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Novel Regulation of mTOR Complex 1 Signaling by Site-Specific mTOR Phosphorylation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Novel Regulation of mTOR Complex 1 Signaling by Site-Specific mTOR Phosphorylation./
作者:	Ustunel, Bilgen Ekim.
面頁冊數:	1 online resource (144 pages)
附註:	Source: Dissertations Abstracts International, Volume: 74-09, Section: B.
Contained By:	Dissertations Abstracts International74-09B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3531113click for full text (PQDT)
ISBN:	9781267719157

Novel Regulation of mTOR Complex 1 Signaling by Site-Specific mTOR Phosphorylation.
Ustunel, Bilgen Ekim.

Novel Regulation of mTOR Complex 1 Signaling by Site-Specific mTOR Phosphorylation. - 1 online resource (144 pages)

Source: Dissertations Abstracts International, Volume: 74-09, Section: B.

Thesis (Ph.D.)--University of Michigan, 2012.

Includes bibliographical references

Aberrant regulation of the kinase mTOR (mammalian target of rapamycin) within mTOR complex 1 (mTORC1) contributes to several pathologic states including cancer, type II diabetes, and cardiovascular diseases. mTORC1 functions as an environmental sensor to promote protein and lipid synthesis, cell growth/size, and cell proliferation in response to growth factors and nutrients. While diverse stimuli regulate mTORC1 signaling, the direct molecular mechanisms by which mTORC1 responds to these signals remain poorly defined. By employing LC-MS/MS and phospho-specific antibodies, we identified S2159 and T2164 as novel sites of mTOR phosphorylation. Mutational analyses of these phosphorylation sites indicate that mTOR S2159 and T2164 phosphorylation cooperatively promotes mTORC1 signaling to its well-characterized substrates S6K1 and 4E-BP1. Mechanistically, mTOR S2159 and T2164 phosphorylation modulates the interactions of mTOR with its partner proteins within mTORC1 and increases intrinsic kinase activity, which promotes biochemical signaling, cell growth, and cell cycle progression. To identify the upstream kinase(s) that directly mediate mTOR S2159 phosphorylation, we performed an in vitro kinome screen. This approach identified TBK1 and IKKϵ, kinases best known to mediate immune signaling in response to viral and bacterial infection, as mTOR S2159 kinases. We confirmed the kinome screen by showing that TBK1 and IKKϵ phosphorylate mTOR in vitro and upon overexpression in intact cells. Moreover, TBK1 and IKKϵ interact with mTOR, and TBK1 or IKKϵ null mouse embryonic fibroblasts (MEFs) display impaired mTOR S2159 phosphorylation. In addition, TBM null MEFs show reduced S6K1 phosphorylation, suggesting that TBK1 promotes mTORC1 signaling. Activation of toll-like receptor 3 (TLR3) and TLR4 signaling pathways that promote TBK1 and IKKϵ activity also increases downstream mTORC1 signaling to S6K1 and 4E-BP1. Oncogenic Ras signaling requires TBK1 and IKKϵ activity to support tumorigenesis. Emerging data suggest that IKKϵ may also contribute to metabolic dysfunction (i.e. insulin resistance) by sustaining chronic, low-grade inflammatory state during obesity. Aberrantly regulated mTOR signaling also plays a central role in the pathophysiology of cancer and metabolic dysfunction. Thus, the novel molecular link between TBK1/IKKϵ and mTOR S2159 phosphorylation we describe here may represent a mechanism for, at least in part, the progression of these pathologic states.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9781267719157Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

PhosphorylationIndex Terms--Genre/Form:

542853
Electronic books.

Novel Regulation of mTOR Complex 1 Signaling by Site-Specific mTOR Phosphorylation.
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502 $a Thesis (Ph.D.)--University of Michigan, 2012.
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520 $a Aberrant regulation of the kinase mTOR (mammalian target of rapamycin) within mTOR complex 1 (mTORC1) contributes to several pathologic states including cancer, type II diabetes, and cardiovascular diseases. mTORC1 functions as an environmental sensor to promote protein and lipid synthesis, cell growth/size, and cell proliferation in response to growth factors and nutrients. While diverse stimuli regulate mTORC1 signaling, the direct molecular mechanisms by which mTORC1 responds to these signals remain poorly defined. By employing LC-MS/MS and phospho-specific antibodies, we identified S2159 and T2164 as novel sites of mTOR phosphorylation. Mutational analyses of these phosphorylation sites indicate that mTOR S2159 and T2164 phosphorylation cooperatively promotes mTORC1 signaling to its well-characterized substrates S6K1 and 4E-BP1. Mechanistically, mTOR S2159 and T2164 phosphorylation modulates the interactions of mTOR with its partner proteins within mTORC1 and increases intrinsic kinase activity, which promotes biochemical signaling, cell growth, and cell cycle progression. To identify the upstream kinase(s) that directly mediate mTOR S2159 phosphorylation, we performed an in vitro kinome screen. This approach identified TBK1 and IKKϵ, kinases best known to mediate immune signaling in response to viral and bacterial infection, as mTOR S2159 kinases. We confirmed the kinome screen by showing that TBK1 and IKKϵ phosphorylate mTOR in vitro and upon overexpression in intact cells. Moreover, TBK1 and IKKϵ interact with mTOR, and TBK1 or IKKϵ null mouse embryonic fibroblasts (MEFs) display impaired mTOR S2159 phosphorylation. In addition, TBM null MEFs show reduced S6K1 phosphorylation, suggesting that TBK1 promotes mTORC1 signaling. Activation of toll-like receptor 3 (TLR3) and TLR4 signaling pathways that promote TBK1 and IKKϵ activity also increases downstream mTORC1 signaling to S6K1 and 4E-BP1. Oncogenic Ras signaling requires TBK1 and IKKϵ activity to support tumorigenesis. Emerging data suggest that IKKϵ may also contribute to metabolic dysfunction (i.e. insulin resistance) by sustaining chronic, low-grade inflammatory state during obesity. Aberrantly regulated mTOR signaling also plays a central role in the pathophysiology of cancer and metabolic dysfunction. Thus, the novel molecular link between TBK1/IKKϵ and mTOR S2159 phosphorylation we describe here may represent a mechanism for, at least in part, the progression of these pathologic states.
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