Integrin-linked kinase at the heart of cardiac contractility, repair, and disease.
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.
Hannigan
Gregory E
GE
Department of Laboratory Medicine & Pathobiology, University of Toronto, and Cell Biology Program, The Hospital for Sick Children MaRS Centre, Ontario, Canada.
Coles
John G
JG
Dedhar
Shoukat
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019703:Calcineurin / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology*; D002311:Cardiomyopathy, Dilated / Q000209:etiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D060588:LIM Domain Proteins; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D009200:Myocardial Contraction; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D000099200:Scaffold Protein ILK
D048868:Adaptor Proteins, Signal Transducing; D019703:Calcineurin; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020764:cdc42 GTP-Binding Protein; D000099200:Scaffold Protein ILK; C088088:LIMS1 protein, human