Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl

Oncogene. 1997 Dec 11;15(24):2909-19. doi: 10.1038/sj.onc.1201468.

Abstract

The 120 kD product of the c-Cbl oncogene is a prominent substrate of protein tyrosine kinases that lacks a known catalytic activity but possesses an array of binding sites for cytoplasmic signalling proteins. An oncogenic form of Cbl was recently identified in the 70Z/3 pre-B cell lymphoma which has a small deletion at the N-terminus of the Ring finger domain. This form of Cbl, termed 70Z-Cbl, exhibits an enhanced level of tyrosine phosphorylation compared with c-Cbl. Here we demonstrate that the expression of 70Z-Cbl induces a tenfold enhancement in the kinase activity of the EGF receptor in serum-starved and EGF-stimulated cells. In serum-starved cells this results in EGF receptor autophosphorylation and the recruitment of Grb2, Shc and Sos1 but does not induce a corresponding increase in MAP kinase activity. Furthermore the expression of 70Z-Cbl greatly enhances EGF-induced tyrosine phosphorylation of the protein tyrosine phosphatase SHP-2. We also show that the Cbl/EGF receptor complex is predominantly associated with CrkII and is distinct to the Grb2/Shc/Sos1 complex that associates with the EGF receptor. These findings therefore demonstrate a biochemical effect of an oncogenic Cbl protein and support predictions from C. elegans that Cbl functions as regulator of receptor tyrosine kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Cell Line, Transformed
  • Culture Media, Serum-Free
  • Cyclin-Dependent Kinases / metabolism
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • GRB2 Adaptor Protein
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Lymphoma, B-Cell
  • Mice
  • Oncogene Protein v-cbl
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / metabolism
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-cbl
  • Retroviridae Proteins, Oncogenic / physiology
  • Tumor Cells, Cultured
  • Tyrosine / metabolism
  • Ubiquitin-Protein Ligases*

Substances

  • Adaptor Proteins, Signal Transducing
  • Culture Media, Serum-Free
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Oncogene Protein v-cbl
  • Proteins
  • Proto-Oncogene Proteins
  • Retroviridae Proteins, Oncogenic
  • Tyrosine
  • Epidermal Growth Factor
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Cyclin-Dependent Kinases
  • CBL protein, human
  • Cbl protein, mouse