Tuberin Regulates E-Cadherin Localization

Abstract

The tuberous sclerosis complex 2 (TSC2) gene en-codes the protein tuberin , which functions as a key negative regulator of both mammalian target of rapa-mycin (mTOR) C1-dependent cell growth and prolif-eration. Loss-of-function mutations of TSC2 result in mTORC1 hyperactivity and predispose individuals to both tuberous sclerosis and lymphangioleiomyoma-tosis. 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(؊/؊) epithe-lial cells display a loss of plasma membrane E-cad-herin that leads to reduced cell-cell adhesion. Under confluent conditions , these cells detach , grow in sus-pension , and undergo epithelial-mesenchymal tran-sition (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 mark-ers 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.