This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0374OCv1 34/4/473    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goncharova, E. A. Articles by Krymskaya, V. P. Search for Related Content PubMed PubMed Citation Articles by Goncharova, E. A. Articles by Krymskaya, V. P.

Modulation of Cell Migration and Invasiveness by Tumor Suppressor TSC2 in Lymphangioleiomyomatosis

Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Department of Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, Kentucky

Correspondence and requests for reprints should be addressed to Elena A. Goncharova, Ph.D., Department of Medicine, University of Pennsylvania, BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. 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. Although 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 GTPase-activating protein 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 with normal human mesenchymal cells. Pharmacologic inhibition of Rho activity abrogates LAM cell migration; RhoA activity was also abolished by TSC2 re-expression or TSC1 knockdown 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.

Key Words: lung • RhoA GTPase • smooth muscle cells • TSC1

This article has been cited by other articles:

				K. Inoki and K.-L. Guan Tuberous sclerosis complex, implication from a rare genetic disease to common cancer treatment Hum. Mol. Genet., April 15, 2009; 18(R1): R94 - R100. [Abstract] [Full Text] [PDF]

				V. P. Krymskaya Smooth Muscle like Cells in Pulmonary Lymphangioleiomyomatosis Proceedings of the ATS, January 1, 2008; 5(1): 119 - 126. [Abstract] [Full Text] [PDF]

				H. Watz, K. Engels, S. Loeschke, M. Amthor, D. Kirsten, and H. Magnussen Lymphangioleiomyomatosis--presence of receptor tyrosine kinases and the angiogenesis factor VEGF-A as potential therapeutic targets Thorax, June 1, 2007; 62(6): 559 - 559. [Full Text] [PDF]

				S. Zarogiannis, C. Hatzoglou, P. A. Molyvdas, and K. Gourgoulianis Lymphangioleiomyomatosis Eur. Respir. J., December 1, 2006; 28(6): 1284 - 1284. [Full Text] [PDF]