TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity

• Published in: PloS one Vol. 8; no. 1; p. e54503
• Main Authors: Ohsawa, Maki, Kobayashi, Toshiyuki, Okura, Hidehiro, Igarashi, Takashi, Mizuguchi, Masashi, Hino, Okio
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.01.2013; Public Library of Science (PLoS)
• Subjects: Actin; Animals; Antibiotics, Antineoplastic - pharmacology; Biology; Cell adhesion & migration; Cell Cycle; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement; Cell Polarity; Cell proliferation; Cell survival; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cytoskeleton; Enzyme inhibitors; Fibers; Filopodia; G proteins; Hereditary diseases; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidneys; Kinases; Lamellipodia; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes; Muscle proteins; Mutation; Neuropeptides - genetics; Neuropeptides - metabolism; Physics; Polarity; Proteins - genetics; Proteins - metabolism; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - metabolism; rac1 GTP-Binding Protein; Rac1 protein; Rapamycin; Rho-associated kinase; rho-Associated Kinases - metabolism; Rocks; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Sirolimus - pharmacology; Spatial distribution; Stress Fibers - genetics; Stress Fibers - metabolism; Stress Fibers - pathology; TOR protein; TOR Serine-Threonine Kinases; Tuberous sclerosis; Tuberous Sclerosis Complex 1; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2; Tuberous Sclerosis Complex 2 Protein; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054503

The tumor-suppressor genes TSC1 and TSC2 are mutated in tuberous sclerosis, an autosomal dominant multisystem disorder. The gene products of TSC1 and TSC2 form a protein complex that inhibits the signaling of the mammalian target of rapamycin complex1 (mTORC1) pathway. mTORC1 is a crucial molecule in the regulation of cell growth, proliferation and survival. When the TSC1/TSC2 complex is not functional, uncontrolled mTORC1 activity accelerates the cell cycle and triggers tumorigenesis. Recent studies have suggested that TSC1 and TSC2 also regulate the activities of Rac1 and Rho, members of the Rho family of small GTPases, and thereby influence the ensuing actin cytoskeletal organization at focal adhesions. However, how TSC1 contributes to the establishment of cell polarity is not well understood. Here, the relationship between TSC1 and the formation of the actin cytoskeleton was analyzed in stable TSC1-expressing cell lines originally established from a Tsc1-deficient mouse renal tumor cell line. Our analyses showed that cell proliferation and migration were suppressed when TSC1 was expressed. Rac1 activity in these cells was also decreased as was formation of lamellipodia and filopodia. Furthermore, the number of basal actin stress fibers was reduced; by contrast, apical actin fibers, originating at the level of the tight junction formed a network in TSC1-expressing cells. Treatment with Rho-kinase (ROCK) inhibitor diminished the number of apical actin fibers, but rapamycin had no effect. Thus, the actin fibers were regulated by the Rho-ROCK pathway independently of mTOR. In addition, apical actin fibers appeared in TSC1-deficient cells after inhibition of Rac1 activity. These results suggest that TSC1 regulates cell polarity-associated formation of actin fibers through the spatial regulation of Rho family of small GTPases.