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J Biol Chem, Vol. 274, Issue 23, 16619-16628, June 4, 1999
From the Lymphocyte Biology Section, Division of Rheumatology,
Immunology and Allergy, Department of Medicine, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts 02115
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-
Cbl-mediated Negative Regulation of Platelet-derived Growth
Factor Receptor-dependent Cell Proliferation
A CRITICAL ROLE FOR Cbl TYROSINE KINASE-BINDING DOMAIN
(PDGFR) and that the expression of
oncogenic Cbl mutants up-regulated the PDGFR signaling machinery
strongly suggested that Cbl negatively regulates PDGFR signaling.
Here, we show that, similar to PDGFR, selective stimulation of
PDGFR
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, as observed with PDGFR. We
show that Cbl-dependent negative regulation of PDGFR and
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.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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