Disease relevance of Ilk

• The anticancer effects of ILK inhibitor QLT0254 were tested in an orthotopic primary xenograft model of pancreatic cancer [1].
• Recently, we demonstrated that ILK is expressed in N1E-115 neuroblastoma cells and controls integrin-dependent neurite outgrowth in serum-starved cells grown on laminin (Ishii, T., Satoh, E., and Nishimura, M. (2001) J. Biol. Chem. 276, 42994-43003) [2].
• A small molecule inhibitor of the ILK kinase reduced the in vitro invasiveness of ILK-overexpressing cells as well as the invasiveness of several human brain tumor cell lines [3].
• Here we show that endothelial cell (EC)-specific deletion of ILK in mice confers placental insufficiency with decreased labyrinthine vascularization, yielding no viable offspring [4].
• These data extend the role of ILK to immune-cell trafficking and survival via modulation of Akt- and Rac-dependent substrates, and have implications for cell recruitment in both homeostatic and pathological processes [5].
• We found down-regulation of Notch1-IC and up-regulation of ILK in basal cell carcinoma and melanoma patients but not in squamous cell carcinoma patients [6].

Psychiatry related information on Ilk

• Stable transfection of a kinase-deficient ILK mutant (DN-ILK) resulted in aberrant tau phosphorylation in N1E-115 cells at sites recognized by the Tau-1 antibody that are identical to some of the phosphorylation sites in paired helical filaments, PHF-tau, in brains of patients with Alzheimer's disease [2].
• Thus, ILK likely influences the initial decision making process of myogenic differentiation by regulation of MAP kinase activation [7].

High impact information on Ilk

• ILK, PINCH and parvin: the tIPP of integrin signalling [8].
• Furthermore, expression of a mutant ILK lacking kinase activity and/or paxillin binding in ILK-deficient fibroblasts can rescue cell spreading, F-actin organization, FA formation, and proliferation [9].
• Altogether these data show that mammalian ILK modulates actin rearrangements at integrin-adhesion sites [9].
• Finally, ILK-deficient fibroblasts have diminished proliferation rates [9].
• Likewise, ILK-deficient fibroblasts showed abnormal F-actin aggregates associated with impaired cell spreading and delayed formation of stress fibers and FAs [9].

Chemical compound and disease context of Ilk

• Thus, high glucose and angiotensin II may affect the regulation of the integrin-ILK system in podocytes; this system may therefore play a role in the pathogenesis of diabetic nephropathy and other renal diseases affecting podocytes [10].
• The role of ILK signaling in podocyte damage was evaluated using puromycin, an agent known to cause selective proteinuria and to increase ILK activity [11].
• Transgenic mice with cardiac-specific expression of a constitutively active ILK (ILK(S343D)) or wild-type ILK (ILK(WT)) exhibited a compensated ventricular hypertrophic phenotype and displayed an activation profile of guanine triphosphatases and downstream protein kinases concordant with that seen in human hypertrophy [12].

Biological context of Ilk

• Surprisingly, phosphorylation of Pkb/Akt and GSK3-beta is unaffected in Ilk-deficient chondrocytes [13].
• The spatial and temporal expression of ILK in embryonic mouse kidney cells suggested a role in branching morphogenesis [14].
• 5. In order to define the phenotype leading to the peri-implantation lethality we made PINCH1-null EBs and found similar but also additional defects not observed in beta1 integrin or Ilk mutant EBs [15].
• Inhibition of ILK with a small compound inhibitor also altered podocyte cytoskeleton and increased apoptosis [16].
• Integrin-linked kinase (Ilk) is a scaffold and kinase that links integrin receptors to the actin cytoskeleton and to signaling pathways involved in cell adhesion, migration, and extracellular matrix deposition [17].

