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Increased Expression of Integrin-Linked Kinase Improves Cardiac Function and Decreases Mortality in Dilated Cardiomyopathy Model of Rats  [PDF]
Rong Gu, Jian Bai, Lin Ling, Liang Ding, Na Zhang, Jiaxin Ye, Albert Ferro, Biao Xu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031279
Abstract: Aims Integrin-linked kinase (ILK) is a multifunctional kinase linking the extracellular matrix to intracellular signaling pathways, whose activation in the heart gives rise to a number of functional consequences. The aim of this study is to demonstrate the therapeutic and survival benefit of cardiac ILK overexpression in a rat model of dilated cardiomyopathy. Methods and Results The dilated cardiomyopathy model was generated in rats by intraperitoneal administration of six equal doses of doxorubicin over a 2 week period. Five weeks after the first injection, echocardiographic analysis demonstrated impaired cardiac function and, at that point, recombinant adenoviral vector harboring ILK cDNA or vehicle was injected into the myocardium, and the rats re-studied 4 weeks later. Compared with vehicle injection, ILK treatment ameliorated inflammatory cell infiltration and cardiomyocyte degeneration, as well as left ventricular dilation and dysfunction. ILK treatment was also associated with a reduction in apoptosis and an increase in proliferation of cardiomyocytes, as well as decreased oxidative stress and autophagic vacuole accumulation. Importantly, mortality was lower in rats following ILK treatment than in those following vehicle injection. In cultured neonatal rat cardiomyocytes, we also found that ILK overexpression protected against doxorubicin-induced apoptosis, giving rise to an increase in their proliferation. Conclusions These data demonstrate for the first time that ILK gene therapy improves cardiac function and survival in a model of dilated cardiomyopathy, and this may be mediated through suppression of inflammation, prevention of ventricular remodeling, inhibition of cardiomyocyte apoptosis and autophagy, and stimulation of cardiomyocyte proliferation.
Integrin-Linked Kinase Regulates Interphase and Mitotic Microtubule Dynamics  [PDF]
Simin Lim, Eiko Kawamura, Andrew B. Fielding, Mykola Maydan, Shoukat Dedhar
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053702
Abstract: Integrin-linked kinase (ILK) localizes to both focal adhesions and centrosomes in distinct multiprotein complexes. Its dual function as a kinase and scaffolding protein has been well characterized at focal adhesions, where it regulates integrin-mediated cell adhesion, spreading, migration and signaling. At the centrosomes, ILK regulates mitotic spindle organization and centrosome clustering. Our previous study showed various spindle defects after ILK knockdown or inhibition that suggested alteration in microtubule dynamics. Since ILK expression is frequently elevated in many cancer types, we investigated the effects of ILK overexpression on microtubule dynamics. We show here that overexpressing ILK in HeLa cells was associated with a shorter duration of mitosis and decreased sensitivity to paclitaxel, a chemotherapeutic agent that suppresses microtubule dynamics. Measurement of interphase microtubule dynamics revealed that ILK overexpression favored microtubule depolymerization, suggesting that microtubule destabilization could be the mechanism behind the decreased sensitivity to paclitaxel, which is known to stabilize microtubules. Conversely, the use of a small molecule inhibitor selective against ILK, QLT-0267, resulted in suppressed microtubule dynamics, demonstrating a new mechanism of action for this compound. We further show that treatment of HeLa cells with QLT-0267 resulted in higher inter-centromere tension in aligned chromosomes during mitosis, slower microtubule regrowth after cold depolymerization and the presence of a more stable population of spindle microtubules. These results demonstrate that ILK regulates microtubule dynamics in both interphase and mitotic cells.
Integrin-linked Kinase: It's Role in the Vascular System  [cached]
Seung-Pyo Lee,Seock-Won Youn,Hyo-Soo Kim
International Journal of Biomedical Science , 2007,
Abstract: Integrin-linked kinase (ILK) is an intracellular molecule that binds to the cytoplasmic domain of β1 and β3-integrin. It has been previously demonstrated in various epithelial cell lines to mediate the ‘outside-in’ signals into the cells and to control the survival of these cells by controlling the phosphorylation of various downstream proteins, such as protein kinase B/Akt (PKB/Akt). We now present in this review the important role of ILK in the vascular system with particular emphasis on its role in endothelial cells (ECs). The results presented here demonstrate that ILK is essential for the proper function, structure and survival of ECs and finally, for the process of neovascularization.
