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J. Biol. Chem., Vol. 279, Issue 44, 46122-46128, October 29, 2004

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An Essential Role of the Jak-2/STAT-3/Cytosolic Phospholipase A₂ Axis in Platelet-derived Growth Factor BB-induced Vascular Smooth Muscle Cell Motility^*

Indira Neeli, Zhimin Liu, Nagadhara Dronadula, Z. Alex Ma, and Gadiparthi N. Rao¶

From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and the Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, New York 10029

Platelet-derived growth factor-BB (PDGF-BB) is a potent motogen for vascular smooth muscle cells (VSMCs). To understand its motogenic signaling events, we have studied the role of the Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT) pathway and cytosolic phospholipase A₂ (cPLA₂). PDGF-BB stimulated tyrosine phosphorylation of Jak-2 and STAT-3 in a time-dependent manner in VSMCs. In addition, AG490 and Jak-2KEpRK5, a selective pharmacological inhibitor and a dominant negative mutant, respectively, of Jak-2, attenuated PDGF-BB-induced STAT-3 tyrosine phosphorylation and its DNA binding and reporter gene activities. PDGF-BB induced VSMC motility in a dose-dependent manner with a maximum effect at 10 ng/ml. Dominant negative mutant-dependent suppression of Jak-2 and STAT-3 blocked PDGF-BB-induced VSMC motility. PDGF-BB induced the expression of cPLA₂ in a Jak-2/STAT-3-dependent manner, and pharmacological inhibitors of cPLA₂ prevented PDGFBB-induced VSMC motility. Furthermore, either exogenous addition of arachidonic acid or forced expression of cPLA₂ rescued PDGF-BB-induced VSMC motility from inhibition by blockade of Jak-2 and STAT-3 activation. Together, these results for the first time show that PDGF-BB-induced VSMC motility requires activation of the Jak-2/STAT-3/cPLA₂ signaling axis.

Received for publication, June 21, 2004 , and in revised form, August 5, 2004.

^* This work was supported by National Institutes of Health Grant HL2RO1064165-06. 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.

^¶ To whom correspondence should be addressed: Dept. of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163. Tel.: 901-448-7321; Fax: 901-448-7126; E-mail: grao{at}physio1.utmem.edu.

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