PINCH-1 Promotes Tubular Epithelial-to-Mesenchymal Transition by Interacting with Integrin-Linked Kinase

Li, Yingjian; Dai, Chunsun; Wu, Chuanyue; Liu, Youhua

doi:10.1681/asn.2007030315

Cited by 60 publications

(54 citation statements)

References 50 publications

(58 reference statements)

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“…11 Cell culture may profoundly alter gene expression and behaviors. 19,20 We believe that organ culture, which preserves in situ cell geometries and although less subject to experimental manipulations, offers a valid and important corrective for experiments with isolated cells and may better reflect what happens in vivo.…”

Section: Discussionmentioning

confidence: 99%

TL1A Both Promotes and Protects from Renal Inflammation and Injury

Al‐Lamki¹,

Wang²,

Tolkovsky

et al. 2008

Journal of the American Society of Nephrology

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Death receptor 3 (DR3), a member of the TNF receptor (TNFR) superfamily, is induced in human renal tubular epithelial cells (TEC) in response to injury. This study examined the expression and actions of TL1A, the principal ligand for DR3. In histologically normal tissue from biopsy or nephrectomy specimens of renal allografts, TL1A mRNA and protein were expressed in vascular endothelial cells but not in TEC. In specimens of acute or antibody-mediated allograft rejection, vascular endothelial cells and infiltrating leukocytes expressed increased TL1A mRNA and protein, but TEC expressed TL1A protein without mRNA, consistent with uptake of exogenous ligand. Addition of TL1A to organ cultures of human or mouse kidney caused activation of NF-B, expression of TNFR2, activation of caspase-3, and apoptosis in TEC. Inhibition of NF-B activation increased TL1A-mediated caspase-3 activation and apoptosis of TEC, but it did not reduce the induction of TNFR2. In organ culture of DR3-deficient mouse kidneys, addition of TL1A induced TNFR2 but did not activate NF-B and did not increase apoptosis of TEC. These data suggest that TL1A may contribute to renal inflammation and injury through DR3-mediated activation of NF-B and caspase-3, respectively, but that an unidentified receptor may mediate the NF-B-independent induction of TNFR2 in TEC.

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Section: Discussionmentioning

confidence: 99%

TL1A Both Promotes and Protects from Renal Inflammation and Injury

Al‐Lamki¹,

Wang²,

Tolkovsky

et al. 2008

Journal of the American Society of Nephrology

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“…Other integrins which are upregulated during EMT, such as α v β 6 -integrin, are also able to increase protease expression and to liberate and activate TGFβ [127][128][129]. Also, the activities of the cytoplasmic interaction partners of integrins, ILK and pinch, have been implicated in the process of EMT [130][131][132].…”

Section: Integrins In Emt and Cell Invasionmentioning

confidence: 99%

EMT, the cytoskeleton, and cancer cell invasion

Yilmaz

Christofori

2009

Cancer Metastasis Rev

1,535

1,314

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The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.

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“…40,41 This study, together with previous reports, 6,9 illustrates that by deciphering the key pathway and its mediators in renal fibrogenesis, it is plausible to develop a completely new class of therapeutic modality for hampering the fibrotic destruction of kidney structure and function after injury. Because hyperactive ILK is implicated in the pathogenesis of various nephropathies, targeting ILK signaling with small-molecule inhibitor might be therapeutically effective in other models of chronic kidney diseases as well.…”

Section: Discussionmentioning

confidence: 53%

“…QLT-0267 also did not abolish PINCH-1 induction by TGF-␤1 ( Figure 2F), which is dependent on Smad signaling. 6 Together, it is clear that smallmolecule inhibitor QLT-0267 specifically blocks ILK signaling in tubular epithelial cells.…”

Section: Small-molecule Inhibitor Qlt-0267 Suppresses Ilk Activity Anmentioning

confidence: 99%

Inhibition of Integrin-Linked Kinase Attenuates Renal Interstitial Fibrosis

Li¹,

Tan²,

Dai³

et al. 2009

Journal of the American Society of Nephrology

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105

117

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Integrin-linked kinase (ILK) is an intracellular serine/threonine protein kinase that regulates cell adhesion, survival, and epithelial-to-mesenchymal transition (EMT). In this study, we investigated the kinase activity of ILK during tubular EMT induced by TGF-␤1 and examined the therapeutic potential of an ILK inhibitor in obstructive nephropathy. TGF-␤1 induced a biphasic activation of ILK in renal tubular epithelial cells, with rapid activation starting at 5 min and the second wave of activation peaking at 24 h; the latter paralleled the induction of ILK protein expression. Pharmacologic inhibition of ILK with small-molecule inhibitor QLT-0267 abolished TGF-␤1-induced phosphorylation of Akt and glycogen synthase kinase-3␤, suppressed cyclin D1 expression, and largely restored the expression of E-cadherin and zonula occludens 1. Inhibition of ILK also blocked TGF-␤1-mediated induction of fibronectin, Snail1, plasminogen activator inhibitor 1, and matrix metalloproteinase 2. In a mouse model of obstructive nephropathy, administration of QLT-0267 inhibited ␤-catenin accumulation; suppressed Snail1, ␣-smooth muscle actin, fibronectin, vimentin, and type I and type III collagen expression; and reduced total tissue collagen content. Inhibition of ILK did not affect kidney structure or function in normal mice. These findings suggest that increased ILK activity mediates EMT and the progression of renal fibrosis. Pharmacologic inhibition of ILK signaling may hold therapeutic potential for fibrotic kidney diseases.

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PINCH-1 Promotes Tubular Epithelial-to-Mesenchymal Transition by Interacting with Integrin-Linked Kinase

Cited by 60 publications

References 50 publications

TL1A Both Promotes and Protects from Renal Inflammation and Injury

TL1A Both Promotes and Protects from Renal Inflammation and Injury

EMT, the cytoskeleton, and cancer cell invasion

Inhibition of Integrin-Linked Kinase Attenuates Renal Interstitial Fibrosis

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