Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy

Abstract

FAK undergoes S910 phosphorylation via PKCδ and Src-dependent pathways that are important for cell spreading and sarcomere reorganization. Reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization in DCM.

Focal adhesion signaling in heart failure

“…However, the rapid turnover of focal adhesion components plays a crucial role in cellular differentiation and migration during cardiac development [18,89,30,23,24], and may also be an important regulatory factor during new sarcomere addition in response to hypertrophic stimuli [47,10]. Using fluorescence recovery after photobleaching (FRAP) and mathematical modeling, Ingber and colleagues [42] showed that various components of the focal adhesion complex display residence times that vary from as little as 1 sec for vinculin, and up to 111 sec for talin.…”

“…Sanger and co-workers [86] had previously observed a similar dynamic range of exchange between costamere/Z-disc proteins and the cytoplasm of spreading skeletal muscle myotubes. Using FRAP, we subsequently demonstrated that the phosphorylation of FAK, a critical component of the signaling layer of cardiomyocyte focal adhesions, regulates the stability of paxillin within cardiomyocyte focal adhesions, and ultimately controls the rate of cell spreading and myofibrillar organization of cultured cardiomyocytes in response to both static stretch, and the hypertrophic agonist endothelin-1 [10]. Thus, the dynamic nature of cytoskeletal assembly and disassembly within focal adhesion complexes appears critical during the response of cultured cardiomyocytes to neurohormonal and mechanical stimuli.…”

“…The functional role of FAK serine phosphorylation in cardiomyocytes is largely unknown, but one report indicates that serine (and tyrosine) phosphorylation of FAK increases dramatically in hypertensive rats, with different sites of phosphorylation appearing to regulate FAK subcellular localization [91]. Our group [10] recently demonstrated that endothelin-1 and other hypertrophic factors induced a time- and dose-dependent increase in FAK-S910 phosphorylation. Endothelin-induced FAK-S910 phosphorylation required endothelin Type A receptor-dependent activation of Protein Kinase Cδ (PKCδ) and Src via parallel Raf-1→ MEK1/2 →ERK1/2 and MEK5 →ERK5 signaling pathways.…”

“…Finally, we found that FAK was serine-phosphorylated at multiple sites in non-failing, human left ventricular tissue, and both FAK-S910 phosphorylation and ERK5 expression were dramatically reduced in patients undergoing heart transplantation for end-stage dilated cardiomyopathy. These results suggest that reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization that is frequently observed in end-stage heart failure patients [10]. …”

“…The ERK-dependent, regulated exit of FAK from cardiomyocyte costameres [10] is reminiscent of the cyclic FAK tyrosine and serine phosphorylation that occurs during migration of nonmuscle cells [52]. In this scenario, FAK/Src tyrosine phosphorylation at Y 397 and Y 925 promotes the assembly of new costameres in response to hypertrophic agonists or mechanical strain.…”