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Am J Physiol Lung Cell Mol Physiol 280: L1049-L1056, 2001;
1040-0605/01 $5.00
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Vol. 280, Issue 5, L1049-L1056, May 2001

Dual signaling by the alpha vbeta 3-integrin activates cytosolic PLA2 in bovine pulmonary artery endothelial cells

Sunita Bhattacharya1, Rashmi Patel2, Namita Sen2,3, Sadiqa Quadri2,3, Kaushik Parthasarathi2,3, and Jahar Bhattacharya2,3

Departments of 1 Pediatrics, 2 Medicine, and 3 Physiology and Cellular Biophysics, College of Physicians and Surgeons and St. Luke's Roosevelt Hospital Center, Columbia University, New York, New York 10019

Vitronectin, which ligates the alpha vbeta 3-integrin, increases both lung capillary permeability and lung endothelial Ca2+. In stable monolayers of bovine pulmonary artery endothelial cells (BPAECs) viewed with confocal microscopy, multimeric vitronectin aggregated the apically located alpha vbeta 3-integrin. This caused arachidonate release that was inhibited by pretreating the monolayers with the anti-alpha vbeta 3 monoclonal antibody (MAb) LM609. No inhibition occurred in the presence of the isotypic MAb PIF6, which recognizes the integrin alpha vbeta 5. Vitronectin also caused membrane translocation and phosphorylation of cytosolic phospholipase A2 (cPLA2) as well as tyrosine phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) 2. The cPLA2 inhibitor arachidonyl trifluoromethylketone, the tyrosine kinase inhibitor genistein, and the MAPK kinase inhibitor PD-98059 all blocked the induced arachidonate release. PD-98059 did not inhibit the increase of cytosolic Ca2+ or cPLA2 translocation, although it blocked tyrosine phosphorylation of ERK2. Moreover, although the intracellular Ca2+ chelator MAPTAM also inhibited arachidonate release, it did not inhibit tyrosine phosphorylation of ERK2. These findings indicate that ligation of apical alpha vbeta 3 in BPAECs caused ERK2 activation and an increase of intracellular Ca2+, both conjointly required for cPLA2 activation and arachidonate release. This is the first instance of a tyrosine phosphorylation-initiated "two-hit" signaling pathway that regulates an integrin-induced proinflammatory response.

vitronectin; SC5b-9; arachidonate; cytosolic phospholipase A2


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