HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 13, 8379-8388, March 31, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/13/8379    most recent M513122200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stamatovic, S. M. Articles by Andjelkovic, A. V. Search for Related Content PubMed PubMed Citation Articles by Stamatovic, S. M. Articles by Andjelkovic, A. V. Social Bookmarking                      What's this?

Protein Kinase C-RhoA Cross-talk in CCL2-induced Alterations in Brain Endothelial Permeability^*

Svetlana M. Stamatovic, Oliver B. Dimitrijevic, Richard F. Keep, and Anuska V. Andjelkovic^¶1

From the Departments of Neurosurgery, ^¶Pathology, and Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Monocyte chemoattractant protein-1 (MCP-1 or 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 the 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 Triton X-100-soluble as well as Triton X-100-insoluble cell fractions. Two protein kinase C (PKC) isoforms, PKC and PKC, had a significant impact on this event. Inhibition of their activity using dominant negative mutants PKC-DN and PKC-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, PKC, and PKC activities were knocked down using dominant negative mutants (T17Rho, PKC-DN, and PKC-DN, respectively). PKC and Rho, but not PKC and Rho, interacted at the level of Rho, with PKC 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/PKC signal pathway interactions.

Received for publication, December 8, 2005 , and in revised form, January 9, 2006.

^* This work was supported by National Institutes of Health Grant NS044907 (to A. V. A.). 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.

¹ To whom correspondence should be addressed: Depts. of Neurosurgery and Pathology, University of Michigan, R5550 Kresge I, Ann Arbor, MI 48109-0532. Tel.: 734-647-0651; Fax: 734-763-7322; E-mail: anuskaa{at}umich.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Thongon, L.-i. Nakkrasae, J. Thongbunchoo, N. Krishnamra, and N. Charoenphandhu Prolactin stimulates transepithelial calcium transport and modulates paracellular permselectivity in Caco-2 monolayer: mediation by PKC and ROCK pathways Am J Physiol Cell Physiol, May 1, 2008; 294(5): C1158 - C1168. [Abstract] [Full Text] [PDF]

				M. R. Gillrie, G. Krishnegowda, K. Lee, A. G. Buret, S. M. Robbins, S. Looareesuwan, D. C. Gowda, and M. Ho Src-family kinase dependent disruption of endothelial barrier function by Plasmodium falciparum merozoite proteins Blood, November 1, 2007; 110(9): 3426 - 3435. [Abstract] [Full Text] [PDF]

				N. S. Harhaj, E. A. Felinski, E. B. Wolpert, J. M. Sundstrom, T. W. Gardner, and D. A. Antonetti VEGF Activation of Protein Kinase C Stimulates Occludin Phosphorylation and Contributes to Endothelial Permeability Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 5106 - 5115. [Abstract] [Full Text] [PDF]

				H. Abdala-Valencia and J. M. Cook-Mills VCAM-1 Signals Activate Endothelial Cell Protein Kinase C{alpha} via Oxidation J. Immunol., November 1, 2006; 177(9): 6379 - 6387. [Abstract] [Full Text] [PDF]