Published ahead of print on December 30, 2005, doi:10.1165/rcmb.2005-0374OC Am. J. Respir. Cell Mol. Biol., Volume 34, Number 4, April 2006, 473-480 A more recent version of this article appeared on April 1, 2006
Submitted on October 5, 2005 Modulation of LAM Cell Migration and Invasiveness by Tumor Suppressor TSC2Elena A Goncharova1*,1 Department of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA, 2 Department of Biochemistry, University of Kentucky, Chandler Medical Center, Lexington, KY, USA * To whom correspondence should be addressed. E-mail: goncharo{at}mail.med.upenn.edu.
The loss of TSC2 function is associated with the pathobiology of lymphangioleiomyomatosis (LAM), which is characterized by the abnormal proliferation, migration, and differentiation of smooth muscle-like cells within the lungs. While the etiology of LAM remains unknown, clinical and genetic evidence provides support for the neoplastic nature of LAM. The goal of this study was to determine the role of tumor suppressor TSC2 in the neoplastic potential of LAM cells. We show that primary cultures of human LAM cells exhibit increased migratory activity and invasiveness, which is abolished by TSC2 re-expression. We found that TSC2 also inhibits cell migration through its N-terminus, independent of its GTP-ase-activating protein (GAP) activity. LAM cells show increased stress fiber and focal adhesion formation, which is attenuated by TSC2 re-expression. The small GTPase RhoA is activated in LAM cells compared to normal human mesenchymal cells. Pharmacological inhibition of Rho activity abrogates LAM cell migration; RhoA activity was also abolished by TSC2 re-expression or TSC1 knock-down with specific siRNA. These data demonstrate that TSC2 controls cell migration through its N-terminus by associating with TSC1 and regulating RhoA activity, suggesting that TSC2 may play a critical role in modulating cell migration and invasiveness, which contributes to the pathobiology of LAM.
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