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(Received for publication, July 13, 1995, and in revised form, March 1, 1996)
From the We and others have shown that Cbl, the protein
product of the c-cbl proto-oncogene, is an early target of
tyrosine phosphorylation upon stimulation through the immune cell
surface receptors, which signal through noncovalently associated
cytoplasmic tyrosine kinases. Using human mammary epithelial cells that
express a natural epidermal growth factor (EGF) receptor and require
EGF as an essential growth factor, we demonstrate here that Cbl is a
prominent target of tyrosine phosphorylation upon stimulation through
the EGF receptor tyrosine kinase. Phosphorylation of Cbl was EGF
dose-dependent, rapid (detectable as early as 5 s and
maximal by 2 min), and relatively sustained (detectable even after
1 h). Co-immunoprecipitation studies demonstrated that Cbl became
associated with the EGF receptor in an EGF-dependent
manner. Cbl was basally associated with the adaptor protein growth
factor receptor-binding protein 2 (Grb2), and this interaction was
further enhanced by EGF stimulation; however, the interaction was
entirely mediated via the Grb2 Src homology 3 (SH3) domains, suggesting
that binding of Grb2 SH2 domain to EGF receptor provides one mechanism
of Cbl's association with the EGF receptor. EGF stimulation also
induced the association of Cbl with Src homology and collagen (Shc)
protein, p85 subunit of the phosphatidylinositol 3-kinase and Crk
proteins, in particular with the CrkL isoform. Interactions of Cbl with
the EGF receptor and multiple downstream signaling proteins suggest a
role for this proto-oncogene product in mitogenic signaling through
growth factor receptor kinases.
Volume 271, Number 24,
Issue of June 14, 1996
pp. 14554-14559
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
and
Lymphocyte Biology Section, Division of
Rheumatology and Immunology, Department of Medicine, Brigham and
Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 and the 
Department of Radiation Oncology, New England
Medical Center and Department of Biochemistry, Tufts University
School of Medicine, Boston, Massachusetts 02111
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