The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt.
The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt.
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先天免疫激酶TBK1直接将MTORC2活性和下游信号提高到Akt。
DOI：
10.1016/j.jbc.2021.100942
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Fingar DC
中科院分区：
文献类型：
--
作者：
Tooley AS;Kazyken D;Bodur C;Gonzalez IE;Fingar DC
TBK1对微生物作出反应，启动对宿主先天免疫防御至关重要的细胞反应。我们先前发现，TBK1在S2159上磷酸化mTOR(雷帕霉素的机械靶标)，以增加mTOR复合体1(MTORC1)的信号转导，以响应生长因子EGF和病毒dsRNA模拟物Poly(I：C)。MTORC1和研究较少的mTORC2响应不同的信号来控制细胞的新陈代谢、增殖和存活。尽管TBK1与Akt磷酸化有关，但它与Akt激酶mTORC2之间的直接关系尚未被描述。通过研究缺乏TBK1的MEF，以及MEF、巨噬细胞和携带mTOR S2159A敲入等位基因(mtorA/A)的小鼠，我们在体外使用激酶分析和基于细胞的方法，在这里证明了TBK1直接激活mTOR复合体2(MTORC2)以增加Akt的磷酸化。我们发现，在几种生长因子和Poly(I：C)的作用下，TBK1和mTOR S2159的磷酸化促进了依赖mTOR的Akt的磷酸化。从机制上讲，TBK1与mTORC2共沉淀，并在细胞内磷酸化mTORC2内的mTOR S2159。激酶分析表明，TBK1和mTOR S2159的磷酸化增强了mTORC2的内在催化活性。生长因子不能激活MTK1，也不能增加MEF中mTOR S2159的磷酸化。因此，基础的TBK1活性与生长因子平行地协同作用，增加mTORC2(和mTORC1)信号。总而言之，这些结果揭示了两个主要信令网络中的关键调控节点TBK1和mTOR之间的串扰。由于TBK1和mTOR参与了肿瘤的发生和代谢紊乱，这些激酶可能在各种生理和病理环境中以直接的方式共同发挥作用。
TBK1 responds to microbes to initiate cellular responses critical for host innate immune defense. We found previously that TBK1 phosphorylates mTOR (mechanistic target of rapamycin) on S2159 to increase mTOR complex 1 (mTORC1) signaling in response to the growth factor EGF and the viral dsRNA mimetic poly(I:C). mTORC1 and the less well studied mTORC2 respond to diverse cues to control cellular metabolism, proliferation, and survival. Although TBK1 has been linked to Akt phosphorylation, a direct relationship between TBK1 and mTORC2, an Akt kinase, has not been described. By studying MEFs lacking TBK1, as well as MEFs, macrophages, and mice bearing an Mtor S2159A knock-in allele (MtorA/A) using in vitro kinase assays and cell-based approaches, we demonstrate here that TBK1 activates mTOR complex 2 (mTORC2) directly to increase Akt phosphorylation. We find that TBK1 and mTOR S2159 phosphorylation promotes mTOR-dependent phosphorylation of Akt in response to several growth factors and poly(I:C). Mechanistically, TBK1 coimmunoprecipitates with mTORC2 and phosphorylates mTOR S2159 within mTORC2 in cells. Kinase assays demonstrate that TBK1 and mTOR S2159 phosphorylation increase mTORC2 intrinsic catalytic activity. Growth factors failed to activate TBK1 or increase mTOR S2159 phosphorylation in MEFs. Thus, basal TBK1 activity cooperates with growth factors in parallel to increase mTORC2 (and mTORC1) signaling. Collectively, these results reveal cross talk between TBK1 and mTOR, key regulatory nodes within two major signaling networks. As TBK1 and mTOR contribute to tumorigenesis and metabolic disorders, these kinases may work together in a direct manner in a variety of physiological and pathological settings.
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影响因子：
4.4
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Fingar, Diane C.
DOI：
10.1126/science.1199498
发表时间：
2011-06-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hsu PP;Kang SA;Rameseder J;Zhang Y;Ottina KA;Lim D;Peterson TR;Choi Y;Gray NS;Yaffe MB;Marto JA;Sabatini DM
通讯作者：
Sabatini DM