Cbl-mediated negative regulation of platelet-derived growth factor receptor-dependent cell proliferation - A critical role for Cbl tyrosine kinase-binding domain

被引:145
作者
Miyake, S [1 ]
Mullane-Robinson, KP [1 ]
Lill, NL [1 ]
Douillard, P [1 ]
Band, H [1 ]
机构
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Med,Div Rheumatol Immunol & Allergy, Lymphocyte Biol Sect, Boston, MA 02115 USA
关键词
D O I
10.1074/jbc.274.23.16619
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Cbl proto-oncogene product has emerged as a novel negative regulator of receptor and non-receptor tyrosine kinases, Our previous observations that Cbl overexpression in NIH3T3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (PDGFR alpha) and that the expression of oncogenic Cbl mutants up-regulated the PDGFRa signaling machinery strongly suggested that Cbl negatively regulates PDGFR alpha signaling. Here, we show that, similar to PDGFR alpha, selective stimulation of PDGFR beta induces Cbl phosphorylation, and its physical association with the receptor. Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFR beta, as observed with PDGFR alpha. We show that Cbl-dependent negative regulation of PDGFR alpha and beta results in a reduction of PDGF-induced cell proliferation and protection against apoptosis. A point mutation (G306E) that inactivates the tyrosine kinase binding domain in the N-terminal transforming region of Cbl compromised the PDGF-inducible tyrosine phosphorylation of Cbl although this mutant could still associate with the PDGFR. More importantly, the G306E mutation abrogated the ability of Cbl to enhance the ligand-induced ubiquitination and degradation of the PDGFR and to inhibit the PDGF-dependent cell proliferation and protection from apoptosis. These results demonstrate that Cbl can negatively regulate PDGFR-dependent biological responses and that this function requires the conserved tyrosine kinase binding domain of Cbl.
引用
收藏
页码:16619 / 16628
页数:10
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