Critical involvement of ILK in TGFβ1-stimulated invasion/migration of human ovarian cancer cells is associated with urokinase plasminogen activator system

Lin, Sui Wen; Ke, Ferng Chun; Hsiao, Pei-Wen; Lee, Ping Ping; Lee, Ming Ting; Hwang, Juey Jen

doi:10.1016/j.yexcr.2006.11.003

Cited by 31 publications

(26 citation statements)

References 64 publications

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“…TGFb1 secretion was impaired in mesangial cells transfected with a kinase-dead mutant of ILK (Ortega-Velazquez et al, 2004). Inhibition of ILK by knockdown (Lin et al, 2007) or by small molecule inhibitors (Edwards et al, 2008) also resulted in selected suppression of secreted vascular endothelial growth factor and urokinase plasminogen activator levels, but not those of PAI-1, indicating that ILK is involved in specific intracellular protein processing events and/or secretory pathways. Alternatively, proteolytic mobilization of latent TGFb1 from extracellular growth factor deposits, on the cell surface or in the ECM, might be impaired, leading to reduced levels of TGFb1 precursor available to the cells for activation.…”

Section: Ilk-deficient Fibroblasts In Mouse Skin Repairmentioning

confidence: 99%

Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts – role of TGFβ1 levels and RhoA activity

Blumbach

Zweers

Brunner

et al. 2010

Journal of Cell Science

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SummaryWound healing crucially relies on the mechanical activity of fibroblasts responding to TGFb1 and to forces transmitted across focal adhesions. Integrin-linked kinase (ILK) is a central adapter recruited to integrin b1 tails in focal adhesions mediating the communication between cells and extracellular matrix. Here, we show that fibroblast-restricted inactivation of ILK in mice leads to impaired healing due to a severe reduction in the number of myofibroblasts, whereas inflammatory infiltrate and vascularization of the granulation tissue are unaffected. Primary ILK-deficient fibroblasts exhibit severely reduced levels of extracellular TGFb1, a-smooth muscle actin (aSMA) production and myofibroblast conversion, which are rescued by exogenous TGFb1. They are further characterized by elevated RhoA and low Rac1 activities, resulting in abnormal shape and reduced directional migration. Interference with RhoA-ROCK signaling largely restores morphology, migration and TGFb1 levels. We conclude that, in fibroblasts, ILK is crucial for limiting RhoA activity, thus promoting TGFb1 production, which is essential for dermal repair following injury.

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Section: Ilk-deficient Fibroblasts In Mouse Skin Repairmentioning

confidence: 99%

Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts – role of TGFβ1 levels and RhoA activity

Blumbach

Zweers

Brunner

et al. 2010

Journal of Cell Science

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“…Importantly, siRNA-mediated depletion of ILK impairs the phosphorylation of Akt at Ser473 in several cancer-cell models (Basaki et al, 2007;Duxbury et al, 2005;Edwards et al, 2006;Liu et al, 2006;McDonald et al, 2008;Tan et al, 2004), which results in the induction of apoptosis (Duxbury et al, 2005;McDonald et al, 2008;Shi et al, 2007). In addition, knockdown of ILK impaired the migration and invasion of cancer cells Shi et al, 2007;Wong et al, 2007) under standard growth conditions and subsequent to agonist stimulation (Lin et al, 2007;Shi et al, 2007). Reduced stress-fiber formation and defects in adhesion and spreading were seen in ILK-depleted melanoma cells, and this might underlie some of the observed migration and invasion defects (Wong et al, 2007).…”

Section: Genetic Inhibition Of Ilk Function In Cancer Cellsmentioning

confidence: 99%

Integrin-linked kinase – essential roles in physiology and cancer biology

McDonald

Fielding

Dedhar

2008

Journal of Cell Science

302

322

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Integrin-linked kinase (ILK) is a multifunctional intracellular effector of cell-matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. The use of recently developed Cre-lox-driven recombination and RNAinterference technologies has enabled the evaluation of the physiological roles of ILK in several major organ systems. Significant developmental and tissue-homeostasis defects occur when the gene that encodes ILK is deleted, whereas the expression of ILK is often elevated in human malignancies. Although the cause(s) of ILK overexpression remain to be fully elucidated, accumulating evidence suggests that its oncogenic capacity derives from its regulation of several downstream targets that provide cells with signals that promote proliferation, survival and migration, supporting the concept that ILK is a relevant therapeutic target in human cancer. Furthermore, a global analysis of the ILK 'interactome' has yielded several novel interactions, and has revealed exciting and unexpected cellular functions of ILK that might have important implications for the development of effective therapeutic agents.

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“…RNAi and antisense oligonucleotides have been used in the cell culture setting to show that depletion of ILK expression leads to the reversal of many of its oncogenic effects, including a decrease in cell migration and invasion [88,91,150] and the induction of apoptosis [87][88][89][90][91]. In vivo, tumour xenografts derived from ILK-depleted cells show slower growth than controls [90,91].…”

Section: Ilk As a Potential Target For Cancer Therapeuticsmentioning

confidence: 99%

The mitotic functions of integrin-linked kinase

Fielding

Dedhar

2009

Cancer Metastasis Rev

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The cytoskeleton is composed of three major constituents: actin filaments, intermediate filaments and microtubules. These are vital for numerous normal cellular processes including cell spreading and migration, intracellular organelle transport, mechanical strength, mitosis and cytokinesis. Deregulation of cytoskeletal components can lead to cells developing several oncogenic phenotypes; for example increased migration and invasiveness, defects in cellular morphogenesis and genetic instabilities due to errors in mitosis and cytokinesis. Integrin-linked kinase (ILK) is a protein with well established roles in regulating actin cytoskeletal reorganization, survival, proliferation, cell migration, invasion and epithelial to mesenchymal transition, and is therefore essential to normal cell physiology. In addition, ILK is overexpressed or deregulated in a number of human cancers and when experimentally overexpressed leads to the acquisition of a number of oncogenic phenotypes, some of which, such as increased cell migration, are actin-dependent. Here we shall focus on the recent finding that ILK also regulates the microtubule cytoskeleton and is involved in mitotic spindle organization. Therefore its deregulation may also lead to errors in cell division causing genomic instability, potentially further contributing to cancer development. In light of these findings, the therapeutic potential of the anti-mitotic effects of genetic or pharmacological inhibition of ILK will also be discussed.

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Critical involvement of ILK in TGFβ1-stimulated invasion/migration of human ovarian cancer cells is associated with urokinase plasminogen activator system

Cited by 31 publications

References 64 publications

Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts – role of TGFβ1 levels and RhoA activity

Defective granulation tissue formation in mice with specific ablation of integrin-linked kinase in fibroblasts – role of TGFβ1 levels and RhoA activity

Integrin-linked kinase – essential roles in physiology and cancer biology

The mitotic functions of integrin-linked kinase

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