title: Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function.
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 Ca(2+)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 (ILK(R211A)) 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.
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Traister
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Mark
authors.initials: M
authors.lastname: Li
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Shabana
authors.initials: S
authors.lastname: Aafaqi
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Lu
authors.affiliation: University Health Network, University of Toronto, Toronto, Ontario, Canada M5S 2J7.
authors.forename: Sara
authors.initials: S
authors.lastname: Arab
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada M5S 3G9.
authors.forename: Milica
authors.initials: M
authors.lastname: Radisic
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Gil
authors.initials: G
authors.lastname: Gross
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Guido
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: John
authors.initials: J
authors.lastname: Sherret
authors.affiliation: Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Cameron
authors.initials: C
authors.lastname: Slorach
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Luc
authors.initials: L
authors.lastname: Mertens
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Wei
authors.initials: W
authors.lastname: Hui
authors.affiliation: 1] Program in Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Anna
authors.initials: A
authors.lastname: Roy
authors.affiliation: 1] Program in Physiology and Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3] Heart &Stroke Richard Lewar Centre of Excellence, Toronto, Ontario, Canada M5B 1W8.
authors.forename: Paul
authors.initials: P
authors.lastname: Delgado-Olguín
authors.affiliation: Cell Adhesion Signaling Laboratory, Monash Institute of Medical Research, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hannigan
authors.affiliation: 1] Department of Anesthesia and Pain Medicine, Division of Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 [2] Departments of Anesthesia and Biochemistry, Universtiy of Toronto, Toronto, Ontario, Canada M5S 2J7.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Maynes
authors.affiliation: Cardiology Division, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: John G
authors.initials: JG
authors.lastname: Coles
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D040542:Mechanotransduction, Cellular / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D000099211:Phospholamban; D000099200:Scaffold Protein ILK
chemical_list: D002135:Calcium-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; D000099200:Scaffold Protein ILK