Regulation of c-myc expression by PDGF through Rho GTPases.
Src family protein-tyrosine kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation and apoptosis. Surprisingly, these kinases also participate in mitogenic signalling by receptors that themselves exhibit an intrinsic protein-tyrosine kinase activity, including those for platelet-derived growth factor (PDGF), epidermal growth factor and colony-stimulating factor-1. Indeed, Src kinases are strictly required for the nuclear expression of the c-myc proto-oncogene and thus for DNA synthesis in response to PDGF. However, the nature of the signalling pathways by which Src kinases participate in the induction of c-myc expression by tyrosine kinase receptors is still unknown. Here we show that PDGF enhances c-myc expression and stimulates the c-myc promoter in a Src-dependent manner, and that neither Ras nor the mitogen-activated protein kinase pathway mediate these effects. In contrast, we present evidence that PDGF stimulates Vav2 through Src, thereby initiating the activation of a Rac-dependent pathway that controls the expression of the c-myc proto-oncogene.
Chiariello
M
M
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Marinissen
M J
MJ
Gutkind
J S
JS
D016475:3T3 Cells; D000818:Animals; D005786:Gene Expression Regulation; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015513:Oncogene Proteins / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D051567:Proto-Oncogene Proteins c-vav; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology
D015513:Oncogene Proteins; D010982:Platelet-Derived Growth Factor; D016271:Proto-Oncogene Proteins c-myc; D051567:Proto-Oncogene Proteins c-vav; C490565:Vav2 protein, mouse; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins