TY - JOUR
T1 - LST8 level controls basal p70 S6 kinase and Akt phosphorylations, and mTORC1 and mTORC2 negatively regulate each other by competing for association with LST8
AU - Kikuchi, Takako
AU - Zhang, Jun
AU - Sakoda, Hideyuki
AU - Koketsu, Yuko
AU - Fujishiro, Midori
AU - Kushiyama, Akifumi
AU - Nakatsu, Yusuke
AU - Kamata, Hideaki
AU - Inoki, Ken
AU - Takahashi, Shin Ichiro
AU - Kurihara, Hiroki
AU - Hideki, Katagiri
AU - Oka, Yoshitomo
AU - Asano, Tomoichiro
PY - 2012/7
Y1 - 2012/7
N2 - LST8 is a component of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Herein, to examine the role of LST8, a common component of mTOR complexes, in the regulation of mTORC1 and mTORC2, first, we showed over-expression of LST8 in HepG2 to markedly enhance basal phosphorylation levels of not only p70 S6 kinase but also Akt. In contrast, LST8 knockdown by siRNA in HepG2 decreased phosphorylation levels of both p70 S6 kinase and Akt. These results indicate the LST8 expression level to determine basal mTORC1 and mTORC2 activities, since LST8 appears to be the component present at the lowest level in both mTORC1 and mTORC2 complexes. Previously, we reported S6 kinase phosphorylation to be reduced by over-expression of the Cterminally deleted Raptor mutant (Raptor-ΔCT) not binding to mTOR or LST8, while phosphorylation levels of Akt were markedly enhanced with no alteration in IRS-1 phosphorylation or PI 3-kinase activity. Using Raptor-ΔCT, we investigated the competition for association with LST8 between mTORC1 and mTORC2. Over-expression of Raptor-ΔCT abolished formation of the Raptor, S6 kinase, mTOR and LST8 complex, while the amount of LST8 in the Rictor-mTOR complex was increased. Therefore, it is likely that Raptor-mTOR and Rictor-mTOR complexes compete for association with LST8, and this mechanism may contribute to the reciprocal negative regulations of mTORC1 and mTORC2 activities, in terms of their LST8 components.
AB - LST8 is a component of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Herein, to examine the role of LST8, a common component of mTOR complexes, in the regulation of mTORC1 and mTORC2, first, we showed over-expression of LST8 in HepG2 to markedly enhance basal phosphorylation levels of not only p70 S6 kinase but also Akt. In contrast, LST8 knockdown by siRNA in HepG2 decreased phosphorylation levels of both p70 S6 kinase and Akt. These results indicate the LST8 expression level to determine basal mTORC1 and mTORC2 activities, since LST8 appears to be the component present at the lowest level in both mTORC1 and mTORC2 complexes. Previously, we reported S6 kinase phosphorylation to be reduced by over-expression of the Cterminally deleted Raptor mutant (Raptor-ΔCT) not binding to mTOR or LST8, while phosphorylation levels of Akt were markedly enhanced with no alteration in IRS-1 phosphorylation or PI 3-kinase activity. Using Raptor-ΔCT, we investigated the competition for association with LST8 between mTORC1 and mTORC2. Over-expression of Raptor-ΔCT abolished formation of the Raptor, S6 kinase, mTOR and LST8 complex, while the amount of LST8 in the Rictor-mTOR complex was increased. Therefore, it is likely that Raptor-mTOR and Rictor-mTOR complexes compete for association with LST8, and this mechanism may contribute to the reciprocal negative regulations of mTORC1 and mTORC2 activities, in terms of their LST8 components.
KW - LST8
KW - Raptor
KW - Rictor
KW - mTOR
UR - http://www.scopus.com/inward/record.url?scp=84864693092&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864693092&partnerID=8YFLogxK
U2 - 10.1016/j.orcp.2011.10.002
DO - 10.1016/j.orcp.2011.10.002
M3 - Article
AN - SCOPUS:84864693092
VL - 6
SP - e215-e224
JO - Obesity Research and Clinical Practice
JF - Obesity Research and Clinical Practice
SN - 1871-403X
IS - 3
ER -