title: Tuberin activates and controls the distribution of Rac1 via association with p62 and ubiquitin through the mTORC1 signaling pathway.
abstract: Recent studies indicated that the tuberous sclerosis 2 (TSC2) gene product, tuberin, regulates Rac1 activity. However, the underlying mechanism by which tuberin regulates Rac1 activity has not been clearly elucidated to date. To better understand the molecular link between tuberin function and Rac1, we characterized the activity and distribution of Rac1 in mouse Tsc2-deficient renal tumor cells using restoration experiments with wild-type tuberin. Rac1 activity was significantly higher in tuberin-expressing cells compared with control Tsc2-deficient cells. Further, Rac1 activation was induced by rapamycin treatment or knockdown of raptor, but not rictor, in Tsc2-deficient cells, indicating that mTORC1 is an upstream negative regulator of Rac1. Intriguingly, Rac1 appeared to form cytoplasmic dots in Tsc2-deficient cells, but not in tuberin-expressing and since rapamycin treatment dispersed these dots, involvement of aberrant mTOR complex 1 (mTORC1) activation in the dot formation was suspected. Moreover, the dots were co-localized with p62/sequestosome-1 and ubiquitin. These findings imply that Rac1 distribution and/or its degradation may be regulated by tuberin through the mTORC1 signaling pathway.
authors.affiliation: Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Okura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Maki
authors.initials: M
authors.lastname: Ohsawa
authors.forename: Danqing
authors.initials: D
authors.lastname: Zhang
authors.forename: Hajime
authors.initials: H
authors.lastname: Arai
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D006360:Heat-Shock Proteins / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; C490981:Gtf2h1 protein, mouse; D006360:Heat-Shock Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C525637:rictor protein, mouse; D051758:Transcription Factor TFIIH; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D020123:Sirolimus