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Am J Physiol Cell Physiol (September 7, 2005). doi:10.1152/ajpcell.00284.2005
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Submitted on June 14, 2005
Accepted on September 5, 2005

Thrombin Induces the Expression of FGF-2 via Activation of PI3K-Akt-Fra-1 Signaling Axis Leading to DNA Synthesis and Motility in Vascular Smooth Muscle Cells

Huiqing Cao1, Nagadhara Dronadula1, and Gadiparthi N Rao1*

1 Physiology, University of Tennessee Health Science Center, Memphis, TN, USA

* To whom correspondence should be addressed. E-mail: grao{at}physio1.utmem.edu.

In order to understand the mechanisms by which thrombin induces vascular smooth muscle cell (VSMC) DNA synthesis and motility, here we have studied the role of PI3K-Akt-mTOR-S6K1 signaling. Thrombin stimulated the phosphorylation of Akt and S6K1 in VSMC in a sustained manner. Blockade of PI3K-Akt-mTOR-S6K1 signaling by LY294002 and rapamycin suppressed both thrombin-induced VSMC DNA synthesis and migration. Adenoviral-mediated expression of dnAkt also inhibited thrombin-induced VSMC DNA synthesis and migration. Furthermore, thrombin induced the expression of Fra-1 in a sustained and PI3K-Akt-dependent and mTOR-independent manner in VSMC. Suppression of Fra-1 by its siRNA attenuated both thrombin-induced VSMC DNA synthesis and migration. Thrombin also induced the expression of FGF-2 in PI3K-Akt-Fra-1-dependent and mTOR-independent manner and neutralizing anti-FGF-2 antibodies inhibited thrombin-stimulated VSMC DNA synthesis and motility. In addition, thrombin stimulated the tyrosine phosphorylation of epidermal growth factor receptor and inhibition of its kinase activity significantly blocked Akt and S6K1 phosphorylation, Fra-1 and FGF-2 expression, DNA synthesis and motility induced by thrombin in VSMC. Together, these observations suggest that thrombin induces both VSMC DNA synthesis and motility via EGFR-dependent stimulation of PI3K/Akt signaling targeting in parallel the Fra-1-mediated FGF-2 expression and mTOR-S6K1 activation.




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[Abstract] [Full Text] [PDF]


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