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Epidermal Growth Factor Induces PC12 Cell Differentiation in the Presence of the Protein Kinase Inhibitor K‐252a
Author(s) -
Isono Fujio,
Widmer Hans R.,
Hefti Franz,
Knüsel Beat
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.63041235.x
Subject(s) - microbiology and biotechnology , tyrosine phosphorylation , platelet derived growth factor receptor , neurotrophin , basic fibroblast growth factor , epidermal growth factor , phospholipase d , neurite , phospholipase c , nerve growth factor , biology , protein tyrosine phosphatase , neurotrophic factors , phosphorylation , signal transduction , chemistry , growth factor , biochemistry , receptor , in vitro
The protein kinase inhibitors K‐252a and K‐252b have been shown earlier to block the actions of nerve growth factor and other neurotrophins and, at lower concentrations, to selectively potentiate neurotrophin‐3 actions. In the present study we show that K‐252a, but not K‐252b, enhances epidermal growth factor (EGF)‐ and basic fibroblast growth factor (bFGF)‐induced neurite outgrowth of PC12 cells at higher concentrations than required for neurotrophin inhibition. In parallel, tyrosine phosphorylation of extracellular signal‐regulated kinases (Erks) elicited by EGF or bFGF was also increased in the presence of K‐252a, and this signal was prolonged for 6 h. EGF‐ and bFGF‐induced phosphorylation of phospholipase C‐γ1 were not changed. The effect of K‐252a on Erks was resistant to chronic treatment with phorbol ester, indicating that protein kinase C is not involved in this potentiation. In partial contrast to the actions of K‐252a, the neurotrophin‐3‐potentiating effect of K‐252b was accompanied by an increase in tyrosine phosphorylation of the Erks and of phospholipase C‐γ1. Finally, although K‐252a alone did not induce neurite outgrowth or tyrosine phosphorylation of Erks or phospholipase C‐γ1, this compound alone stimulated phosphatidylinositol hydrolysis. Our findings identify activities of K‐252a besides the direct interaction with neurotrophin receptors and suggest that a K‐252a‐sensitive protein kinase or phosphatase might be involved in signal transduction for EGF and bFGF. Our results are further compatible with the hypothesis that sustained activation of Erks may be important in PC12 differentiation.