Integrin-linked kinase (ILK): a “hot” therapeutic target

Yoganathan, Thillainathan; Costello, Penny; Chen, Xiaoyi; Jabali, Mojgan; Yan, Jun; Leung, Dan; Zhang, Zaihui; Yee, Arthur M.F.; Dedhar, Shoukat; Sanghera, Jasbinder S.

doi:10.1016/s0006-2952(00)00444-5

Cited by 88 publications

(75 citation statements)

References 26 publications

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“…Another integrin-dependent molecule, ILK (integrin-linked kinase), is a serine-threonine protein kinase that can interact directly with b-integrin. ILK activates the PI3K/AKT pathway by directly phosphorylating protein kinase B/Akt (Yoganathan et al, 2000), which is one of the main signaling pathways in which TWIST is involved. Accordingly, ILK plays similar and parallel roles to TWIST in determining cell polarity, cell migration, and EMT (Guo et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Feng

Wang

Shi

et al. 2008

The Anatomical Record

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TWIST is an important transcription factor during embryonic development and has recently been found to promote the epithelial-mesenchymal transition (EMT) phenomenon seen during the initial steps of tumor metastasis. To further investigate the potential targets and interacting genes of TWIST in human gastric cancer, we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion. Moreover, TWIST-depleted HGC-27 cells showed a reversal of the morphologic and molecular changes associated with EMT. These results provide evidence that TWIST regulates the expression of several genes involved in the differentiation, adhesion, and proliferation of gastric cancer cells. The role of TWIST in the development of certain types of gastric cancer is discussed. Anat Rec, 292:262-270, 2009Rec, 292:262-270, . 2008 Wiley-Liss, Inc.Key words: TWIST; siRNA; epithelial-mesenchymal transition; gastric cancer; microarray Epithelial-mesenchymal transition (EMT) is pivotal for morphogenesis and in the transformation of early stage tumors into invasive malignancies (Kang and Massague, 2004). Cells undergoing EMT-characterized by the loss of cell polarity, cell-basement membrane adhesion, and cell-cell contacts-lose expression of epithelial markers (such as E-cadherin and catenin) and acquire expression of mesenchymal components (such as vimentin, fibronectin, and N-cadherin). Recent studies have shown that TWIST is one of the main regulatory proteins that promote EMT and the metastatic phenotype of cells (Karreth and Tuveson, 2004). Increased levels of TWIST are found in a wide range of cancers and are positively correlated with tumor aggressiveness and poor survival rates (Yang et al., 2004), suggesting a general role for TWIST in cancer development.TWIST is a basic helix-loop-helix (bHLH) transcription regulator that can form homodimers or heterodimers with partners that also contain an HLH domain. Depending on the protein partners in the dimers, these complexes play distinct roles in regulating the expression of downstream genes, acting either as activators or repressors. For example, TWIST homodimers can bind to the E-box of the E-cadherin promoter, repressing its expression, whereas their binding to the E-box of the Akt2 gene enhances its expression (Cheng et al

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Feng

Wang

Shi

et al. 2008

The Anatomical Record

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“…GSK-3␤ has a high basal activity, phosphorylating its substrates in the default state, whereas stimulation decreases its activity. Many kinases phosphorylate and inactivate GSK-3␤, such as the cAMP-dependent protein kinase A (26), protein kinase C (27), and integrin-linked kinase (28), but the Wnt͞Wg and insulinsignaling pathways are the two most studied. Both of these signaling pathways lead to inactivation of GSK-3␤, but crosstalk between them is prevented and followed by different downstream effects (29).…”

Section: Discussionmentioning

confidence: 99%

Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH ₂ -terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease

Papasozomenos

Shanavas

2002

Proc. Natl. Acad. Sci. U.S.A.

