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and CaMKII2 Mediate ATP-Dependent Activation of ERK1/2 in Vascular Smooth Muscle
1 Cardiovascular Sciences, Albany Medical College, Albany, NY, USA
2 Cell Biology and Cancer Research, Albany Medical College, Albany, NY, USA
* To whom correspondence should be addressed. E-mail: singerh{at}mail.amc.edu.
ATP, a purinergic receptor agonist, has been shown to be involved in vascular smooth muscle cell (VSM) DNA synthesis and cell proliferation during embryonic and postnatal development, after injury, and in atherosclerosis. One mechanism that ATP utilizes to regulate cellular function is through activation of ERK1/2. In the present study, we provide evidence that ATP-dependent activation of ERK1/2 in VSM cells utilizes specific isoforms of the multifunctional serine/threonine kinases, protein kinase C (PKC) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) as intermediates. Selective inhibition of PKC
activity with rottlerin, or adenoviral overexpression of kinase-negative PKC(Ad.KN-PKC
, attenuated the ATP- and PDBu-stimulated ERK1/2 activation. Inhibition of PKC activity with Go6976, or adenoviral overexpression of kinase-negative PKC (Ad.KN-PKC), was ineffective. Alternatively, treatment with KN93, a selective inhibitor of CaMKII activation, or adenoviral overexpression of kinase-negative CaMKII2 (Ad.KN-CaMKII2), inhibited ATP-dependent activation of ERK1/2 but had no effect on PDBu- or PDGF-stimulated ERK1/2. Additionally, adenoviral overexpression of dominant-negative ras (AD.HA-RasN17) partially inhibited the ATP- and PDBu-induced activation of ERK1/2 and blocked ionomycin- and EGF-stimulated ERK1/2 and inhibition of tyrosine kinases with AG1478, an EGFR inhibitor, or the SFK inhibitor PP2, attenuated ATP-stimulated ERK1/2 activation. Taken together, these data indicate that PKC and CaMKII2 coordinately mediate ATP-dependent transactivation of EGFR resulting in increased ERK1/2 activity in VSM cells.
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