ATP, a purinergic receptor agonist, has been shown to be involved in vascular 
smooth muscle (VSM) cell 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, PKC, and Ca(2+)/calmodulin-dependent protein kinase II 
(CaMKII) as intermediates. Selective inhibition of PKC-delta activity with 
rottlerin, or adenoviral overexpression of kinase-negative PKC-delta, attenuated 
the ATP- and phorbol 12,13-dibutyrate (PDBu)-stimulated ERK1/2 activation. 
Inhibition of PKC-alpha activity with Gö-6976, or adenoviral overexpression of 
kinase-negative PKC-alpha, was ineffective. Alternatively, treatment with KN-93, 
a selective inhibitor of CaMKII activation, or adenoviral overexpression of 
kinase-negative CaMKII-delta(2), inhibited ATP-dependent activation of ERK1/2 
but had no effect on PDBu- or PDGF-stimulated ERK1/2. In addition, adenoviral 
overexpression of dominant-negative ras (Ad.HA-Ras(N17)) 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 AG-1478, an EGFR 
inhibitor, or the src family kinase inhibitor PP2 attenuated ATP-stimulated 
ERK1/2 activation. Taken together, these data indicate that PKC-delta and 
CaMKII-delta(2) coordinately mediate ATP-dependent transactivation of EGF 
receptor, resulting in increased ERK1/2 activity in VSM cells.