title: Paxillin and Focal Adhesion Kinase (FAK) Regulate Cardiac Contractility in the Zebrafish Heart.
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.
authors.affiliation: Molecular Cardiology, University of Ulm, Ulm, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Hirth
authors.affiliation: Molecular Cardiology, University of Ulm, Ulm, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Bühler
authors.affiliation: Molecular Cardiology, University of Ulm, Ulm, Germany.
authors.forename: John B
authors.initials: JB
authors.lastname: Bührdel
authors.affiliation: Molecular Cardiology, University of Ulm, Ulm, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Rudeck
authors.affiliation: Department of Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Tillman
authors.initials: T
authors.lastname: Dahme
authors.affiliation: Department of Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
authors.affiliation: Molecular Cardiology, University of Ulm, Ulm, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
mesh_terms: D000818:Animals; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051419:Paxillin / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D016596:Vinculin / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051419:Paxillin; D029961:Zebrafish Proteins; C496064:pxna protein, zebrafish; D016596:Vinculin; D051416:Focal Adhesion Protein-Tyrosine Kinases