Tuberous Sclerosis Complex 2 (TSC2) regulates cell migration and polarity through activation of CDC42 and RAC1

Yan Larson, Jianyu Liu, Payton D. Stevens, Xin Li, Jing Li, B. Mark Evers, Tianyan Gao

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays important roles in regulating cell motility. TSC2, a downstream target of AKT, is a central player in negatively controlling cell proliferation and protein translation through suppressing the activity of mTOR (mammalian target of rapamycin). However, the function of TSC2 in regulating cell migration remains unclear. Here, we show that TSC2 plays a critical role in the control of cell spreading, polarity, and migration. TSC2-deficient fibroblast cells were impaired in their ability to spread and alter actin cytoskeleton upon stimulation with insulin-like growth factor-1. Using scratch-induced polarization assay, we demonstrate that TSC2(-/-) fibroblast cells polarized poorly toward the wound compared with wild-type cells. Similarly, knockdown of TSC2 expression in colon cancer cells resulted in a marked decrease in cell motility. Functionally, the activation of CDC42- and RAC1-GTPase was largely reduced in TSC2 knock-out fibroblast and TSC2 knockdown cancer cells. Furthermore, overexpression of an activating p110α mutant or short term rapamycin treatment rescued the cell polarization defect in TSC2(-/-) fibroblast cells. Concurrently, the activation of CDC42 and RAC1 increased. The defect in cell migration and CDC42 and RAC1 activation was reversed by reintroducing TSC2 back into TSC2(-/-) fibroblast cells. Taken together, we identified a novel role of TSC2 in controlling cell polarity and migration by regulating CDC42 and RAC1 activation.

Original languageEnglish
Pages (from-to)24987-24998
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number32
DOIs
StatePublished - Aug 6 2010

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