Oncogenic forms of Cbl abrogate the anchorage requirement but not the growth factor requirement for proliferation.
Recent studies have demonstrated that Cbl, the 120 kDa protein product of the c-cbl proto-oncogene, becomes tyrosine phosphorylated in response to stimulation of growth factor receptors and upon integrin-mediated cell adhesion. As a result, Cbl forms complexes with SH2 and SH3 domain-containing proteins, pointing to its role in signal transduction. The cellular form of Cbl can be rendered into transforming by naturally occurring or engineered mutations to its amino acid sequence. To gain insight into the mechanisms how oncogenic forms of Cbl render cells tumorigenic and what the function of the cellular Cbl might be, we have undertaken an analysis of NIH3T3 cells transfected with wild-type and oncogenic forms of Cbl. We demonstrate that unlike cellular Cbl, the mutant forms of Cbl are tyrosine phosphorylated in an adhesion-independent manner and interact with and activate SH2-containing signaling molecules in both suspended and adherent cells. Our data further show that oncogenic forms of Cbl induce anchorage-independent but serum-dependent growth. These results support the view that transformation by oncogenic forms of Cbl results from constitutive activation of integrin-dependent, rather than growth factor-dependent signaling events and, as a corollary, suggest that cellular Cbl might be a functionally important mediator of integrin signaling.
La Jolla Cancer Research Center, The Burnham Institute, California 92037, USA.
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Ojaniemi
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Langdon
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Vuori
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D006133:Growth Substances / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D018909:src Homology Domains
D006133:Growth Substances; D016023:Integrins; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C493849:Cbl protein, mouse