2006 Fiscal Year Final Research Report Summary
Study on the Mammalian target of rapamycin in thrombocytepoiesis, wound healing, and hyperlipemia
| Project/Area Number |
16390094
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Kobe University |
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Principal Investigator |
YOSHINO Ken-ichi Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (90280792)
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| Co-Investigator(Kenkyū-buntansha) |
OSHIRO Noriko Kobe University, Biosignal Research Center, Assistant Professor, バイオシグナル研究センター, 助手 (70372662)
KIKKAWA Ushio Kobe University, Biosignal Research Center, Professor, バイオシグナル研究センター, 教授 (40150354)
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| Project Period (FY) |
2004 – 2006
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| Keywords | immunosuppressant / rapamycin / mTOR / cell growth / PRAS40 / restenosis prevention / side effect / amino acids |
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| Research Abstract |
The mammalian target of rapamycin (mTOR) is a Ser/Thr protein kinase that plays a crucial role in a nutrient-sensitive signalling pathway that regulates cell growth. TOR signalling is potently inhibited by rapamycin, through the direct binding of a FK506-binding protein 12 (FKBP12)/rapamycin complex to the TOR FRB domain, a segment amino terminal to the kinase catalytic domain. Raptor (regulatory associated protein of mTOR) is a recently identified mTOR binding partner that is essential for mTOR signalling in vivo, and whose binding to mTOR is critical for mTOR-catalyzed substrate phosphorylation in vitro.
Here we investigated the stability of endogenous mTOR/raptor complex in response to rapamycin in vivo, and to the direct addition of a FKBP12/rapamycin complex in vitro. We demonstrated that rapamycin inhibits mTOR function, at least in part, by inhibiting the interaction of raptor with mTOR; this action uncouples mTOR from its substrates, and inhibits mTOR signalling without altering
… More
mTOR's intrinsic catalytic activity.
We showed that heat shock protein 90 (Hsp90) is involved in the regulation of protein translation by facilitating the phosphorylation reaction of eukaryotic initiation factor-4E (eIF4E) binding protein 1 (4E-BP1) and p70 S6 kinase (S6K) catalyzed by the mTOR/raptor complex through the association with raptor, and that the mTOR signaling pathway is a novel target of geldanamycin.
We found that the TOS motif has an essential function whereas the RAIP motif has an accessory role in the association with raptor and mTOR-mediated phosphorylation of 4E-BP1 to dissociate it from raptor and release eIF4E in response to amino acid stimulation leading to the control of cell size.
The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor binding protein that is phosphorylated directly by mTOR complex (mTORC) 1 but not mTORC 2 in vitro, predominantly at PRAS40 (Serl 83). We establish PRAS40 as a physiological mTORCl substrate that contains a variant TOS motif Moreover, they indicate that the capacity or ability of raptor to bind endogenous substrates is limiting for the activity of mTORCl in vivo, and is therefore a potential locus of regulation, as suggested by others. Less
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Research Products
(51 results)
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[Journal Article] The proline-Rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mTOR complex 12007
Author(s)
Oshiro, N., Takahashi, R., Yoshino, K., Tanimura, K., Nakashima, A., Eguchi, S., Miyamoto, T., Hara, K., Takehana, K., Avruch, J., Kikkawa, U., Yonezawa, K.
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Journal Title
J. Biol. Chem. 282(in press)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Suppression of the mTOR-raptor signaling pathway by the inhibitor of heat shock protein 90 geldanamycin2006
Author(s)
Ohji, G., Hidayat, S., Nakashima, A., Tokunaga, C., Oshiro, N., Yoshino, K., Yokono, K., Kikkawa, U., Yonezawa, K.
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Journal Title
J. Biochem. 139 (1)
Pages: 129-135
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification and comparative analysis of the large subunit mitochondrial ribosomal proteins of Neurospora crassa2006
Author(s)
Gan, X., Arita, K., Isono, S., Kitakawa, M., Yoshino, K., Yonezawa, K., Kato, A., Inoue, H., Isono, K.
