c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases.
The protooncogenic protein c-Cbl has been shown to act as a multivalent adaptor and a negative regulator of protein tyrosine kinase-mediated signaling. Recent studies have implicated it in the regulation of cell adhesion-related events. We have previously shown that c-Cbl facilitates adhesion and spreading of v-Abl-transformed fibroblasts, and that these effects are dependent on its tyrosine phosphorylation. However, the mechanisms mediating effects of c-Cbl on fibroblast adhesion remain poorly understood. In this study we demonstrate that the tyrosine phosphorylation-dependent effect of c-Cbl on adhesion of v-Abl-transformed fibroblasts is primarily mediated by an increase in fibronectin matrix deposition by these cells. This increase in fibronectin matrix deposition and, hence, in cell adhesion is dependent on cytoskeletal rearrangements induced by RhoA, Rac1 and, possibly, Rap1 activation caused by c-Cbl. The observed activation of these GTPases is mediated by the recruitment of phosphatidylinositol-3' kinase, CrkL and Vav2 to the C-terminal tyrosine residues of c-Cbl. The results of this study also demonstrate that ubiquitination is essential for the observed effects of c-Cbl on fibronectin matrix production and cell adhesion.
Teckchandani
A M
AM
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, PA 19140, USA.
Feshchenko
E A
EA
Tsygankov
A Y
AY
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic; D003599:Cytoskeleton / Q000737:chemistry; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000096:biosynthesis*; D016313:Genes, abl; D016023:Integrins / Q000502:physiology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology
D005353:Fibronectins; D016023:Integrins; D011518:Proto-Oncogene Proteins; D014452:Ubiquitins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein; D020827:rap1 GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C493849:Cbl protein, mouse