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PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase.
J Am Soc Nephrol. 2007 Sep; 18(9):2534-43.JA

Abstract

PINCH-1 is an adaptor protein that binds to the integrin-linked kinase (ILK), an intracellular serine/threonine protein kinase that plays a critical role in mediating tubular epithelial-to-mesenchymal transition (EMT). To determine whether PINCH-1 is also involved in the EMT process, we investigated its regulation and function during TGF-beta1-stimulated EMT. TGF-beta1 induced PINCH-1 mRNA and protein expression in human proximal tubular epithelial cells in a time-dependent fashion, an effect that was largely dependent on intracellular Smad signaling. Overexpression of PINCH-1 suppressed epithelial markers E-cadherin and ZO-1 and increased fibronectin expression and extracellular assembly, whereas knockdown of PINCH-1 via small interfering RNA reduced TGF-beta1-mediated fibronectin expression and partially restored E-cadherin. PINCH-1 formed a ternary complex with ILK at the focal adhesion sites of tubular epithelial cells. Treatment with an ILK inhibitor or disruption of the ILK/PINCH-1 interaction by overexpressing a dominant-negative N-terminal ankyrin domain of ILK resulted in reduced fibronectin deposition, indicating that the ability of PINCH-1 to stimulate EMT is ILK-dependent. In a mouse model of obstructive nephropathy, PINCH-1 expression increased in a time-dependent manner, suggesting that it may play a role in EMT and renal fibrosis in vivo. We conclude that PINCH-1, through its interaction with ILK, plays an important role in regulating TGF-beta1-mediated EMT and could be a potential future therapeutic target to prevent progression of renal disease.

Authors+Show Affiliations

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17656471

Citation

Li, Yingjian, et al. "PINCH-1 Promotes Tubular Epithelial-to-mesenchymal Transition By Interacting With Integrin-linked Kinase." Journal of the American Society of Nephrology : JASN, vol. 18, no. 9, 2007, pp. 2534-43.
Li Y, Dai C, Wu C, et al. PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase. J Am Soc Nephrol. 2007;18(9):2534-43.
Li, Y., Dai, C., Wu, C., & Liu, Y. (2007). PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase. Journal of the American Society of Nephrology : JASN, 18(9), 2534-43.
Li Y, et al. PINCH-1 Promotes Tubular Epithelial-to-mesenchymal Transition By Interacting With Integrin-linked Kinase. J Am Soc Nephrol. 2007;18(9):2534-43. PubMed PMID: 17656471.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase. AU - Li,Yingjian, AU - Dai,Chunsun, AU - Wu,Chuanyue, AU - Liu,Youhua, Y1 - 2007/07/26/ PY - 2007/7/28/pubmed PY - 2007/11/14/medline PY - 2007/7/28/entrez SP - 2534 EP - 43 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 18 IS - 9 N2 - PINCH-1 is an adaptor protein that binds to the integrin-linked kinase (ILK), an intracellular serine/threonine protein kinase that plays a critical role in mediating tubular epithelial-to-mesenchymal transition (EMT). To determine whether PINCH-1 is also involved in the EMT process, we investigated its regulation and function during TGF-beta1-stimulated EMT. TGF-beta1 induced PINCH-1 mRNA and protein expression in human proximal tubular epithelial cells in a time-dependent fashion, an effect that was largely dependent on intracellular Smad signaling. Overexpression of PINCH-1 suppressed epithelial markers E-cadherin and ZO-1 and increased fibronectin expression and extracellular assembly, whereas knockdown of PINCH-1 via small interfering RNA reduced TGF-beta1-mediated fibronectin expression and partially restored E-cadherin. PINCH-1 formed a ternary complex with ILK at the focal adhesion sites of tubular epithelial cells. Treatment with an ILK inhibitor or disruption of the ILK/PINCH-1 interaction by overexpressing a dominant-negative N-terminal ankyrin domain of ILK resulted in reduced fibronectin deposition, indicating that the ability of PINCH-1 to stimulate EMT is ILK-dependent. In a mouse model of obstructive nephropathy, PINCH-1 expression increased in a time-dependent manner, suggesting that it may play a role in EMT and renal fibrosis in vivo. We conclude that PINCH-1, through its interaction with ILK, plays an important role in regulating TGF-beta1-mediated EMT and could be a potential future therapeutic target to prevent progression of renal disease. SN - 1046-6673 UR - https://www.unboundmedicine.com/medline/citation/17656471/PINCH_1_promotes_tubular_epithelial_to_mesenchymal_transition_by_interacting_with_integrin_linked_kinase_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=17656471 DB - PRIME DP - Unbound Medicine ER -