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¹ Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
² Department of Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, KY 40536

Correspondence to Vera P. Krymskaya: krymskay{at}mail.med.upenn.edu

Tuberous sclerosis complex (TSC) 1 and TSC2 are thought to be involved in protein translational regulation and cell growth, and loss of their function is a cause of TSC and lymphangioleiomyomatosis (LAM). However, TSC1 also activates Rho and regulates cell adhesion. We found that TSC2 modulates actin dynamics and cell adhesion and the TSC1-binding domain (TSC2-HBD) is essential for this function of TSC2. Expression of TSC2 or TSC2-HBD in TSC2–/– cells promoted Rac1 activation, inhibition of Rho, stress fiber disassembly, and focal adhesion remodeling. The down-regulation of TSC1 with TSC1 siRNA in TSC2–/– cells activated Rac1 and induced loss of stress fibers. Our data indicate that TSC1 inhibits Rac1 and TSC2 blocks this activity of TSC1. Because TSC1 and TSC2 regulate Rho and Rac1, whose activities are interconnected in a reciprocal fashion, loss of either TSC1 or TSC2 function may result in the deregulation of cell motility and adhesion, which are associated with the pathobiology of TSC and LAM.

Abbreviations used in this paper: ERM, ezrin-radixin-moesin; GAP, GTPase-activating protein; LAM, lymphangioleiomyomatosis; LAMD, human LAM-derived; mTOR, mammalian target of rapamycin; PDGFR, PDGF receptor; S6K, p70 S6 kinase; SE, standard error; TSC, tuberous sclerosis complex; TSC2-HBD, TSC1-binding domain of TSC2.

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