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Vol. 20, Issue 19, 4225-4234, October 1, 2009

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Golgi-associated cPLA2 Regulates Endothelial Cell–Cell Junction Integrity by Controlling the Trafficking of Transmembrane Junction Proteins

Elsa Regan-Klapisz^*,, Vincent Krouwer^*, Miriam Langelaar-Makkinje^*, Laxman Nallan, Michael Gelb, Hans Gerritsen, Arie J. Verkleij^*, and Jan Andries Post^*

*Cellular Architecture and Dynamics, Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands; Molecular Biophysics, Debye Institute for Nanomaterials Science, 3584 CC Utrecht, The Netherlands; and Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195

Submitted February 26, 2008; Revised July 6, 2009; Accepted July 30, 2009
Monitoring Editor: Vivek Malhotra

In endothelial cells specifically, cPLA2 translocates from the cytoplasm to the Golgi complex in response to cell confluence. Considering the link between confluence and cell–cell junction formation, and the emerging role of cPLA2 in intracellular trafficking, we tested whether Golgi-associated cPLA2 is involved in the trafficking of junction proteins. Here, we show that the redistribution of cPLA2 from the cytoplasm to the Golgi correlates with adherens junction maturation and occurs before tight junction formation. Disruption of adherens junctions using a blocking anti-VE-cadherin antibody reverses the association of cPLA2 with the Golgi. Silencing of cPLA2 and inhibition of cPLA2 enzymatic activity using various inhibitors result in the diminished presence of the transmembrane junction proteins VE-cadherin, occludin, and claudin-5 at cell–cell contacts, and in their accumulation at the Golgi. Altogether, our data support the idea that VE-cadherin triggers the relocation of cPLA2 to the Golgi and that in turn, Golgi-associated cPLA2 regulates the transport of transmembrane junction proteins through or from the Golgi, thereby controlling the integrity of endothelial cell–cell junctions.

Address correspondence to: Elsa Regan-Klapisz (E.E.Regan1{at}uu.nl).

Abbreviations used: cPLA2, cytosolic PLA2 alpha; HUVEC, human umbilical vein endothelial cell; MAFP, methylarachidonyl fluorophosphonate; PLA2, phospholipase A2; VE-cadherin, vascular endothelial cadherin.