Protein kinase C epsilon and neurite outgrowth

Sammanfattning: Protein kinase C (PKC) is a serine/threonine kinase family with 10 identified isoforms. The contribution of PKC isoforms to cell growth and differentiation, with focus on neurite outgrowth, was investigated, using neuroblastoma and immortalised neural cells as model systems. In neuroblastoma cells one or several of the classical PKC isoforms are of importance for driving proliferation, protecting against apoptosis and mediating upregulation of neuronal differentiation markers. Overexpression of the novel isoform PKC epsilon, but not of other classical or novel PKC isoform normally expressed in neuroblastoma and neural cells, induce neurite outgrowth in these cells. This effect is mediated by the regulatory domain and is hence independent of PKC catalytic activity. The C1 domains with surrounding amino acids were found to be the structures that mediate neurite outgrowth. The fact that neurites are induced in both cell types indicate that neurite induction by PKC epsilon might be a general phenomenon in neuronal cells. Several structures, both in the regulatory and the catalytic domain, are necessary for PKC epsilon-specific neurite induction, including an F-actin-binding site situated between the C1 domains of PKC epsilon. Inhibitory fragments derived from PKC epsilon suppressed both PKC epsilon, retinoic acid and growth factor-induced neuritogenesis, suggesting that PKC epsilon may be of importance for neurite outgrowth during neuronal differentiation. Optimal neurite induction by PKC epsilon requires membrane localisation and/or association to the cortical cytoskeleton, shown by removal decreased neurite induction by a PKC epsilon variant without an F-actin-binding site and increased neurite inducing potential by myristoylated PKC epsilon .