title: Integration of cell attachment, cytoskeletal localization, and signaling by integrin-linked kinase (ILK), CH-ILKBP, and the tumor suppressor PTEN.
abstract: Cell attachment and the assembly of cytoskeletal and signaling complexes downstream of integrins are intimately linked and coordinated. Although many intracellular proteins have been implicated in these processes, a new paradigm is emerging from biochemical and genetic studies that implicates integrin-linked kinase (ILK) and its interacting proteins, such as CH-ILKBP (alpha-parvin), paxillin, and PINCH in coupling integrins to the actin cytoskeleton and signaling complexes. Genetic studies in Drosophila, Caenorhabditis elegans, and mice point to an essential role of ILK as an adaptor protein in mediating integrin-dependent cell attachment and cytoskeletal organization. Here we demonstrate, using several different approaches, that inhibiting ILK kinase activity, or expression, results in the inhibition of cell attachment, cell migration, F-actin organization, and the specific cytoskeletal localization of CH-ILKBP and paxillin in human cells. We also demonstrate that the kinase activity of ILK is elevated in the cytoskeletal fraction and that the interaction of CH-ILKBP with ILK within the cytoskeleton stimulates ILK activity and downstream signaling to PKB/Akt and GSK-3. Interestingly, the interaction of CH-ILKBP with ILK is regulated by the Pi3 kinase pathway, because inhibition of Pi3 kinase activity by pharmacological inhibitors, or by the tumor suppressor PTEN, inhibits this interaction as well as cell attachment and signaling. These data demonstrate that the kinase and adaptor properties of ILK function together, in a Pi3 kinase-dependent manner, to regulate integrin-mediated cell attachment and signal transduction.
authors.affiliation: BC Cancer Agency, Jack Bell Research Centre, Vancouver, BC, V6H 3Z6, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Attwell
authors.forename: Julia
authors.initials: J
authors.lastname: Mills
authors.forename: Armelle
authors.initials: A
authors.lastname: Troussard
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000185:Actinin / Q000378:metabolism* / Q000502:physiology; D000199:Actins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism / Q000502:physiology; D022001:Focal Adhesions / Q000201:enzymology / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099200:Scaffold Protein ILK; D000096985:Calponins
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000185:Actinin; D000199:Actins; D004791:Enzyme Inhibitors; D005353:Fibronectins; D038362:Glycogen Synthase Kinase 3; D008840:Microfilament Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D000099200:Scaffold Protein ILK; C486590:PARVA protein, human; D000096985:Calponins; C486591:PARVB protein, human; C494929:PTEN protein, human