Calmodulin-Dependent Kinase II Mediates Vascular Smooth Muscle Cell Proliferation and Is Potentiated by Extracellular Signal Regulated Kinase

Abstract

Vascular smooth muscle cell (VSMC) proliferation contributes to vascular remodeling in atherosclerosis and hypertension. Calcium-dependent signaling through calcium/calmodulin-dependent kinase II (CaMKII) and ERK1/2 activation plays an important role in the regulation of VSMC proliferation by agents such as alpha-adrenergic receptor agonists. Nevertheless, how the CaMKII and ERK pathways interact in VSMCs has yet to be characterized. The aim of the present study was to clarify this interaction in response to alpha(1)-adrenergic receptor-mediated VSMC proliferation. We discovered that phenylephrine stimulation resulted in complex formation between CaMKII and ERK in a manner that facilitated phosphorylation of both protein kinases. To assess the effects of CaMKII/ERK association on VSMC proliferation, we inhibited endogenous CaMKII either pharmacologically or by adenoviral-mediated gene transfer of a kinase-inactive CaMKII mutant. Inhibition of CaMKII activation but not CaMKII autonomous activity significantly decreased formation of the CaMKII/ERK complex. On the contrary, the expression of constitutively active CaMKII enhanced VSMC growth and CaMKII/ERK association. In addressing the mechanism of this effect, we found that CaMKII could not directly phosphorylate ERK but instead enhanced Raf1 activation. By contrast, ERK interaction with CaMKII facilitated CaMKII phosphorylation and promoted its nuclear localization. Our results reveal a critical role for CaMKII in VSMC proliferation and imply that CaMKII facilitates assembly of the Raf/MEK/ERK complex and that ERK enhances CaMKII activation and influences its subcellular localization.

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

“…Inhibition of the chloride channel activity or knockdown of ANO1 decreased EGFR phosphorylation and subsequently inhibited AKT, SRC, and ERK activation. Furthermore, depletion of ANO1 or inhibition of its biochemical activity blocked CAMKII activation, perhaps also contributing to decreased AKT and ERK phosphorylation as reported previously (33,(36)(37)(38). Consistent with these findings, overexpression of ANO1 in an ANO1-negative cell line promoted cell growth and led to the phosphorylation of both EGFR and CAMKII, indicating the activation of both pathways by ANO1 overexpression.…”

Phylogenetic and in silico structural analysis of the Parkinson disease‐related kinase PINK1

“…A site for JAK2 (MIM] 147796) and NTRK1 (MIM] 191315) tyrosine kinases is conserved in the two CaMKs, which is in good agreement with the recent report of CaMKII phosphorylation by NTRK1 [Lu et al, 2010]. At the activation loop, a well-known target for regulatory phosphorylation [Hanks and Hunter, 1995] there are four putative phosphorylation sites ( CaMKII and DMPK and was experimentally demonstrated for CaMKII [Cipolletta et al, 2010]. Also, a recognition site for JAK2/ NTRK1 is present at the conserved PFY motif of all NSKs except CaMKI.…”

Intracellular Transactivation of Epidermal Growth Factor Receptor byα1A-Adrenoceptor Is Mediated by Phosphatidylinositol 3-Kinase Independently of Activation of Extracellular Signal Regulated Kinases 1/2 and Serine-Threonine Kinases in Chinese Hamster Ovary Cells

“…The induction of vascular contraction and cellular growth and proliferation by a 1 -AR involves the activation of complex signaling pathways including phospholipase C, protein kinase C, calcium/calmodulin-dependent kinase II (CaMKII), phosphatidylinositol 3-kinase (PI3K), Src, mitogen-activated protein kinases, extracellular signal regulated kinases (ERK1/2), and serine-threonine kinases (Akt) (Wu et al, 1992;Xiao et al, 2001;Illario et al, 2003;Koshimizu et al, 2003;Cipolletta et al, 2010;Haba et al, 2010). Modulation of all these intracellular signaling molecules may, at least in part, be dependent on transactivation of EGFR by a 1 -AR.…”