Suppression of growth factor-mediated MAP kinase activation by v-raf in macrophages: a putative role for the MKP-1 phosphatase.
Many tyrosine kinase growth factor receptors activate the MAP Kinase (MAPK) pathway by stimulating the activity of the RAF kinase. In some, but not all cell types, the expression of activated RAF is sufficient to induce constitutive MAPK activation. In BAC-1.2F5 macrophages the expression of virally activated RAF does not correlate with constitutive MAPK activation; on the contrary, growth factor-mediated stimulation of MAPK activity is suppressed in these cells. Suppression correlates with v-RAF expression, as MAPK activation is normal in a revertant cell line that stopped expressing v-RAF. Inhibition of MAPK activation is associated with lack of ERK-2 tyrosine phosphorylation, and is not due to the suppression of CSF-1-mediated MEK activation. Pretreatment with vanadate restores growth factor-stimulated activation and tyrosine phosphorylation of MAPK in v-RAF-expressing macrophages, indicating the involvement of a tyrosine phosphatase. Interestingly, v-RAF-expressing macrophages contain low constitutive levels of MKP-1 mRNA, an immediate early gene that encodes a MAPK-specific phosphatase and is induced in the parental cell line by CSF-1 treatment. The restoration of MAPK activation by vanadate pretreatment and the presence of MKP-1 mRNA in v-RAF-expressing macrophages raise the intriguing possibility that in macrophages RAF may be feeding back on the MAPK pathway by participating in the control of MKP-1 expression.
Krautwald
S
S
Department of Immunobiology, Fraunhofer Institute for Toxicology and Molecular Biology, Hannover, Germany.
Büscher
D
D
Dent
P
P
Ruthenberg
K
K
Baccarini
M
M
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D002460:Cell Line; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D008969:Molecular Sequence Data; D027384:Oncogene Proteins v-raf; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D015682:Retroviridae Proteins, Oncogenic; D014443:Tyrosine; D016173:Macrophage Colony-Stimulating Factor; D011494:Protein Kinases; D027384:Oncogene Proteins v-raf; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases