PKC{varepsilon}, Via its Regulatory Domain and Independently of its Catalytic Domain, Induces Neurite-like Processes in Neuroblastoma Cells

doi:10.1083/jcb.145.4.713

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© The Rockefeller University Press, 0021-9525/1999//713 $5.00
The Journal of Cell Biology, Volume 145, Number 4, , 1999 713-726

Regular Articles

PKC ${varepsilon}$ , Via its Regulatory Domain and Independently of its Catalytic Domain, Induces Neurite-like Processes in Neuroblastoma Cells

Ruth Zeidman, Bjarne Löfgren, Sven Påhlman, and Christer Larsson

Lund University, Department of Laboratory Medicine, Molecular Medicine, Malmö University Hospital, S-205 02 Malmö, Sweden

To investigate the role of protein kinase C (PKC) isoformsin regulation of neurite outgrowth, PKC ${alpha}$ , βII, ${delta}$ , and ${varepsilon}$ fusedto enhanced green fluorescent protein (EGFP) were transientlyoverexpressed in neuroblastoma cells. Overexpression of PKC ${varepsilon}$ –EGFP induced cell processes whereas the other isoforms did not.The effect of PKC ${varepsilon}$ –EGFP was not suppressed by the PKCinhibitor GF109203X. Instead, process formation was more pronouncedwhen the regulatory domain was introduced. Overexpression ofvarious fragments from PKC ${varepsilon}$ regulatory domain revealed thata region encompassing the pseudosubstrate, the two C1 domains,and parts of the V3 region were necessary and sufficient forinduction of processes. By deleting the second C1 domain fromthis construct, a dominant-negative protein was generated whichsuppressed processes induced by full-length PKC ${varepsilon}$ and neuritesinduced during retinoic acid- and growth factor–induced differentiation. As with neurites in differentiated neuroblastomacells, processes induced by the PKC ${varepsilon}$ – PSC1V3 protein contained ${alpha}$ -tubulin, neurofilament-160, and F-actin, but the PKC ${varepsilon}$ –PSC1V3-inducedprocesses lacked the synaptic markers synaptophysin and neuropeptideY. These data suggest that PKC ${varepsilon}$ , through its regulatory domain,can induce immature neurite-like processes via a mechanismthat appears to be of importance for neurite outgrowth duringneuronal differentiation.

Key Words: C1 domains • neuroblastoma cells • neuronal differentiation • neurite outgrowth • protein kinase C

Abbreviations used in this paper: CNTF, ciliary neurotrophic factor; EGFP, enhanced green fluorescent protein; FL, full-length PKC; FLE, full-length PKC bound to EGFP; GFP, green fluorescent protein; NF-160, neurofilament-160; NPY, neuropeptide Y; PKC, protein kinase C; RA, retinoic acid; RACK, receptor for activated C-kinase; RD, regulatory domain; TPA, 12-O-tetradecanoylphorbol-13-acetate.

Financial support was obtained from The Swedish Society forMedical Research, The Swedish Cancer Society, The Children'sCancer Foundation of Sweden, HKH Kronprinsessan Lovisas föreningför barnasjukvård, Malmö University HospitalResearch Funds, and Magnus Bergvall, Crafoord, Ollie and ElofEricsson, Hans von Kantzow, Gunnar, Arvid, and Elisabeth Nilsson,and John and Augusta Persson Foundations.

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