Tyrosine Phosphorylation of Cbl upon Epidermal Growth Factor (EGF) Stimulation and Its Association with EGF Receptor and Downstream Signaling Proteins
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 c...
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Published in | The Journal of biological chemistry Vol. 271; no. 24; pp. 14554 - 14559 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
14.06.1996
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.271.24.14554 |