Ubiquitin
Sorting
Degradation
Binding Sites
Phosphotyrosine
Ubiquitin-Protein Ligases
src Homology Domains
phospholipase C1
Receptor Protein-Tyrosine Kinases
Ablation
Lysosomes
Cell Movement
Association reactions
Ligands

ASJC Scopus subject areas

  • Biochemistry

Cite this

Binding of Cbl to a phospholipase Cγ1-docking site on platelet-derived growth factor receptor β provides a dual mechanism of negative regulation. / Reddi, Alagarsamy Lakku; Ying, GuoGuang; Duan, Lei; Chen, Gengsheng; Dimri, Manjari; Douillard, Patrice; Druker, Brian; Naramura, Mayumi; Band, Vimla; Band, Hamid.

In: Journal of Biological Chemistry, Vol. 282, No. 40, 05.10.2007, p. 29336-29347.

Research output: Contribution to journalArticle

Reddi, Alagarsamy Lakku ; Ying, GuoGuang ; Duan, Lei ; Chen, Gengsheng ; Dimri, Manjari ; Douillard, Patrice ; Druker, Brian ; Naramura, Mayumi ; Band, Vimla ; Band, Hamid. / Binding of Cbl to a phospholipase Cγ1-docking site on platelet-derived growth factor receptor β provides a dual mechanism of negative regulation. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 40. pp. 29336-29347.
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