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The Journal of Neuroscience, April 8, 2009, 29(14):4605-4615; doi:10.1523/JNEUROSCI.5126-08.2009

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Neurobiology of Disease
ADAM-10-Mediated N-Cadherin Cleavage Is Protein Kinase C- Dependent and Promotes Glioblastoma Cell Migration

Zachary A. Kohutek,¹ Charles G. diPierro,² Gerard T. Redpath,¹ and Isa M. Hussaini¹

Departments of ¹Pathology and ²Molecular Physiology and Biological Physics, University of Virginia Health System, Charlottesville, Virginia 22908

Correspondence should be addressed to Zachary A. Kohutek, Department of Pathology, University of Virginia Health System, P.O. Box 800904, Charlottesville, VA 22908. Email: zsk3k{at}virginia.edu

MMPs (matrix metalloproteinases) and the related "a disintegrin and metalloproteinases" (ADAMs) promote tumorigenesis by cleaving extracellular matrix and protein substrates, including N-cadherin. Although N-cadherin is thought to regulate cell adhesion, migration, and invasion, its role has not been characterized in glioblastomas (GBMs). In this study, we investigated the expression and function of posttranslational N-cadherin cleavage in GBM cells as well as its regulation by protein kinase C (PKC). N-Cadherin cleavage occurred at a higher level in glioblastoma cells than in non-neoplastic astrocytes. Treatment with the PKC activator phorbol 12-myristate 13-acetate (PMA) increased N-cadherin cleavage, which was reduced by pharmacological inhibitors and short interfering RNA (siRNA) specific for ADAM-10 or PKC-. Furthermore, treatment of GBM cells with PMA induced the translocation of ADAM-10 to the cell membrane, the site at which N-cadherin was cleaved, and this translocation was significantly reduced by the PKC- inhibitor Gö6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole] or PKC- short hairpin RNA. In functional studies, N-cadherin cleavage was required for GBM cell migration, as depletion of N-cadherin cleavage by N-cadherin siRNA, ADAM-10 siRNA, or a cleavage-site mutant N-cadherin, decreased GBM cell migration. Together, these results suggest that N-cadherin cleavage is regulated by a PKC-–ADAM-10 cascade in GBM cells and may be involved in mediating GBM cell migration.

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Received Oct. 22, 2008; revised Feb. 17, 2009; accepted March 6, 2009.

Correspondence should be addressed to Zachary A. Kohutek, Department of Pathology, University of Virginia Health System, P.O. Box 800904, Charlottesville, VA 22908. Email: zsk3k{at}virginia.edu

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