Integrin-linked kinase and PINCH: partners in regulation of cell-extracellular matrix interaction and signal transduction.
Integrin-linked kinase (ILK) is a focal adhesion serine/threonine protein kinase that is emerging as a key signaling protein functioning at one of the early convergence points of integrin- and growth factor-signaling pathways. ILK binds to PINCH through the N-terminal ankyrin (ANK) repeat domain and the PINCH binding is crucial for focal adhesion localization of ILK. The ILK-PINCH interaction also connects ILK to Nck-2, an SH2-SH3-containing adaptor protein that interacts with components of growth factor and small GTPase signaling pathways. The kinase activity of ILK is regulated by both cell adhesion and growth factors in a phosphoinositide 3-kinase (PI3K)-dependent manner. ILK phosphorylates downstream targets such as protein kinase B (PKB, also known as Akt) and glycogen synthase kinase 3 (GSK-3) and regulates their activities. Overexpression of ILK in epithelial cells leads to striking morphological changes mimicking epithelial-mesenchymal transition, including upregulation of integrin-mediated fibronectin matrix assembly and downregulation of cell-cell adhesions. Furthermore, ILK regulates nuclear translocation of (beta)-catenin and gene expression, and promotes cell cycle progression and tumor formation. Recent genetic studies in Drosophila melanogaster and Caenorhabditis elegans have shown that lack of expression of ILK or PINCH results in phenotypes resembling those of integrin-null mutants, which demonstrates that ILK and PINCH are indispensable for integrin function during embryonic development.
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Department of Cell Biology and The Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA. cwu@cellbio.bhs.uab.edu
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099200:Scaffold Protein ILK
D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C088088:LIMS1 protein, human; C490233:pin-2 protein, C elegans