Anatomical context of Ilk

• Ligated integrins are recruited to focal adhesions (FAs) together with scaffolding proteins and kinases, such as integrin-linked kinase (Ilk) [13].
• In addition, Ilk-deficient chondrocytes showed adhesion defects, failed to spread and formed fewer FAs and actin stress fibres [13].
• Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis [14].
• Expression of chondrocyte differentiation markers such as collagen type II, collagen type X, Indian hedgehog and the PTH-PTHrP receptor was normal in ILK-deficient growth plates [18].
• Additional defects, which were not observed in beta1 integrin- or ILK-deficient mice or EBs, included abnormal cell-cell adhesion of endoderm and epiblast as well as the presence of apoptotic cells in the endodermal cell layer [15].

Associations of Ilk with chemical compounds

• Integrin-linked kinase (ILK) is a focal adhesion serine/threonine protein kinase with an important role in integrin and growth factor signaling pathways [2].
• Moreover, inhibition of GSK-3beta with lithium prevented aberrant tau phosphorylation in the DN-ILK-expressing cells [2].
• Mutations at the alpha-parvin N-terminal proline-directed serine phosphorylation sites reduced its complex formation with ILK and resulted in defects in podocyte adhesion, architecture, and survival [16].
• Integrin-linked kinase (ILK) is a serine/threonine kinase that is important in cell-matrix interactions and cell signaling [5].
• Integrin-linked kinase (ILK) is a phosphoinositide 3-kinase-dependent serine/threonine kinase that interacts with beta integrins [4].
• We conclude that ILK plays important roles for epidermis and hair follicle morphogenesis by modulating integrin-mediated adhesion, actin reorganization, and plasma membrane dynamics in keratinocytes [19].

Physical interactions of Ilk

• By phage display, we identify integrin-linked kinase as a potential binding partner of SPARC and verify the interaction by co-immunoprecipitation and colocalization in vitro [20].

Regulatory relationships of Ilk

• Here we report that ILK controls tau phosphorylation via regulation of glycogen synthase kinase-3beta (GSK-3beta) activity in N1E-115 cells [2].
• These findings suggest that Ilk regulates actin reorganization in chondrocytes and modulates chondrocyte growth independently of phosphorylation of Pkb/Akt and GSK3-beta [13].
• Inactivation of integrin-linked kinase induces aberrant tau phosphorylation via sustained activation of glycogen synthase kinase 3beta in N1E-115 neuroblastoma cells [2].
• In addition, the up-regulation of ILK synthesis induced by these stimuli was related to beta1 integrin synthesis and increased ILK kinase activity [10].
• To examine the role of ILK in leukocyte trafficking and survival, we generated T cell-specific ILK knockouts by breeding ILK(flox/flox) mice to transgenic mice expressing Cre recombinase under control of the Lck proximal promoter [5].

Other interactions of Ilk

• Expression of HER2/neu increases ILK activity [21].
• ILK inactivation in chondrocytes resulted in reduced cyclin D1 expression, and this most likely explains the defect in chondrocyte proliferation observed when ILK is inactivated in growth plate cells [18].
• Disruption of the PINCH-1-ILK-alpha-parvin complex significantly reduced the podocyte-matrix adhesion and foot process formation [16].
• Concomitantly, an increased amount of the PINCH-1-ILK-alpha-parvin complex was detected in the differentiated, foot process-containing podocytes [16].
• They consist of three members (alpha-, beta-, and gamma-parvin), form a functional complex with integrin-linked kinase (ILK) and PINCH, and link integrins to the actin cytoskeleton [22].

Analytical, diagnostic and therapeutic context of Ilk

• Here, we demonstrate a novel role for integrin-linked kinase (ILK) in mediating renal epithelial cell morphogenesis in embryonic kidney explants and identify p38(MAPK) as a target of ILK signaling in a cell culture model of renal epithelial morphogenesis [14].
• Analysis of peripheral T cells by quantitative PCR and by breeding Lck-Cre(+)/ILK(flox/flox) mice to a YFP-transgenic reporter strain demonstrated an approximate 20-fold enrichment of ILK-competent cells, suggesting these cells have a competitive advantage in trafficking to and/or survival in peripheral lymphatic organs [5].
• To investigate beta1-integrin activity, integrin-linked kinase (ILK) expression was measured by immunoblotting [23].
• Electron microscopy revealed an early foot process effacement, as well as morphologic abnormality, in ILK-deficient podocytes [24].

References