Early activation of the multicomponent signaling complex associated with focal adhesion kinase induced by pressure overload in the rat heart

Mechanical overload elicits functional and structural adaptive mechanisms i n cardiac muscle. Signaling pathways Linked to integrin/cytoskeleton comple xes may have a function in mediation of the effects of mechanical stimulus in myocardial cells. We investigated the tyrosine phosphorylation and the a ssembly of the multicomponent signaling complex associated with focal adhes ion kinase (Fak) and the actin cytoskeleton in the overloaded myocardium of rats. Pressure overload induced a 3-fold increase in Fak tyrosine phosphor ylation within 3 minutes after a 60-mm Hg rise in aortic pressure. A pressu re stimulus that lasted for 60 minutes was accompanied by a 5-fold increase in the amount of tyrosine-phosphorylated Fak, and a stimulus as low as 10 mm Hg doubled the amount of tyrosine-phosphorylated Fak in the myocardium w ithin 10 minutes. Pressure overload also induced a time-dependent associati on of actin with Fak and an increase in the amount of Fak detected in the c ytoskeletal fraction of the myocardium. These events were paralleled by c-S rc activation and binding to Fak and by an association of Grb2 and p85 subu nit of phosphatidylinositol 3-kinase with Fak. Erk1/2 and Akt, two possible downstream effecters of Fak via Grb2 and phosphatidylinositol 3-kinase, we re also shown to be activated in parallel with Fak. These findings show tha t pressure overload induced a rapid activation of the Fak multiple signalin g complex in the myocardium of rats, which Suggests that this mechanism may have a role in mechanotransduction in the myocardium.