Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Alexandra Traister, Mark Li, Shabana Aafaqi, Mingliang Lu, Sara Arab, Milica Radisic, Gil Gross, Fiorella Guido, John Sherret, Subodh Verma, Cameron Slorach, Luc Mertens, Wei Hui, Anna Roy, Paul Delgado-Olguín, Gregory Hannigan, Jason T. Maynes () and John G. Coles ()
Additional contact information
Alexandra Traister: Hospital for Sick Children
Mark Li: Hospital for Sick Children
Shabana Aafaqi: Hospital for Sick Children
Mingliang Lu: Hospital for Sick Children
Sara Arab: University Health Network, University of Toronto
Milica Radisic: Institute of Biomaterials and Biomedical Engineering, University of Toronto
Gil Gross: Hospital for Sick Children
Fiorella Guido: Hospital for Sick Children
John Sherret: Hospital for Sick Children
Subodh Verma: Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital
Cameron Slorach: Hospital for Sick Children
Luc Mertens: Hospital for Sick Children
Wei Hui: Hospital for Sick Children
Anna Roy: Program in Physiology and Experimental Medicine, Hospital for Sick Children
Paul Delgado-Olguín: Program in Physiology and Experimental Medicine, Hospital for Sick Children
Gregory Hannigan: Cell Adhesion Signaling Laboratory, Monash Institute of Medical Research, Monash University
Jason T. Maynes: Hospital for Sick Children
John G. Coles: Hospital for Sick Children

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca2+ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILKR211A) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

Date: 2014
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DOI: 10.1038/ncomms5533

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