title: Induction of the mitogen-activated protein kinase phosphatase MKP3 by nerve growth factor in differentiating PC12.
abstract: 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.
authors.affiliation: Geneva Biomedical Research Institute, Glaxo-Wellcome Research and Development S.A., Switzerland. Montserrat.camps.CH_GVA03@serono.com
authors.forename: M
authors.initials: M
authors.lastname: Camps
authors.forename: C
authors.initials: C
authors.lastname: Chabert
authors.forename: M
authors.initials: M
authors.lastname: Muda
authors.forename: U
authors.initials: U
authors.lastname: Boschert
authors.forename: C
authors.initials: C
authors.lastname: Gillieron
authors.forename: S
authors.initials: S
authors.lastname: Arkinstall
mesh_terms: 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
chemical_list: 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