Modulation of integrin-linked kinase (ILK) expression in human oesophageal squamous cell carcinoma cell lines by the EGF and TGFβ1 growth factors
Glenn A Driver, Robin B Veale
Cancer Cell International , 2006, DOI: 10.1186/1475-2867-6-12
Abstract: In this study we identify the ILK isoform expressed in five human oesophageal squamous cell carcinoma cell lines of South African origin as ILK1, and demonstrate its cellular distribution. ILK expression, although similar in the majority of the cell lines, did show variation. Furthermore, the ILK expressed was shown to be catalytically functional. The effect of growth factors on ILK expression was examined. An increase in ILK expression, following EGF and TGFβ1 exposure, was a trend across all the five oesophageal carcinoma cell lines tested.These results suggest that growth factor modulation of ILK expression relies on the internalisation/recycling of growth factor receptors and stimulation of the PI3K pathway, which may have implications with regards to cell adhesion and tumourigenesis.While responsiveness to growth factors is central to a host of normal cellular events, aberrant activity plays a key role in tumour development [1-3]. Among the numerous growth factors identified, epidermal growth factor (EGF) and transforming growth factor-1 (TGFβ1) are key players in neoplastic progression [2,4]. The action of EGF has been implicated in malignant transformation in squamous cancers of the bladder, breast and lung [5], whereas colon, gastric, endometrial, ovarian and cervical malignancies exhibit loss of response to TGFβ1 as a growth inhibitor [6,7]. Regarding carcinoma of the oesophagus in particular, reduced TGFβ1 has been correlated with depth of invasion, lymph node metastasis and poor prognosis [8].In normal epithelial cells, appropriate cellular attachment is necessary for signalling pathways to be elicited [9,10]. More specifically, the response to growth factors can be potentiated by the integrin class of adhesion receptors through the integrin-associated protein, integrin-linked kinase (ILK) [1,7,11].The ILK protein is a ubiquitously expressed serine/threonine protein kinase that is activated in response to PI3K stimulation [9,11-17]. Once activated, ILK co
The Integrin-Linked Kinase-PINCH-Parvin Complex Supports Integrin αIIbβ3 Activation  [PDF]
Shigenori Honda, Hiroko Shirotani-Ikejima, Seiji Tadokoro, Yoshiaki Tomiyama, Toshiyuki Miyata
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0085498
Abstract: Integrin-linked kinase (ILK) is an important signaling regulator that assembles into the heteroternary complex with adaptor proteins PINCH and parvin (termed the IPP complex). We recently reported that ILK is important for integrin activation in a Chinese hamster ovary (CHO) cell system. We previously established parental CHO cells expressing a constitutively active chimeric integrin (αIIbα6Bβ3) and mutant CHO cells expressing inactive αIIbα6Bβ3 due to ILK deficiency. In this study, we further investigated the underlying mechanisms for ILK-dependent integrin activation. ILK-deficient mutant cells had trace levels of PINCH and α-parvin, and transfection of ILK cDNA into the mutant cells increased not only ILK but also PINCH and α-parvin, resulting in the restoration of αIIbα6Bβ3 activation. In the parental cells expressing active αIIbα6Bβ3, ILK, PINCH, and α-parvin were co-immunoprecipitated, indicating the formation of the IPP complex. Moreover, short interfering RNA (siRNA) experiments targeting PINCH-1 or both α- and β-parvin mRNA in the parent cells impaired the αIIbα6Bβ3 activation as well as the expression of the other components of the IPP complex. In addition, ILK mutants possessing defects in either PINCH or parvin binding failed to restore αIIbα6Bβ3 activation in the mutant cells. Kindlin-2 siRNA in the parental cells impaired αIIbα6Bβ3 activation without disturbing the expression of ILK. For CHO cells stably expressing wild-type αIIbβ3 that is an inactive form, overexpression of a talin head domain (THD) induced αIIbβ3 activation and the THD-induced αIIbβ3 activation was impaired by ILK siRNA through a significant reduction in the expression of the IPP complex. In contrast, overexpression of all IPP components in the αIIbβ3-expressing CHO cells further augmented THD-induced αIIbβ3 activation, whereas they did not induce αIIbβ3 activation without THD. These data suggest that the IPP complex rather than ILK plays an important role and supports integrin activation probably through stabilization of the active conformation.
Integrin-Linked Kinase Overexpression and Its Oncogenic Role in Promoting Tumorigenicity of Hepatocellular Carcinoma  [PDF]
Jenny Chan,Frankie Chi Fat Ko,Yin-Shan Yeung,Irene Oi-Lin Ng,Judy Wai Ping Yam
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016984
Abstract: Integrin-linked kinase (ILK) was first discovered as an integrin β1-subunit binding protein. It localizes at the focal adhesions and is involved in cytoskeleton remodeling. ILK overexpression and its dysregulated signaling cascades have been reported in many human cancers. Aberrant expression of ILK influenced a wide range of signaling pathways and cellular functions. Although ILK has been well characterized in many malignancies, its role in hepatocellular carcinoma (HCC) is still largely unknown.