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We have shown previously that glycogen synthase kinase-3␤ (GSK-3␤), cyclin-dependent kinase 5, and c-Jun NH2-terminal kinase become overactivated and hyperphosphorylate in heat-shocked female rats. This hyperphosphorylation of is estrogen-independent, prevented by androgens, and similar to Alzheimer's disease. In this study, ovariectomized (OVX) Sprague-Dawley rats (n ‫؍‬ 75) received daily injections of 10 g of 17␤-estradiol benzoate (EB), or 250 g of testosterone propionate (TP), or both EB and TP, or sesame oil (SO) vehicle for 4 -6 weeks. In kinase assays of forebrain homogenates, overactivation of GSK-3␤ at 0 -6 h after heat shock toward human recombinant , bovine , and phosphoglycogen synthase peptide 2 was prevented in OVX ؉ TP and OVX ؉ (EB ؉ TP) but not in sham-OVX ؉ SO, OVX ؉ SO, and OVX ؉ EB. Abs against inactive (pSer 9 ) and activity-enhanced (pTyr 216 ) GSK-3␤ showed marked increase of pSer 9 -and decrease of pTyr 216 -GSK-3␤ in both OVX ؉ TP and OVX ؉ (EB ؉ TP) but not in sham-OVX ؉ SO, OVX ؉ SO, and OVX ؉ EB. EB enhanced the overactivation of cyclin-dependent kinase 5. The activity of c-Jun NH2-terminal kinase was gonadal hormone-independent. The serum concentrations of testosterone and 17␤-estradiol were 2.53 ng͞ml and 201 pg͞ml in OVX ؉ TP and OVX ؉ EB, respectively. These findings demonstrate that testosterone prevents the hyperphosphorylation of by inhibiting the heat shock-induced overactivation of GSK-3␤ and suggest that androgens given to aging men or, in combination with estrogens, to postmenopausal women could prevent or delay Alzheimer's disease.A bout two times more women than men have Alzheimer's disease (AD) (1), partly because women with AD live longer. However, recent studies showed that women carry an innate higher risk for AD (2). The precipitous decline and loss of neuroprotective effects of estrogens in postmenopausal women-in contrast to the gradual decline of androgens in aging men-are offered as an explanation. However, recent studies showed no beneficial effects of estrogens on mild-to-moderate AD (3). On the other hand, a possible advantageous role of androgens in the prevention and͞or treatment of AD has not been tried yet despite their neuroprotective effects (4), the century-old suggestion that they may rejuvenate aged men (5), lower serum testosterone concentration in men with AD (6), the increasing evidence that stressful stimuli play a role in the etiopathogenesis of AD (7,8), and inhibition of stress response by androgens (9).The cause of AD is not known, but it seems to be a syndrome resulting from an interplay among a genetic predisposition, environmental stress factors, and the aging process. The histologic hallmarks of AD are the senile plaques made of A␤ amyloid, dystrophic neurites, and reactive glial cells, and the neurofibrillary tangles composed of bundles of abnormal filaments, the so-called paired-helical filaments, the major component of which is hyperphosphorylated (10-12). However, the earliest manifestation of hyperphosphorylated is a granular form in...

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“…PD98059, wortmannin, myristoylated protein kinase A inhibitor, and SC 68376 were purchased from Calbiochem (La Jolla, CA). Small-molecule ILK inhibitor KP392 was described elsewhere (19,20).…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Tubular Epithelial Cell Dedifferentiation Is Driven by the Helix-Loop-Helix Transcriptional Inhibitor Id1

Yang

Luo

et al. 2007

Journal of the American Society of Nephrology

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In the fibrotic kidney, tubular cells undergo epithelial-to-mesenchymal transition (EMT), a phenotypic conversion that is characterized by sequential loss of epithelial markers and gain of mesenchymal features. For understanding of the molecular mechanism that governs this process, a high-throughput gene expression microarray analysis was used to identify the critical genes in the initial phase of the TGF-␤1-mediated EMT. Inhibitor of differentiation-1 (Id1), a dominant negative antagonist of the basic helix-loop-helix transcription factors, was found to be induced rapidly in human proximal tubular epithelial cells after TGF-␤1 treatment. This induction of Id1 depended on intracellular Smad signaling. Ectopic expression of Id1 suppressed epithelial E-cadherin and zonula occludens-1 expression. Id1 physically formed complex with basic helix-loop-helix transcription factor HEB (Hela E-box binding factor), sequestered its ability to bind to E-box, and repressed the trans-activation of E-cadherin promoter. However, overexpression of Id1 failed to induce ␣-smooth muscle actin, matrix metalloproteinase-2, fibronectin, and integrin-linked kinase (ILK), indicating its inability to confer a complete EMT. Overexpression of ILK or inhibition of ILK activity had no effect on Id1 induction by TGF-␤1, suggesting that Id1 and ILK have independent roles in epithelial dedifferentiation and EMT. In vivo, Id1 was induced exclusively in the degenerated, dilated renal tubular epithelium after unilateral ureteral obstruction. These studies identify Id1 transcriptional inhibitor as a crucial player in mediating cell dedifferentiation of renal tubular epithelium and suggest that EMT is a multistep process in which loss of epithelial adhesion does not necessarily lead to an autonomous mesenchymal transition.

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Integrin-linked kinase (ILK): a “hot” therapeutic target

Cited by 88 publications

References 26 publications

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH ₂ -terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease

Tubular Epithelial Cell Dedifferentiation Is Driven by the Helix-Loop-Helix Transcriptional Inhibitor Id1

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Integrin-linked kinase (ILK): a “hot” therapeutic target

Cited by 88 publications

References 26 publications

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH 2 -terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease

Tubular Epithelial Cell Dedifferentiation Is Driven by the Helix-Loop-Helix Transcriptional Inhibitor Id1

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Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH ₂ -terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease