Deacetylated αβ-tubulin acts as a positive regulator of Rheb GTPase through increasing its GTP-loading

Ras homolog enriched in brain (Rheb) regulates diverse cellular functions by modulating its nucleotide-bound status. Although Rheb contains a high basal GTP level, the regulatory mechanism of Rheb is not well understood. In this study, we propose soluble αβ-tubulin acts as a constitutively active Rh...

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Published in:Cellular signalling 2013-02, Vol.25 (2), p.539-551
Main Authors: Lee, Mi Nam, Koh, Ara, Park, Dohyun, Jang, Jin-Hyeok, Kwak, Dongoh, Jeon, Hyeona, Kim, Jaeyoon, Choi, Eun-Jeong, Jeong, Heeyoon, Suh, Pann-Ghill, Ryu, Sung Ho
Format: Article
Language:English
Subjects:
Acetylation
Cell Line, Tumor
Guanosine Triphosphate - metabolism
HEK293 Cells
HeLa Cells
Histidine - genetics
Histidine - metabolism
Humans
MCF-7 Cells
Microtubules - metabolism
Mitosis
Monomeric GTP-Binding Proteins - chemistry
Monomeric GTP-Binding Proteins - genetics
Monomeric GTP-Binding Proteins - metabolism
mTOR
Neuropeptides - chemistry
Neuropeptides - genetics
Neuropeptides - metabolism
Oligopeptides - genetics
Oligopeptides - metabolism
Protein Binding
Ras Homolog Enriched in Brain Protein
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - chemistry
Recombinant Fusion Proteins - genetics
Rheb
Soluble tubulin
Transfection
Tubulin - metabolism
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Summary:Ras homolog enriched in brain (Rheb) regulates diverse cellular functions by modulating its nucleotide-bound status. Although Rheb contains a high basal GTP level, the regulatory mechanism of Rheb is not well understood. In this study, we propose soluble αβ-tubulin acts as a constitutively active Rheb activator, which may explain the reason why Rheb has a high basal GTP levels. We found that soluble αβ-tubulin is a direct Rheb-binding protein and that its deacetylated form has a high binding affinity for Rheb. Modulation of both soluble and acetylated αβ-tubulin levels affects the level of GTP-bound Rheb. This occurs in the mitotic phase in which the level of acetylated αβ-tubulin is increased but that of GTP-bound Rheb is decreased. Constitutively active Rheb-overexpressing cells showed an abnormal mitotic progression, suggesting the deacetylated αβ-tubulin-mediated regulation of Rheb status may be important for proper mitotic progression. Taken together, we propose that deacetylated soluble αβ-tubulin is a novel type of positive regulator of Rheb and may play a role as a temporal regulator for Rheb during the cell cycle. ► The mechanism of how GTP-bound Rheb is generated remains unclear. ► Deacetylated tubulin activates Rheb function by increasing the GTP-bound Rheb level. ► Accumulation of acetylated tubulins reduces Rheb-tubulin bindings and GTP-Rheb levels. ► Deacetylated tubulin acts as a temporal Rheb regulator during the cell cycle. ► Our findings provide new insights into small GTPases cycling and tubulin function.
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2012.11.006