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J. Biol. Chem., Vol. 279, Issue 49, 51601-51611, December 3, 2004

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Regulation of ADAM12 Cell-surface Expression by Protein Kinase C ^*

Christina Sundberg¶, Charles Kumar Thodeti, Marie Kveiborg¶, Christer Larsson||, Peter Parker**, Reidar Albrechtsen, and Ulla M. Wewer

From the Institute of Molecular Pathology, University of Copenhagen, Frederik V's Vej 11, Copenhagen, DK-2100, Denmark, ^||Department of Laboratory Medicine, University Hospital, Lund University, S-20502 Malmö, Sweden, and ^**Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

The ADAM (a disintegrin and metalloprotease) family consists of multidomain cell-surface proteins that have a major impact on cell behavior. These transmembrane-anchored proteins are synthesized as proforms that have (from the N terminus): a prodomain; a metalloprotease-, disintegrin-like-, cysteine-rich, epidermal growth factor-like, and transmembrane domain; and a cytoplasmic tail. The 90-kDa mature form of human ADAM12 is generated in the trans-Golgi through cleavage of the prodomain by a furin-peptidase and is stored intracellularly until translocation to the cell surface as a constitutively active protein. However, little is known about the regulation of ADAM12 cell-surface translocation. Here, we used human RD rhabdomyosarcoma cells, which express ADAM12 at the cell surface, in a temporal pattern. We report that protein kinase C (PKC) induces ADAM12 translocation to the cell surface and that catalytic activity of PKC is required for this translocation. The following results support this conclusion: 1) treatment of cells with 0.1 µM phorbol 12-myristate 13-acetate (PMA) enhanced ADAM12 cell-surface immunostaining, 2) ADAM12 and PKC could be co-immunoprecipitated from membrane-enriched fractions of PMA-treated cells, 3) RD cells transfected with EGFP-tagged, myristoylated PKC expressed more ADAM12 at the cell surface than did non-transfected cells, and 4) RD cells transfected with a kinase-inactive PKC mutant did not exhibit ADAM12 cell-surface translocation upon PMA treatment. Finally, we demonstrate that the C1 and C2 domains of PKC both contain a binding site for ADAM12. These studies show that PKC plays a critical role in the regulation of ADAM12 cell-surface expression.

Received for publication, April 5, 2004 , and in revised form, September 9, 2004.

^* This study was supported in part by grants from the Danish Cancer Society, Danish Medical Research Council, Neye Foundation, Velux, Novo Nordisk, Munksholm, Friis, and Haensch Foundations, and by Medical Devices Agency and European Union grants, Quality of Life and Management of Living Resources (contract no. QLG1-CT-1999-00870, designated Genetic Resolution of Myopathies: European cluster [Myocluster]). 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.

Both authors contributed equally to this work.

^¶ Supported by postdoctoral fellowships from the Danish Medical Research Council.

Corresponding author. Tel.: 45-3532-6056; Fax: 45-3532-6081; E-mail: ullaw{at}pai.ku.dk.

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