The role of integrin-linked kinase (ILK) in cancer progression.
Integrin-linked kinase (ILK) is an intracellular protein, which interacts with the cytoplasmic domains of integrin beta and beta3 subunits. ILK is a 59 kDa protein containing a phosphoinositide phospholipid-binding domain flanked by an N-terminal ankyrin repeat domain and a C-terminal serine/threonine protein kinase domain. Genetic and biochemical evidence have established an essential role of ILK in connecting integrins to the actin cytoskeleton. Apart from integrins, ILK interacts with several adaptor and signaling proteins resulting in its activation and localization to focal adhesion plaques. The kinase activity of ILK is stimulated upon integrin engagement, as well as by growth factors and chemokines in a PI-3Kinase-dependent manner. ILK can mediate the phosphorylation of a variety of intracellular substrates, most notable of which are: protein kinase B (PKB/Akt), glycogen synthase kinase-3 (GSK-3) and myosin light chain. Gain and loss of function strategies have shown that overexpression, and/or constitutive activation of ILK results in oncogenic transformation and progression to invasive and metastatic phenotypes. In addition ILK expression and activity are upregulated in several types of cancers. In this review, we summarize the adaptor and signaling properties ofILK, and also progress in the identification of therapeutic strategies for inhibition of ILK activity.
Persad
Sujata
S
Hamilton Regional Cancer Center and McMaster University, Hamilton, Ontario, Canada.
Dedhar
Shoukat
S
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D002453:Cell Cycle; D002455:Cell Division; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D015854:Up-Regulation; D000099200:Scaffold Protein ILK
D000199:Actins; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D016023:Integrins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000099200:Scaffold Protein ILK; C494918:AKT1 protein, human