Sequence 652 (ILK)

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Sequence ILK
Target ILK ( Homo sapiens )
Description Integrin-linked kinase

Ensembl: ENSG00000166333 UniGene: Hs.5158 EntrezGene: 3611 Ensembl Chr11: 6581540 - 6588673 Strand: 1 GO terms: 0000166 0001658 0004672 0004674 0004713 0005515 0005524 0005737 0005925 0006468 0007160 0007229 0008283 0008284 0016740 0030054 0045197

Design siRNA
Chemistry RNA
Sequence siRNA sense (21b) GGACACATTCTGGAAGGGGTT / siRNA antisense (21b) CCCCTTCCAGAATGTGTCCTT
Application gene silencing
Name ILK

References

PINCH-1 is an obligate partner of integrin-linked kinase (ILK)functioning in cell shape modulation, motility, and survival.Fukuda T, Chen K, Shi X, Wu C.J Biol Chem. 2003 Dec 19;278(51) :51324-33. Epub 2003 Oct 8.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478

Comments

Background

Description. ILK is a serine-threonine protein kinase that associates with the cytoplasmic domain of beta integrins and acts as a proximal receptor kinase regulating integrin-mediated signal transduction (Melchior et al., 2002). Gene Function. Hannigan et al. (1996) found that ILK coimmunoprecipitated with beta-1 integrin from cell lysates, and that overexpression of ILK disrupted cell architecture and inhibited adhesion to integrin substrates, while inducing anchorage-independent growth in epithelial cells, suggesting that ILK regulates integrin-mediated signal transduction.

By knockout of the ILK gene in human embryonic kidney cells and mouse macrophages, Troussard et al. (2003) showed that ILK is essential for regulation of AKT (see AKT1; 164730) activity. ILK knockout had no effect on phosphorylation of AKT on thr308, but resulted in almost complete inhibition of phosphorylation on ser473, causing significant inhibition of AKT activity accompanied by significant stimulation of apoptosis. ILK knockout also suppressed phosphorylation of GSK3B (605004) on ser9 and cyclin D1 (168461) expression. Troussard et al. (2003) concluded that ILK is an essential upstream regulator of AKT activation.

Fukuda et al. (2003) found that PINCH1 (LIMS1; 602567) and ILK are essential for prompt HeLa cell spreading and motility following passage, and that they are crucial for cell survival. While ILK depletion reduced AKT phosphorylation on ser473, PINCH1 depletion reduced AKT phosphorylation on both ser473 and thr308. PINCH1 also regulated ILK protein levels. Fukuda et al. (2003) concluded that PINCH1 is an obligate partner of ILK and both are indispensable for proper control of cell shape change, motility, and survival.

Bock-Marquette et al. (2004) demonstrated that the G-actin sequestering peptide thymosin beta-4 (300159) promoted myocardial and endothelial cell migration in the embryonic heart and retained this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta-4. Thymosin beta-4 formed a functional complex with PINCH1 and ILK, resulting in activation of the survival kinase AKT, also known as protein kinase B. After coronary artery ligation in mice, thymosin beta-4 treatment resulted in upregulation of Ilk and Akt activity in the heart, enhanced early myocyte survival, and improved cardiac function. Bock-Marquette et al. (2004) concluded that thymosin beta-4 promotes cardiomyocyte migration, survival, and repair.

