Protein kinase C-alpha:Rhoa cross talk in CCL2-induced alterations in brain endothelial permeability

doi:10.1074/jbc.M513122200

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Papers In Press, published online ahead of print January 26, 2006
J. Biol. Chem, 10.1074/jbc.M513122200
Submitted on December 8, 2005
Revised on January 9, 2006
Accepted on January 26, 2006

Protein kinase C-alpha:Rhoa cross talk in CCL2-induced alterations in brain endothelial permeability

Svetlana M. Stamatovic, Oliver B. Dimitrijevic, Richard F. Keep, and Anuska V. Andjelkovic

Pathology and Neurosurgery, University of Michigan, Ann Arbor, MI 48109

Corresponding Author: anuskaa{at}umich.edu

Monocyte chemoattractant protein-1 (MCP-1, CCL2) regulates blood-brain barrier permeability by inducing morphological and biochemical alterations in the tight junction (TJ) complex between brain endothelial cells. The present study used cultured brain endothelial cells to examine the signaling networks involved in the redistribution of TJ proteins (occludin, ZO-1, ZO-2, claudin-5) by CCL2. The CCL2-induced alterations in brain endothelial barrier were associated with de novo Ser/Thr phosphorylation of occludin, ZO-1, ZO-2 and claudin-5. The phosphorylated TJ proteins were redistributed/localized in TritonX-100 soluble as well as TritonX-100 insoluble cell fractions. Two PKC isoforms, PKCa and PKCz, had a significant impact on this event. Inhibition of their activity using dominant negative mutants, PKCa-DN and PKCz-DN, diminished CCL2 effects on brain endothelial permeability. Previous data indicate that Rho/Rho kinase signaling is involved in CCL2 regulation of brain endothelial permeability. The interactions between the PKC and Rho/Rho kinase pathways were, therefore, examined. Rho, PKCa and PKCz activities were knocked down using dominant negative mutants (T17Rho, PKCa-DN, PKCz-DN, respectively). PKCa and Rho, but not PKCz and Rho, interacted at the level of Rho, with PKCa being a downstream target for Rho. Double transfection experiments using dominant negative mutants confirmed that this interaction is critical for CCL2-induced redistribution of TJ proteins. Collectively these data suggest for the first time that CCL2 induces brain endothelial hyperpermeability via Rho/PKCa signal pathway interactions.

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