Nutrient-dependent multimerization of the mammalian target of rapamycin through the N-terminal HEAT repeat region.
The mammalian target of rapamycin (mTOR) plays a pivotal role in the regulation of cell growth in response to a variety of signals such as nutrients and growth factors. mTOR forms two distinct complexes in vivo. mTORC1 (mTOR complex 1) is rapamycin-sensitive and regulates the rate of protein synthesis in part by phosphorylating two well established effectors, S6K1 (p70 ribosomal S6 kinase 1) and 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1). mTORC2 is rapamycin-insensitive and likely regulates actin organization and activates Akt/protein kinase B. Here, we show that mTOR forms a multimer via its N-terminal HEAT repeat region in mammalian cells. mTOR multimerization is promoted by amino acid sufficiency, although the state of multimerization does not directly correlate with the phosphorylation state of S6K1. mTOR multimerization was insensitive to rapamycin treatment but hindered by butanol treatment, which inhibits phosphatidic acid production by phospholipase D. We also found that mTOR forms a multimer in both mTORC1 and mTORC2. In addition, Saccharomyces cerevisiae TOR proteins Tor1p and Tor2p also exist as homomultimers. These results suggest that TOR multimerization is a conserved mechanism for TOR functioning.
Takahara
Terunao
T
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Hara
Kenta
K
Yonezawa
Kazuyoshi
K
Sorimachi
Hiroyuki
H
Maeda
Tatsuya
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins; D002522:Chlorocebus aethiops; D003470:Culture Media / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D010712:Phosphatidic Acids / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000502:physiology*; D017434:Protein Structure, Tertiary; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D003470:Culture Media; C087000:EIF4EBP1 protein, human; D010712:Phosphatidic Acids; D010750:Phosphoproteins; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D