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PMID: 10330161 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Protein kinase Cdelta mediates neurogenic but not mitogenic activation of mitogen-activated protein kinase in neuronal cells.

Molecular and cellular biology ·Vol. 19 ·No. 6 ·1999-06-00 ·Pages 4209-18

Corbit KC, Foster DA, Rosner MR

Abstract

In several neuronal cell systems, fibroblast-derived growth factor (FGF) and nerve growth factor (NGF) act as neurogenic agents, whereas epidermal growth factor (EGF) acts as a mitogen. The mechanisms responsible for these different cellular fates are unclear. We report here that although FGF, NGF, and EGF all activate mitogen-activated protein (MAP) kinase (extracellular signal-related kinase [ERK]) in rat hippocampal (H19-7) and pheochromocytoma (PC12) cells, the activation of ERK by the neurogenic agents FGF and NGF is dependent upon protein kinase Cdelta (PKCdelta), whereas ERK activation in response to the mitogenic EGF is independent of PKCdelta. Antisense PKCdelta oligonucleotides or the PKCdelta-specific inhibitor rottlerin inhibited FGF- and NGF-induced, but not EGF-induced, ERK activation. In contrast, EGF-induced ERK activation was inhibited by the phosphatidylinositol-3-kinase inhibitor wortmannin, which had no effect upon FGF-induced ERK activation. Rottlerin also inhibited the activation of MAP kinase kinase (MEK) in response to activated Raf, but had no effect upon c-Raf activity or ERK activation by activated MEK. These results indicate that PKCdelta functions either downstream from or in parallel with c-Raf, but upstream of MEK. Inhibition of PKCdelta also blocked neurite outgrowth induced by FGF and NGF in PC12 cells and by activated Raf in H19-7 cells, indicating a role for PKCdelta in the neurogenic effects of FGF, NGF, and Raf. Interestingly, the PKCdelta requirement is apparently cell type specific, since FGF-induced ERK activation was independent of PKCdelta in NIH 3T3 murine fibroblasts, in which FGF is a mitogen. These data demonstrate that PKCdelta contributes to growth factor specificity and response in neuronal cells and may also promote cell-type-specific differences in growth factor signaling.

MeSH Terms
Acetophenones/pharmacology Androstadienes/pharmacology Animals Benzopyrans/pharmacology Calcium-Calmodulin-Dependent Protein Kinases/metabolism,physiology Cell Line Enzyme Inhibitors/pharmacology Estradiol/pharmacology Fibroblast Growth Factors/physiology Isoenzymes/physiology Mitogen-Activated Protein Kinase 1 Nerve Growth Factors/physiology Neurites/pathology Neurons/enzymology Oligonucleotides, Antisense PC12 Cells Protein Kinase C/physiology Protein Kinase C-delta Proto-Oncogene Proteins c-raf/metabolism Rats Transfection Wortmannin
Chemicals
Acetophenones Androstadienes Benzopyrans Enzyme Inhibitors Isoenzymes Nerve Growth Factors Oligonucleotides, Antisense Estradiol Fibroblast Growth Factors rottlerin Prkcd protein, rat Proto-Oncogene Proteins c-raf Protein Kinase C Protein Kinase C-delta Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinase 1 Wortmannin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Corbit K C
Department of Pharmacological and Physiological Sciences and The Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.
Foster D A
Rosner M R
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.19.6.4209
Published
1999-06-00
Pages
4209-18
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC104380
Subset
IM
Grants
NIGMS NIH HHS · T32 GM007151 · United States
NCI NIH HHS · CA46677 · United States
NIGMS NIH HHS · 5 T32 GM 07151-24 · United States
NINDS NIH HHS · NS33858 · United States
NINDS NIH HHS · R01 NS033858 · United States
NCRR NIH HHS · G12 RR003037 · United States
NCI NIH HHS · R01 CA046677 · United States
External Links
PubMed source DOI: 10.1128/MCB.19.6.4209 PMC Full Text View journal details
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