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1 Cardiovascular Sciences, Albany Medical College, Albany, NY, USA
* To whom correspondence should be addressed. E-mail: singerh{at}mail.amc.edu.
Cell adhesion-dependent activation of ERK1/2 has been linked functionally to focal adhesion dynamics. We previously reported that in adherent vascular smooth muscle (VSM) cells, Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates ERK1/2 activation in response to Ca2+-mobilizing stimuli. In this study, we tested if CaMKII regulated ERK1/2 signaling in response to VSM cell adhesion. Using an antibody that specifically recognizes CaMKII (auto)phosphorylated on thr287, we determined that CaMKII is rapidly (within 1 min) activated following adherence of cells on multiple extracellular matrix substrates. Activation of CaMKII on fibronectin was unaffected in cells overexpressing FAK-related non-kinase (FRNK), an endogenous inhibitor of FAK. Furthermore, CaMKII was rapidly and robustly activated in VSM cells plated on poly-l-lysine. These results suggest that adhesion-dependent CaMKII activation is integrin-independent. Adhesion-dependent FAK activation on fibronectin was not affected in cells treated with the selective CaMKII inhibitor KN93 (30 µM) or by suppressing expression of CaMKII with siRNA, although tyrosine phosphorylation of paxillin was inhibited in CaMKII
2 suppressed cells. Sustained ERK1/2 activation that was dependent upon FAK activation (inhibited by FRNK) was also attenuated by CaMKII inhibition or siRNA-mediated gene silencing. Rapid ERK1/2 activation that preceded FAK and paxillin activation, was detected upon VSM cell adhesion to poly-l-lysine, and this response was inhibited by CaMKII gene silencing. The results indicate that integrin-independent CaMKII activation is an early signal during VSM cell adhesion that positively modulates ERK1/2 signaling through FAK-dependent and -independent mechanisms.
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