Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis.
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.
Goncharova
Elena A
EA
Department of Medicine, University of Pennsylvania, BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, USA. goncharo@mail.med.upenn.edu
Goncharov
Dmitriy A
DA
Lim
Poay N
PN
Noonan
Daniel
D
Krymskaya
Vera P
VP
D002465:Cell Movement; D022001:Focal Adhesions; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000473:pathology*; D008648:Mesoderm / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D034741:RNA, Small Interfering; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D020742:rhoA GTP-Binding Protein