Tuberin activates and controls the distribution of Rac1 via association with p62 and ubiquitin through the mTORC1 signaling pathway

Okura,Hidehiro; Kobayashi,Toshiyuki; Koike,Masato; Ohsawa,Maki; Zhang,Danqing; Arai,Hajime; Uchiyama,Yasuo; Hino,Okio

doi:10.3892/ijo.2013.1984

Tuberin activates and controls the distribution of Rac1 via association with p62 and ubiquitin through the mTORC1 signaling pathway

Authors:
- Hidehiro Okura
- Toshiyuki Kobayashi
- Masato Koike
- Maki Ohsawa
- Danqing Zhang
- Hajime Arai
- Yasuo Uchiyama
- Okio Hino
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Affiliations: Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan, Department of Cell Biology and Neuroscience, Juntendo University School of Medicine, Tokyo, Japan, Department of Pediatrics, University of Tokyo, Tokyo, Japan, Department of Neurosurgery, Juntendo University School of Medicine, Tokyo, Japan
Published online on: June 12, 2013 https://doi.org/10.3892/ijo.2013.1984
Pages: 447-456

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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.

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