Tuberin Regulates E-Cadherin Localization Implications in Epithelial-Mesenchymal Transition

被引:50
作者
Barnes, Elizabeth A. [1 ]
Kenerson, Heidi L. [1 ]
Jiang, Xiuyun [1 ]
Yeung, Raymond S. [1 ]
机构
[1] Univ Washington, Dept Surg, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
SCLEROSIS COMPLEX; BETA-CATENIN; CELL; TSC2; LYMPHANGIOLEIOMYOMATOSIS; EXPRESSION; CARCINOMA; TARGET; LYMPHANGIOMYOMATOSIS; TRANSPLANTATION;
D O I
10.2353/ajpath.2010.090233
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
The tuberous sclerosis complex 2 (TSC2) gene encodes the protein tuberin, which functions as a key negative regulator of both mammalian target of rapamycin (mTOR) Cl-dependent cell growth and proliferation. Loss-of-function mutations of TSC2 result in mTORC1 hyperactivity and predispose individuals to both tuberous sclerosis and lymphangioleiomyomatosis. These overlapping diseases have in common the abnormal proliferation of smooth muscle-like cells. Although the origin of these cells is unknown, accumulating evidence suggests that a metastatic mechanism may be involved, but the means by which the mTOR pathway contributes to this disease process remain poorly understood. In this study, we show that tuberin regulates the localization of E-cadherin via an Akt/mTORC1/CLIP170-dependent, rapamycin-sensitive pathway. Consequently, Tsc2(-/-) epithelial cells display a loss of plasma membrane E-cadherin that leads to reduced cell-cell adhesion. Under confluent conditions, these cells detach, grow in suspension, and undergo epithelial-mesenchymal transition (EMT) that is marked by reduced expression levels of both E-cadherin and occludin and increased expression levels of both Snail and smooth muscle actin. Functionally, the Tsc2(-/-) cells demonstrate anchorage-independent growth, cell scattering, and anoikis resistance. Human renal angiomyolipomas and lymphangioleiomyomatosis also express markers of EMT and exhibit an invasive phenotype that can be interpreted as consistent with EMT. Together, these results suggest a novel relationship between TSC2/mTORC1 and the E-cadherin pathways and implicate EMT in the pathogenesis of tuberous sclerosis complex-related diseases. (Am J Pathol 2010, 177:1765-177%. DOI: 10.2353/ajpath.2010.090233)
引用
收藏
页码:1765 / 1778
页数:14
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