Silencing of the integrin-linked kinase gene suppresses the proliferation, migration and invasion of pancreatic cancer cells (Panc-1)
Zhu, Xiang-Yu;Liu, Ning;Liu, Wei;Song, Shao-Wei;Guo, Ke-Jian;
Genetics and Molecular Biology , 2012, DOI: 10.1590/S1415-47572012005000028
Abstract: integrin-linked kinase (ilk) is an ankyrin repeat-containing serine-threonine protein kinase that is involved in the regulation of integrin-mediated processes such as cancer cell proliferation, migration and invasion. in this study, we examined the effect of a lentivirus-mediated knockdown of ilk on the proliferation, migration and invasion of pancreatic cancer (panc-1) cells. immunohistochemical staining showed that ilk expression was enhanced in pancreatic cancer tissue. the silencing of ilk in human panc-1 cells led to cell cycle arrest in the g0/g1 phase and delayed cell proliferation, in addition to down-regulating cell migration and invasion. the latter effects were mediated by up-regulating the expression of e-cadherin, a key protein in cell adhesion. these findings indicate that ilk may be a new diagnostic marker for pancreatic cancer and that silencing ilk could be a potentially useful therapeutic approach for treating pancreatic cancer.
Multiple Roles of Integrin-Linked Kinase in Epidermal Development, Maturation and Pigmentation Revealed by Molecular Profiling  [PDF]
David Judah, Alena Rudkouskaya, Ryan Wilson, David E. Carter, Lina Dagnino
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036704
Abstract: Integrin-linked kinase (ILK) is an important scaffold protein that mediates a variety of cellular responses to integrin stimulation by extracellular matrix proteins. Mice with epidermis-restricted inactivation of the Ilk gene exhibit pleiotropic phenotypic defects, including impaired hair follicle morphogenesis, reduced epidermal adhesion to the basement membrane, compromised epidermal integrity, as well as wasting and failure to thrive leading to perinatal death. To better understand the underlying molecular mechanisms that cause such a broad range of alterations, we investigated the impact of Ilk gene inactivation on the epidermis transcriptome. Microarray analysis showed over 700 differentially regulated mRNAs encoding proteins involved in multiple aspects of epidermal function, including keratinocyte differentiation and barrier formation, inflammation, regeneration after injury, and fundamental epidermal developmental pathways. These studies also revealed potential effects on genes not previously implicated in ILK functions, including those important for melanocyte and melanoblast development and function, regulation of cytoskeletal dynamics, and homeobox genes. This study shows that ILK is a critical regulator of multiple aspects of epidermal function and homeostasis, and reveals the previously unreported involvement of ILK not only in epidermal differentiation and barrier formation, but also in melanocyte genesis and function.
Purification and SAXS Analysis of the Integrin Linked Kinase, PINCH, Parvin (IPP) Heterotrimeric Complex  [PDF]
Amy L. Stiegler, Thomas D. Grant, Joseph R. Luft, David A. Calderwood, Edward H. Snell, Titus J. Boggon
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055591
Abstract: The heterotrimeric protein complex containing the integrin linked kinase (ILK), parvin, and PINCH proteins, termed the IPP complex, is an essential component of focal adhesions, where it interacts with many proteins to mediate signaling from integrin adhesion receptors. Here we conduct a biochemical and structural analysis of the minimal IPP complex, comprising full-length human ILK, the LIM1 domain of PINCH1, and the CH2 domain of α-parvin. We provide a detailed purification protocol for IPP and show that the purified IPP complex is stable and monodisperse in solution. Using small-angle X-ray scattering (SAXS), we also conduct the first structural characterization of IPP, which reveals an elongated shape with dimensions 120×60×40 ?. Flexibility analysis using the ensemble optimization method (EOM) is consistent with an IPP complex structure with limited flexibility, raising the possibility that inter-domain interactions exist. However, our studies suggest that the inter-domain linker in ILK is accessible and we detect no inter-domain contacts by gel filtration analysis. This study provides a structural foundation to understand the conformational restraints that govern the IPP complex.
Integrin-Linked Kinase Is a Functional Mn2+-Dependent Protein Kinase that Regulates Glycogen Synthase Kinase-3β (GSK-3β) Phosphorylation  [PDF]
Mykola Maydan,Paul C. McDonald,Jasbinder Sanghera,Jun Yan,Charalampos Rallis,Sheena Pinchin,Gregory E. Hannigan,Leonard J. Foster,David Ish-Horowicz,Michael P. Walsh,Shoukat Dedhar
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012356
Abstract: Integrin-linked kinase (ILK) is a highly evolutionarily conserved, multi-domain signaling protein that localizes to focal adhesions, myofilaments and centrosomes where it forms distinct multi-protein complexes to regulate cell adhesion, cell contraction, actin cytoskeletal organization and mitotic spindle assembly. Numerous studies have demonstrated that ILK can regulate the phosphorylation of various protein and peptide substrates in vitro, as well as the phosphorylation of potential substrates and various signaling pathways in cultured cell systems. Nevertheless, the ability of ILK to function as a protein kinase has been questioned because of its atypical kinase domain.
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