Lu et al. (2006) demonstrated a marked increase in ILK protein levels in hypertrophic ventricles of patients with congenital and acquired outflow tract obstruction. The increase in ILK was associated with the activation of Rho family guanine triphosphatases, RAC1 (602048) and CDC42 (116952), and known hypertrophic signaling kinases, including extracellular signal-related kinases, such as ERK1/2 (see 601795) and p70-S6-kinase (RPS6KB1; 608938). Transgenic mice with cardiac-specific expression of a constitutively active or wildtype ILK 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. In contrast, transgenic mice with cardiomyocyte-restricted expression of a kinase-inactive ILK were unable to mount a compensatory hypertrophic response to angiogensin II (see 106150) in vivo. Lu et al. (2006) concluded that ILK-regulated signaling represents a broadly adaptive hypertrophic response mechanism relevant to a wide range of clinical heart disease. Animal Model.Sakai et al. (2003) found that embryonic mice lacking Ilk expression died at the periimplantation stage due to failure of epiblast polarization and cavitation. The impaired epiblast polarization was associated with abnormal F-actin accumulation at sites of integrin attachment to the basement membrane zone. Likewise, Ilk-deficient fibroblasts showed abnormal F-actin aggregates associated with impaired cell spreading and delayed formation of stress fibers and focal adhesions. Ilk-deficient fibroblasts also had diminished proliferation rates. The proliferation defect was not due to absent or reduced Ilk-mediated phosphorylation of Akt or Gsk3b. Expression of mutant Ilk lacking kinase activity and/or paxillin (602505) binding in Ilk-deficient fibroblasts rescued cell spreading, F-actin organization, focal adhesion formation, and proliferation.

Friedrich et al. (2004) found that endothelial cell-specific deletion of Ilk in mice conferred placental insufficiency with decreased labyrinthine vascularization, and yielded no viable offspring. Deletion of Ilk in zebrafish resulted in marked patterning abnormalities of the vasculature and was similarly lethal. Phenotypic rescue of Ilk-deficient mouse lung endothelial cells with wildtype Ilk, but not by a constitutively active mutant of Akt, suggested that regulation of endothelial cell survival by ILK is independent of AKT.

The recessive 'main squeeze' (msq) mutation in zebrafish is embryonic lethal due to heart failure. Bendig et al. (2006) found that stretch-responsive genes, such as atrial natriuretic factor (ANF; 108780) and Vegf (192240), were downregulated in msq mutant hearts. Through positional cloning, they found that heart failure in msq mutants was due to a point mutation in the Ilk gene. In normal hearts, Ilk specifically localized to costameres and sarcomeric Z discs. The msq mutation reduced Ilk kinase activity and disrupted binding of Ilk to the Z disc adaptor protein beta-parvin (PARVB; 608121). In msq mutant embryos, heart failure could be suppressed by expression of Ilk or constitutively active forms of Akt and Vegf. Antisense-mediated abrogation of zebrafish beta-parvin phenocopied the msq phenotype.

White et al. (2006) performed targeted ablation of Ilk expression in the mouse heart and observed spontaneous cardiomyopathy and heart failure by 6 weeks of age. The murine symptoms reflected classic human symptoms of dilated cardiomyopathy (CMD; see 115200), with labored breathing, lack of strength, and sudden death; postmortem examination revealed grossly enlarged hearts in all animals, with dramatically dilated left ventricular chambers and evidence of fibrosis on histology. Immunofluorescence analysis of frozen heart sections from the mutant mice revealed loss of Ilk from the sarcolemma, resulting in disaggregation of adjacent cardiomyocytes within the heart tissue; trichrome staining confirmed the dramatic disaggregation in mutant mice compared to the compact arrangement of cardiomyocytes in controls. Deletion of Ilk was associated with disruption of adhesion signaling through the beta-1 integrin (135630)/Fak (PTK2; 600758) complex, and loss of Ilk was accompanied by a reduction in cardiac Akt (164730) phosphorylation, which normally provides a protective response against stress. White et al. (2006) suggested that ILK plays a central role in protecting the mammalian heart against cardiomyopathy and failure.

Lange et al. (2009) showed that mice carrying point mutations in the proposed autophosphorylation site of the putative kinase domain and in the pleckstrin homology domain of Ilk 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 (608120), die owing to renal agenesis. Similar renal defects occur in alpha-parvin-null mice. Lange et al. (2009) concluded that their results provided 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.

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