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in Neonatal Rat Ventricular Myocytes
1 Cardiovascular Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
* To whom correspondence should be addressed. E-mail: mheidka{at}lumc.edu.
Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase critical for cardiomyocyte survival, and for sarcomeric assembly during endothelin (ET)-induced cardiomyocyte hypertrophy. ET-induced FAK activation requires upstream activation of one or more isoenzymes of protein kinase C (PKC). Therefore, using replication-defective adenoviruses (Adv) to overexpress constitutively active (ca) and dominant-negative (dn) mutants of PKCs, we examined which PKC isoenzymes are necessary for FAK activation, and what downstream signaling components are involved. FAK activation was assessed by Western blotting with an antibody specific for FAK autophosphorylated at Y397 (Y397pFAK). ET (10nmol/L; 2-30 min) resulted in the time-dependent activation of FAK, which was inhibited by chelerythrine (5µmol/L; 1h pretreatment). Adv-caPKC
, but not Adv-caPKC
, activated FAK, compared to a control Adv encoding 
-galactosidase. Conversely, Adv-dnPKC inhibited ET-induced FAK activation. Y-27632 (10µmol/L; 1h pretreatment), an inhibitor of Rho-associated protein kinases (ROCK), prevented ET- and caPKC-induced FAK activation, as well as cofilin phosphorylation. Pretreatment with cytochalasin D (1µmol/L, 1h pretreatment) also inhibited ET-induced Y397pFAK and cofilin phosphorylation and caPKC-induced Y397pFAK. Neither inhibitor, however, interfered with ET-induced ERK1/2 activation. Finally, PP2 (50µmol/L; 1h pretreatment), a highly selective Src inhibitor, did not alter basal or ET-induced Y397pFAK. PP2 did, however, reduce basal and ET-induced phosphorylation of other sites on FAK, namely Y576, Y577, Y861 and Y925. We conclude that the ET-induced signal transduction pathway resulting in downstream Y397pFAK is partially dependent on PKC, ROCK, cofilin, and assembled actin filaments, but not ERK1/2 or Src.
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