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Protein Kinase C- Plays a Role in Neurite Outgrowth in Response to Epidermal Growth Factor and Nerve Growth Factor in PC12 Cells

Molecular Mechanisms of Tumor Promotion Section, LCCTP [C. B., K. B., P. A., P. M. B.] and Signal Transduction Section, LCO [G. P., W. B. A.], National Cancer Institute, NIH, Bethesda, Maryland 20892, and Gonda-Goldschmied Center, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel [C. B., P. L.]

In this study, we examined the role of specific protein kinase C (PKC) isoforms in the differentiation of PC12 cells in response to nerve growth factor (NGF) and epidermal growth factor (EGF). PC12 cells express PKC-, -ß, -, -, -, -µ, and -. For PKC-, -, and -, NGF and EGF exerted differential effects on translocation. Unlike overexpression of PKC- and -, overexpression of PKC- caused enhanced neurite outgrowth in response to NGF. In the PKC--overexpressing cells, EGF also dramatically induced neurite outgrowth, arrested cell proliferation, and induced a sustained phosphorylation of mitogen-activated protein kinase (MAPK), in contrast to its mitogenic effects on control cells or cells overexpressing PKC- and -. The induction of neurite outgrowth by EGF was inhibited by the MAPK kinase inhibitor PD95098. In cells overexpressing a PKC- dominant negative mutant, NGF induced reduced neurite outgrowth and a more transient phosphorylation of MAPK than in controls. Our results suggest an important role for PKC- in neurite outgrowth in PC12 cells, probably via activation of the MAPK pathway.

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