TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase

Abstract

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.

A pharmacological activator of AMP-activated protein kinase (AMPK) induces astrocyte stellation

“…There are two functionally distinct mTOR complexes, mTORC1, responsible for cell growth and proliferation, and mTORC2, which signals through Rho GTPases to stimulate actin stress fiber formation [31]. TSC2 can also inhibit Rho by binding to TSC1, and thus promote stress fiber disassembly and focal adhesion remodeling [23]. Therefore, AMPK modulates substrates that potentially control actin stress fiber dynamics.…”

Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2

“…Although it has been best characterized as a controller of cell size through its regulation of ribosomal synthesis proteins including ribosomal S6 kinase (17,18), TSC2 has been implicated in a number of related signaling pathways in a variety of cell types (19). Investigations of Madin-Darby canine kidney epithelial cells demonstrated that overexpression of TSC2 results in activation of Rho and increased cellular motility (15), and analysis of TSC2-deficient cells has shown reduced Rho activity (16), although these effects may depend on the cell type investigated (20). Although mutational inactivation of TSC2 contributes to tuberous sclerosis complex, regulation of intact TSC2 occurs principally through the action of the serine͞threonine kinase Akt1͞protein kinase B (21,22).…”

Akt1 governs breast cancer progression in vivo

“…Tsc2 modulates actin dynamics, inducing a cortical F-actin distribution and regulating RhoA activity (16). A subset of key downstream transcriptional targets, including forkhead ligand1 (FKHR-L1), MDM2, BAD, Huntington, and arfaptin2, are phosphorylated by Akt (17).…”