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Journal Title
FEMS Microbiol. Lett. 254 (1)
Pages: 157-164
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Phylogeny of vertebrate Src tyrosine kinases as revealed by the epitope region for mAb3272006
Author(s)
Iwasaki, T., Sato, K., Yoshino, K., Itakura, S., Kosuge, K., Tokmakov, A.A., Owada, K., Yonezawa, K., Fukami, Y.
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Journal Title
J. Biochem. 139 (3)
Pages: 347-354
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Different roles for the TOS and RAIP motifs of the translational regulator protein 4E-BP1 in the association with raptor and phosphorylation by mTOR in the regulation of cell size2006
Author(s)
Eguchi, S., Tokunaga, C., Hidayat, S., Oshiro, N., Yoshino, K., Kikkawa, U., Yonezawa, K.
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Journal Title
Genes Cells 11 (7)
Pages: 757-766
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] TOR regulates late steps of ribosome maturation in the nucleoplasm via Nog1 in response to nutrients2006
Author(s)
Honma, Y., Kitamura, A., Shioda, R., Maruyama, H., Ozaki, K., Oda, Y., Mini, T., Jeno, P., Maki, Y., Yonezawa, K., Hurt, E., Ueno, M., Uritani, M., Hall, M.N., Ushimaru, T.
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Journal Title
EMBO J. 25 (16)
Pages: 3832-3842
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Phosphorylation and up-regulation of diacylglycerol kinase y via its interaction with protein kinase Cy2006
Author(s)
Yamaguchi, Y., Shirai, Y., Matsubara, T., Sanse, K., Kuriyama, M., Oshiro, N., Yoshino, K., Yonezawa, K., Ono, Y., Saito, N.
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Journal Title
J. Biol. Chem. 281 (42)
Pages: 31627-31637
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase2006
Author(s)
Avruch, J., Hara, K., Lin, Y., Liu, M., Long, X., Ortiz-Vega, S., Yonezawa, K.
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Journal Title
Oncogene 25 (48)
Pages: 6361-6372
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular identification and characterization of Xenopus egg uroplakin III, an egg raft-associated transmembrane protein that is tyrosine-phosphorylated upon fertilization2005
Author(s)
Sakakibara, K., Sato, K., Yoshino, K., Oshiro, N., Hirahara, S., Hasan, A.K.M.M., Iwasaki, T., Ueda, Y., Iwao, Y., Yonezawa, K, Fukami, Y.
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Journal Title
J. Biol. Chem. 280 (15)
Pages: 15029-15037
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Glutamine is a key regulator for amino acid-controlled cell growth through the mTOR signaling pathway in rat intestinal epithelial cells2005
Author(s)
Nakajo, T., Yamatsuji, T., Ban, H., Shigemitsu, K., Haisa, M., Motoki, T., Noma, K., Nobuhisa, T., Matsuoka, J., Gunduz, M., Yonezawa, K., Tanaka, N., Naomoto, Y.
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Journal Title
Biochem. Biophys. Res. Commun. 326 (1)
Pages: 174-180
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function2004
Author(s)
Oshiro, N., Yoshino, K., Hidayat, S., Tokunaga, C., Hara, K., Eguchi, S., Avruch, J., Yonezawa, K.
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Journal Title
Genes Cells 9 (4)
Pages: 359-366
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells2004
Author(s)
Murakami, M., Ichisaka, T., Maeda, M., Oshiro, N., Hara, K., Edenhofer, F., Kiyama, H., Yonezawa, K., Yamanaka, S.
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Journal Title
Mol. Cell Biol. 24 (15)
Pages: 6710-6718
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites2004
Author(s)
Takei, N., Inamura, N., Kawamura, M., Namba, H., Hara, K., Yonezawa, K., Nawa, H.
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Journal Title
J. Neurosci. 24 (44)
Pages: 9760-9769
Description
「研究成果報告書概要(欧文)」より
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