Focal adhesion signaling in heart failure

Abstract

In this brief review, recent evidence is presented to indicate a role for specific components of the cardiomyocyte costamere (and its related structure the focal adhesion complex of cultured cardiomyocytes) in initiating and sustaining the aberrant signal transduction that contributes to myocardial remodeling and the progression to heart failure (HF). Special attention is devoted to the focal adhesion kinase family of nonreceptor protein tyrosine kinases in bidirectional signal transduction during cardiac remodeling and HF progression. Finally, some speculations and directions for future study are provided for this rapidly developing field of research.

Figure 1. Cellular localization of costameres in striated muscle

(A) A schematic diagram is depicted, illustrating costameres as circumferential elements that physically couple peripheral myofibrils to the sarcolemma in periodic register with the Z-disk. The protein composition of costameres includes integrins, a variety of cytoskeletal and adaptor proteins, and signaling kinases. (B) An inside-out sarcolemma that was mechanically peeled from a single myofiber and stained with antibodies to γ-actin to reveal the costameric cytoskeleton. Bar = 10 μm. The figure was reproduced from [17] by copyright permission of The American Society for Biochemistry and Molecular Biology.

Figure 2. Nanoscale architecture of focal adhesions

Schematic model of focal adhesion molecular architecture, depicting experimentally determined protein positions. Note that the model does not depict protein stoichiometry. The figure was reproduced from [33] by copyright permission of the Nature Publishing Group.

Figure 3. Expression of talin-1 (Tln1) and talin-2 (Tln2) in adult human cardiac tissue

Adult human cardiac tissue was evaluated for expression of Tln1 and Tln2. Tln1 was weakly detected in the cardiomyocyte membrane, as shown by co-localization with Dystrophin (Dys), a muscle-specific membrane marker. It was also detected in non-myocyte cells (*). Tln2 was detected in a costameric pattern in cardiomyocytes as demonstrated by strong co-localization with Dys (arrows). DAPI staining (blue) shows the position of cell nuclei. Scale bar = 20 μm. The figure was reproduced from [45] by copyright permission of The American Society for Biochemistry and Molecular Biology.

Figure 4. Structural domains of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (PYK2)

Proline-rich tyrosine kinase-2 (PYK2) shares a similar domain arrangement with focal adhesion kinase (FAK), with 60% sequence identity in the central kinase domain, conservation of proline-rich regions (PRRs), and identical positions of four tyrosine phosphorylation sites. PYK2 tyrosines 402, 579, 580 and 881 correspond to FAK tyrosines 397, 576, 577 and 925, respectively. FAK and PYK2 both contain a C-terminal focal adhesion targeting (FAT) domain that binds to paxillin. However, PYK2 shows a perinuclear distribution and is not strongly localized to focal contacts in many cells. The figure was reproduced from [49] by copyright permission of the Nature Publishing Group.