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

Maria L Galisteo,Ivan Dikic,Andreas G Batzer,Wallace Y Langdon,Joseph Schlessinger

doi:10.1074/jbc.270.35.20242

Maria L Galisteo, Ivan Dikic + Show 3 more

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https://doi.org/10.1074/jbc.270.35.20242

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Abstract

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, p12ocbl 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.

Highlights

From the Wepartment of Pharmacology, New York University Medical Center, New York, New York 10016 and the Wepartment of Biochemistry, University of Western Australia, Nedlands, Western Australia 6009, Australia
Grb2 binding site in the Ras guanine nucleotide releasing factor "Sos" [6]. This observation prompted us to examine in detail a possible interaction between p120cb1 and Grb2 in the context ofthe Ras signaling pathway initiated by the epidermal growth factor receptor (EGFR)
In this report we demonstrate that p120cbl becomes strongly tyrosine-phosphorylated upon stimulation of EGFR, platelet-derived growth factor (PDGF), nerve growth factor (NGF), and fibroblast growth factor (FGFRl) receptors

Summary

Introduction

From the Wepartment of Pharmacology, New York University Medical Center, New York, New York 10016 and the Wepartment of Biochemistry, University of Western Australia, Nedlands, Western Australia 6009, Australia. This observation prompted us to examine in detail a possible interaction between p120cb1 and Grb2 in the context ofthe Ras signaling pathway initiated by the epidermal growth factor receptor (EGFR).1 In this report we demonstrate that p120cbl becomes strongly tyrosine-phosphorylated upon stimulation of EGFR, platelet-derived growth factor (PDGF), nerve growth factor (NGF), and fibroblast growth factor (FGFRl) receptors.

Results

Conclusion