Tyrosine Phosphorylation of the c-cbl Proto-oncogene Protein Product and Association with Epidermal Growth Factor (EGF) Receptor upon EGF Stimulation (∗)

The murine retroviral oncogene v-cbl induces pre-B cell lymphomas and myelogenous leukemias. The protein product of the mammalian c-cbl proto-oncogene is a widely expressed cytoplasmic 120-kDa protein (p120cbl) whose normal cellular function has not been determined. Here we show that upon stimulatio...

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Bibliographic Details
Published in:The Journal of biological chemistry 1995-09, Vol.270 (35), p.20242-20245
Main Authors: Galisteo, Maria L., Dikic, Ivan, Batzer, Andreas G., Langdon, Wallace Y., Schlessinger, Joseph
Format: Article
Language:English
Subjects:
Animals
caenorhabditis elegans
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Cell Line
Epidermal Growth Factor - pharmacology
ErbB Receptors - metabolism
Glutathione Transferase - biosynthesis
Humans
Mice
Mutagenesis
Phosphorylation
Polymerase Chain Reaction
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins - biosynthesis
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-cbl
Proto-Oncogenes
Recombinant Fusion Proteins - metabolism
Retroviridae
Sequence Deletion
Signal Transduction
Transfection
Tyrosine
Ubiquitin-Protein Ligases
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Summary:The murine retroviral oncogene v-cbl induces pre-B cell lymphomas and myelogenous leukemias. The protein product of the mammalian c-cbl proto-oncogene is a widely expressed cytoplasmic 120-kDa protein (p120cbl) whose normal cellular function has not been determined. Here we show that upon stimulation of human epidermal growth factor (EGF) receptor, p120cbl becomes strongly tyrosine-phosphorylated and associates with activated EGF receptor in vivo. A GST fusion protein containing amino acids 1-486 of p120cbl, including a region highly conserved in nematodes, binds directly to the autophosphorylated carboxyl-terminal tail of the EGF receptor. Platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), or nerve growth factor (NGF) stimulation also results in tyrosine phosphorylation of p120cbl. Recent genetic studies in Caenorhabditis elegans indicate that Sli-1, a p120cbl homologue, plays a negative regulatory role in control of the Ras signaling pathway initiated by the C. elegans EGF receptor homologue. Our results indicate that p120cbl is involved in an early step in the EGF signaling pathway that is conserved from nematodes to mammals.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.270.35.20242