Activation of extracellular signal-regulated kinase (ERK) by mitogenic stimuli is repressed in v-Src-transformed cells.
Stimulation of mitogenic signaling pathways results in transient activation of the extracellular signal-regulated kinase (ERK) subfamily of mitogen-activated protein kinases (MAPK) in normal cells. We demonstrate here that activation of ERKs in response to serum or phorbol ester stimulation was markedly repressed in three different rodent fibroblast cell lines stably transformed by v-Src. Activation of the MAPK/ERK kinase (MEK) was also repressed in v-Src-transformed cells, indicating that the repression occurs upstream of ERK. Consistent with repression occurring predominantly at the level of MEK, the phosphatase inhibitor orthovanadate could restore ERK activation to a limited extent in some but not all v-Src-transformed cell lines. A similar repression of ERK activation was observed in v-Ras- and v-Raf-transformed cells. In addition, ERK activity was not constitutively elevated in exponentially growing cells transformed by v-Src, v-Ras, or v-Raf as compared with normal cells. These results establish that the ERK activation pathway is repressed in rodent fibroblasts stably transformed by viral oncoproteins that chronically stimulate receptor tyrosine kinase signaling pathways. Furthermore, our findings suggest that elevated ERK activity above basal levels is not required for maintaining cell transformation by these oncoproteins. Taken together, these results indicate that ERK signaling pathways are subject to negative feedback regulation upstream of ERK as a consequence of oncogenic transformation.
Stofega
M R
MR
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor 48109, USA.
Yu
C L
CL
Wu
J
J
Jove
R
R
D016475:3T3 Cells; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000502:physiology; D005347:Fibroblasts; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000235:genetics; D016391:Genes, src / Q000235:genetics* / Q000502:physiology*; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D008934:Mitogens; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D027384:Oncogene Proteins v-raf; D010703:Phorbol Esters / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic; D014638:Vanadates / Q000494:pharmacology
D001798:Blood Proteins; D008934:Mitogens; D009419:Nerve Tissue Proteins; D010703:Phorbol Esters; D015682:Retroviridae Proteins, Oncogenic; D014638:Vanadates; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D027384:Oncogene Proteins v-raf; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases