Raf-1 kinase and ERK2 uncoupled from mitogenic signals in rat fibroblasts.
The MAP kinase pathway impinging on ERK2 has been shown to be integrally associated with mitogenic signalling in many cell types. Previously, we and others have demonstrated that oncogenic forms of Raf-1 kinase, when expressed in fibroblasts, lead to the constitutive activation of ERK2, the de-regulation of c-fos expression and increased cell proliferation. Here we describe an exception to this scenario. In Rat6 cells, although both ERK1 and ERK2 are activated in response to mitogens that induce c-fos expression, such as Epidermal Growth Factor (EGF), lysophosphatidic acid (LPA) or serum, expression of v-Raf fails to induce c-fos expression and increase proliferation. However, ERK2 is activated by v-Raf expression. The co-transfection of an interfering mutant of ERK2 has no effect on the level of c-fos reporter expression in Rat6 cells whereas the analogous ERK1 mutant reduces its expression. Furthermore, the spontaneous focus formation observed in Rat6 cells is susceptible to the interfering mutant of ERK1 but resistant to that of ERK2. Thus, not only do mitogenic signals appear to by-pass both Raf-1 kinase and ERK2, the Raf-1-ERK2 pathway seems to be functionally compromised in Rat6 cells as its activation leads neither to c-fos expression nor to increased proliferation.
D016475:3T3 Cells / Q000201:enzymology / Q000502:physiology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D016762:Genes, fos; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection
D008934:Mitogens; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases