Induction of the mitogen-activated protein kinase phosphatase MKP3 by nerve growth factor in differentiating PC12.
In PC12 sympathetic neurons activation and nuclear translocation of ERK family MAP kinases plays an essential role in processes underlying nerve growth factor (NGF)-dependent differentiation. We have recently cloned MKP-3 as a novel dual specificity phosphatase displaying selectivity towards inactivation of the ERK1 and ERK2 MAP kinases. Here we report that in PC12 cells, MKP-3 undergoes powerful and specific up-regulation by NGF while a number of mitogens and cellular stresses are ineffective. NGF-stimulated MKP-3 expression appears after 1 h, is maximal at 3 h, and is sustained for 5 days. This coincides with a critical period of neurite outgrowth and terminal differentiation. Consistent with a role mediating inhibition of PC12 cell MAP kinases, NGF-stimulated ERK2 activation was suppressed considerably following pretreatment with fibroblast growth factor and 9-cis-retinal, two additional differentiation factors found to induce powerfully MKP-3 expression. Given the clear cytosolic localization of MKP3 in PC12 cells and sympathetic neurons, these results suggest a critical role for inactivating ERK MAP kinases in non-nuclear compartments during essential stages of NGF-mediated PC12 differentiation.
Camps
M
M
Geneva Biomedical Research Institute, Glaxo-Wellcome Research and Development S.A., Switzerland. Montserrat.camps.CH_GVA03@serono.com
Chabert
C
C
Muda
M
M
Boschert
U
U
Gillieron
C
C
Arkinstall
S
S
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D004224:Diterpenes; D054642:Dual Specificity Phosphatase 6; D004790:Enzyme Induction; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis*; D051381:Rats; D012172:Retinaldehyde / Q000494:pharmacology
D004224:Diterpenes; D009414:Nerve Growth Factors; D016222:Fibroblast Growth Factor 2; C031390:9-cis-retinal; D054642:Dual Specificity Phosphatase 6; C517037:Dusp6 protein, rat; D017027:Protein Tyrosine Phosphatases; D012172:Retinaldehyde