Early Activation of the Multicomponent Signaling Complex Associated With Focal Adhesion Kinase Induced by Pressure Overload in the Rat Heart

• Published in: Circulation research 2000-09, Vol.87 (7), p.558-565
• Main Authors: Franchini, Kleber G, Torsoni, Adriana S, Soares, Paulo H. A, Saad, Mario J. A
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Aorta; Biological and medical sciences; Blood Pressure; Enzyme Activation; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Fundamental and applied biological sciences. Psychology; GRB2 Adaptor Protein; Heart; Male; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Myocardium - enzymology; Myocardium - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Pressure - adverse effects; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins pp60(c-src) - metabolism; Rats; Rats, Wistar; Signal Transduction; Tissue Distribution; Tyrosine - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.87.7.558

Mechanical overload elicits functional and structural adaptive mechanisms in cardiac muscle. Signaling pathways linked to integrin/cytoskeleton complexes may have a function in mediation of the effects of mechanical stimulus in myocardial cells. We investigated the tyrosine phosphorylation and the assembly of the multicomponent signaling complex associated with focal adhesion kinase (Fak) and the actin cytoskeleton in the overloaded myocardium of rats. Pressure overload induced a 3-fold increase in Fak tyrosine phosphorylation within 3 minutes after a 60-mm Hg rise in aortic pressure. A pressure 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 within 10 minutes. Pressure overload also induced a time-dependent association of actin with Fak and an increase in the amount of Fak detected in the cytoskeletal fraction of the myocardium. These events were paralleled by c-Src activation and binding to Fak and by an association of Grb2 and p85 subunit of phosphatidylinositol 3-kinase with Fak. Erk1/2 and Akt, two possible downstream effectors of Fak via Grb2 and phosphatidylinositol 3-kinase, were also shown to be activated in parallel with Fak. These findings show that pressure overload induced a rapid activation of the Fak multiple signaling complex in the myocardium of rats, which suggests that this mechanism may have a role in mechanotransduction in the myocardium.