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Protein kinase C-epsilon regulates sphingosine-1-phosphate-mediated migration of human lung endothelial cells through activation of phospholipase D2, protein Kinase C-zeta, and Rac1

Gorshkova, Irina and He, Donghong and Berdyshev, Evgeny and Usatuyk, Peter and Burns, Michael and Kalari, Satish and Zhao, Yutang and Pendyala, Srikanth and Garcia, Joe G.N. and Pyne, N.J. and Brindley, David N. and Natarajan, Viswanathan (2008) Protein kinase C-epsilon regulates sphingosine-1-phosphate-mediated migration of human lung endothelial cells through activation of phospholipase D2, protein Kinase C-zeta, and Rac1. Journal of Biological Chemistry, 283 (17). pp. 11794-11806. ISSN 0021-9258

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Abstract

The signaling pathways by which sphingosine 1-phosphate (S1P) potently stimulates endothelial cell migration and angiogenesis are not yet fully defined. We, therefore, investigated the role of protein kinase C (PKC) isoforms, phospholipase D (PLD), and Rac in S1P-induced migration of human pulmonary artery endothelial cells (HPAECs). S1P-induced migration was sensitive to S1P1 small interfering RNA (siRNA) and pertussis toxin, demonstrating coupling of S1P1 to Gi. Overexpression of dominant negative (dn) PKC-ε or -ζ, but not PKC-α or -δ, blocked S1P-induced migration. Although S1P activated both PLD1 and PLD2, S1P-induced migration was attenuated by knocking down PLD2 or expressing dnPLD2 but not PLD1. Blocking PKC-ε, but not PKC-ζ, activity attenuated S1P-mediated PLD stimulation, demonstrating that PKC-ε, but not PKC-ζ, was upstream of PLD. Transfection of HPAECs with dnRac1 or Rac1 siRNA attenuated S1P-induced migration. Furthermore, transfection with PLD2 siRNA, infection of HPAECs with dnPKC-ζ, or treatment with myristoylated PKC-ζ peptide inhibitor abrogated S1P-induced Rac1 activation. These results establish that S1P signals through S1P1 and Gi to activate PKC-ε and, subsequently, a PLD2-PKC-ζ-Rac1 cascade. Activation of this pathway is necessary to stimulate the migration of lung endothelial cells, a key component of the angiogenic process.