Abstract
An orchestrated interplay of adaptor and signaling proteins at mechano-sensitive sites is essential to maintain cardiac contractility and when defective leads to heart failure. We recently showed that Integrin-linked Kinase (ILK), ß-Parvin and PINCH form the IPP-complex to grant tuned Protein Kinase B (PKB) signaling in the heart. Loss of one of the IPP-complex components results in destabilization of the whole complex, defective PKB signaling and finally heart failure. Two components of IPP, ILK and ß-Parvin directly bind to Paxillin; however, the impact of this direct interaction on the maintenance of heart function is not known yet. Here, we show that targeted gene inactivation of Paxillin results in progressive decrease of cardiac contractility and heart failure in zebrafish without affecting IPP-complex stability and PKB phosphorylation. However, we found that Paxillin deficiency leads to the destabilization of its known binding partner Focal Adhesion Kinase (FAK) and vice versa resulting in degradation of Vinculin and thereby heart failure. Our findings highlight an essential role of Paxillin and FAK in controlling cardiac contractility via the recruitment of Vinculin to mechano-sensitive sites in cardiomyocytes.
Highlights
Integrin-linked Kinase (ILK) is a crucial regulator of cardiomyocyte contractility [1, 2]
Fractional shortening (FS) of paxillin morphant ventricles was reduced to 49.29% ± 4.39% compared to control morphants (FS: 69.3% ± 4.36%) at 72 hpf
We show here for the first time that an orchestrated interplay of Paxillin, Focal Adhesion Kinase (FAK) and Vinculin localizing to sarcomeric Z-disks and costameres in cardiomyocytes is essential for the regulation of cardiac contractility
Summary
Integrin-linked Kinase (ILK) is a crucial regulator of cardiomyocyte contractility [1, 2]. Together with Parvin and PINCH, it forms the ternary IPP-(ILK-Parvin-PINCH) complex which modulates the expression of stretch-responsive genes such as atrial natriuretic factor (anf) or vascular endothelial growth factor (vegf) by the regulation of Protein Kinase B (PKB) phosphorylation and activation in the heart [1, 3]. We and others depicted that loss of each of the IPP-complex components leads to IPP-complex destabilization, reduced PKB phosphorylation and heart failure in zebrafish, mice and humans [1, 3,4,5,6,7]. The IPP-complex is located at focal adhesions and Z-discs where it interacts via ILK and Parvin with Paxillin [8, 9]. Paxillin is a focal adhesion associated adaptor protein that recruits diverse signaling proteins such as Focal adhesion Kinase (FAK) and PLOS ONE | DOI:10.1371/journal.pone.0150323 March 8, 2016
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