doi: 10.1161/01.RES.0000265233.40455.62
© 2007 American Heart Association, Inc.
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Integrin-Linked Kinase at the Heart of Cardiac Contractility, Repair, and Disease
From the Department of Laboratory Medicine & Pathobiology, University of Toronto, and Cell Biology Program (G.E.H.), The Hospital for Sick Children MaRS Centre, Ontario; Department of Surgery, University of Toronto, and Physiology & Experimental Medicine Program (J.G.C.), Hospital for Sick Children Research Institute, Ontario; and Department of Biochemistry and Molecular Biology (S.D.), University of British Columbia and British Columbia Cancer Research Centre, Vancouver, Canada.
Correspondence to Dr G. Hannigan, The Hospital for Sick Children, MaRS Centre, Toronto Medical Discovery Tower, Room 12-308, 101 College St, Toronto, ON M5G 1L7, Canada.
Abstract
Recent advances in cardiac physiology identify the integrin-linked kinase (ILK) as an essential molecule regulating cardiac growth, contractility, and repair. A key transducer of biochemical signals initiated at the plasma membrane by cell–matrix interactions, ILK now emerges as a crucial player in mechanotransduction by integrins. Animal models have been particularly instructive in dissecting the cardiac functions of ILK and its associated proteins, such as parvins and PINCH, and have clearly established ILK as a major contributor to cardiac health. ILK gene knockouts in mice, flies, and worms result in early embryonic lethality because of cell adhesion defects and cytoskeletal disorganization. Although widely distributed in mammalian tissues, ILK expression is highest in the heart, and cardiac-specific ablation of ILK causes cardiomyopathy and sudden death in mice. ILK protein complexes are found in the sarcomere, which is the basic contractile unit of myocytes. A natural inactivating mutation in the kinase domain of ILK disrupts ILK protein interactions in the sarcomere, causing a contractile defect in the zebrafish heart. The relatively subtle phenotype of mutant ILK hearts, compared with ILK-ablated hearts, suggests multiple cardiac ILK functions. Cardiac-specific expression of ILK in transgenic mice induces a hypertrophic program, pointing to ILK as a proximal regulator of multiple hypertrophic signal transduction pathways. ILK protein interactions may also be important in mediating postinfarct cell migration and myocardial repair.
Key Words: integrin-linked kinase • cardiac hypertrophy • cardiomyopathy
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