title: Integrin-linked kinase is an adaptor with essential functions during mouse development.
abstract: The development of multicellular organisms requires integrin-mediated interactions between cells and their extracellular environment. Integrin binding to extracellular matrix catalyses assembly of multiprotein complexes, which transduce mechanical and chemical signals that regulate many aspects of cell physiology. Integrin-linked kinase (Ilk) is a multifunctional protein that binds beta-integrin cytoplasmic domains and regulates actin dynamics by recruiting actin binding regulatory proteins such as alpha- and beta-parvin. Ilk has also been shown to possess serine/threonine kinase activity and to phosphorylate signalling proteins such as Akt1 and glycogen synthase kinase 3beta (Gsk3beta) in mammalian cells; however, these functions have been shown by genetic studies not to occur in flies and worms. Here we show that mice carrying point mutations in the proposed autophosphorylation site of the putative kinase domain and in the pleckstrin homology domain are normal. In contrast, mice with point mutations in the conserved lysine residue of the potential ATP-binding site of the kinase domain, which mediates Ilk binding to alpha-parvin, die owing to renal agenesis. Similar renal defects occur in alpha-parvin-null mice. Thus, we provide genetic evidence that the kinase activity of Ilk is dispensable for mammalian development; however, an interaction between Ilk and alpha-parvin is critical for kidney development.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Lange
authors.forename: Sara A
authors.initials: SA
authors.lastname: Wickström
authors.forename: Madis
authors.initials: M
authors.lastname: Jakobson
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.forename: Kirsi
authors.initials: K
authors.lastname: Sainio
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000737:chemistry; D002465:Cell Movement; D020043:Genes, Essential; D007668:Kidney / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D054238:Perinatal Mortality; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D000099200:Scaffold Protein ILK
chemical_list: D001798:Blood Proteins; D008239:Lysine; D008840:Microfilament Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D000099200:Scaffold Protein ILK; C519774:Parva protein, mouse; C039077:platelet protein P47