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

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 acti...

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Bibliographic Details
Published in:The Journal of cell biology 2004-12, Vol.167 (6), p.1171-1182
Main Authors: Goncharova, Elena, Goncharov, Dmitry, Noonan, Daniel, Krymskaya, Vera P
Format: Article
Language:English
Subjects:
3T3 Cells
Actins
Actins - metabolism
Animals
Antibodies
Cell adhesion & migration
Cell Adhesion - drug effects
Cell Adhesion - physiology
Cell Line, Tumor
Cell motility
Cellular biology
Cytoskeleton - metabolism
Cytoskeleton - physiology
Down-Regulation
Focal adhesions
Gene expression regulation
Mice
Plasmids
Proteins
Proteins - antagonists & inhibitors
Proteins - genetics
Proteins - metabolism
rac1 GTP-Binding Protein - antagonists & inhibitors
rac1 GTP-Binding Protein - metabolism
Rats
Renovations
Repressor Proteins - genetics
Repressor Proteins - metabolism
Repressor Proteins - pharmacology
rho GTP-Binding Proteins - antagonists & inhibitors
rho GTP-Binding Proteins - metabolism
RNA, Small Interfering - genetics
Small interfering RNA
Stress fibers
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200405130