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J. Biol. Chem., Vol. 279, Issue 30, 31750-31760, July 23, 2004

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Identification of an Amino Acid Residue in the Protein Kinase C C1b Domain Crucial for Its Localization to the Golgi Network^*

Anna Schultz, Mia Ling, and Christer Larsson

From the Department of Laboratory Medicine, Molecular Medicine, Lund University, 205 02 Malmö, Sweden

Protein kinase C (PKC) isoforms have been reported to be targeted to the Golgi complex via their C1 domains. We have shown recently that the regulatory domain of PKC induces apoptosis in neuroblastoma cells and that this effect is correlated to Golgi localization via the C1b domain. This study was designed to identify specific residues in the C1 domains that mediate Golgi localization. We demonstrate that the isolated C1b domains from PKC, -, -, -, and - are targeted to the Golgi complex, whereas the corresponding C1a domains localize throughout the cell. Sequence alignment showed that amino acid residues corresponding to Glu-246 and Met-267 in PKC are conserved among C1b but absent from C1a domains. Mutation of Met-267, but not of Glu-246, to glycine abolished the Golgi localization of the isolated C1b domain and the regulatory domain of PKC. The mutated PKC regulatory domain constructs lacking Golgi localization were unable to induce apoptosis, suggesting a direct correlation between Golgi localization and apoptotic activity of PKC regulatory domain. Mutation of analogous residues in the C1b domain of PKC abrogated its Golgi localization, demonstrating that this effect is not restricted to one PKC isoform. The abolished Golgi localization did not affect neurite induction by PKC. However, the PKC mutant did not relocate to the Golgi network in response to ceramide and ceramide did not suppress the neurite-inducing capacity of the protein. Thus, the specific mutations in the C1b domain influence both the localization and function of full-length PKC.

Received for publication, December 1, 2003 , and in revised form, May 4, 2004.

^* This work was supported by grants from The Swedish Cancer Society, The Children's Cancer Foundation of Sweden, The Swedish Society for Medical Research, Malmö University Hospital Research Funds, and Crafoord, Ollie and Olof Ericsson, Gunnar Nilsson and Greta and Johan Kock Foundations. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Molecular Medicine, Entrance 78, 3rd floor, UMAS, 205 02 Malmö, Sweden. Tel.: 46-40-337404; Fax: 46-40-337322; E-mail: christer.larsson{at}molmed.mas.lu.se.

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