AKAP13 couples GPCR signaling to mTORC1 inhibition.
AKAP13 couples GPCR signaling to mTORC1 inhibition.
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DOI：
10.1371/journal.pgen.1009832
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发表时间：
2021-10
期刊：
影响因子：
4.5
通讯作者：
Jewell JL
中科院分区：
文献类型：
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作者：
Zhang S;Wang H;Melick CH;Jeong MH;Curukovic A;Tiwary S;Lama-Sherpa TD;Meng D;Servage KA;James NG;Jewell JL
雷帕霉素复合体1 （mTORC1）的哺乳动物靶点感知多种刺激来调节合成代谢和分解代谢过程。mTORC1通常在多种人类疾病中过度激活，如癌症和2型糖尿病。广泛的研究集中在可以激活mTORC1的信号通路上，如生长因子和氨基酸。然而，对于可以直接抑制mTORC1活性的信号线索知之甚少。在这里，我们发现a激酶锚定蛋白13 （AKAP13）是mTORC1结合蛋白，也是g蛋白偶联受体（GPCR）信号抑制mTORC1的关键调节因子。gpcr与Gαs蛋白配对，增加环腺苷3′5′单磷酸（cAMP），激活蛋白激酶A （PKA）。从机制上讲，AKAP13作为PKA和mTORC1的支架，其中PKA通过Raptor在Ser 791上的磷酸化抑制mTORC1。重要的是，AKAP13介导mtorc1诱导的细胞增殖、细胞大小和集落形成。AKAP13表达与mTORC1激活、肺腺癌患者总体生存以及体内肺癌肿瘤生长相关。我们的研究发现AKAP13是gpcr抑制mTORC1的重要参与者，靶向这一途径可能对mTORC1过度激活的人类疾病有益。哺乳动物雷帕霉素复合体1靶点（mTORC1）可以感知多种上游刺激来调节细胞生长和代谢。mTORC1激活的增加导致许多人类疾病，如癌症。像雷帕霉素这样的靶向和抑制mTORC1的小分子药物在临床中取得了有限的成功。因此，解码涉及mTORC1调控的机制至关重要。大多数研究都集中在激活mTORC1的刺激上。对直接抑制mTORC1活性的信号通路知之甚少。g蛋白偶联受体（gpcr）偶联Gαs蛋白信号并有效抑制mTORC1。在本研究中，我们发现AKAP13通过GPCR信号在mTORC1抑制中发挥关键作用。重要的是，GPCRs是最大的药物靶点家族，有许多FDA批准的化合物。靶向这一信号通路可能对mTORC1过度激活的人类疾病有益。
The mammalian target of rapamycin complex 1 (mTORC1) senses multiple stimuli to regulate anabolic and catabolic processes. mTORC1 is typically hyperactivated in multiple human diseases such as cancer and type 2 diabetes. Extensive research has focused on signaling pathways that can activate mTORC1 such as growth factors and amino acids. However, less is known about signaling cues that can directly inhibit mTORC1 activity. Here, we identify A-kinase anchoring protein 13 (AKAP13) as an mTORC1 binding protein, and a crucial regulator of mTORC1 inhibition by G-protein coupled receptor (GPCR) signaling. GPCRs paired to Gαs proteins increase cyclic adenosine 3’5’ monophosphate (cAMP) to activate protein kinase A (PKA). Mechanistically, AKAP13 acts as a scaffold for PKA and mTORC1, where PKA inhibits mTORC1 through the phosphorylation of Raptor on Ser 791. Importantly, AKAP13 mediates mTORC1-induced cell proliferation, cell size, and colony formation. AKAP13 expression correlates with mTORC1 activation and overall lung adenocarcinoma patient survival, as well as lung cancer tumor growth in vivo. Our study identifies AKAP13 as an important player in mTORC1 inhibition by GPCRs, and targeting this pathway may be beneficial for human diseases with hyperactivated mTORC1. The mammalian target of rapamycin complex 1 (mTORC1) can sense multiple upstream stimuli to regulate cell growth and metabolism. Increased mTORC1 activation results in many human diseases such as cancer. Small molecules like rapamycin that target and inhibit mTORC1, are available in the clinic with limited success. Thus, decoding the mechanisms involved in mTORC1 regulation is crucial. Most of the research has focused on stimuli that activate mTORC1. Less is known about signaling pathways that can directly inhibit mTORC1 activity. G-protein coupled receptors (GPCRs) coupled to Gαs proteins signal to and potently inhibit mTORC1. In this study, we have identified AKAP13 to play a crucial role in mTORC1 inhibition by GPCR signaling. Importantly, GPCRs are the largest family of drug targets with many approved FDA compounds. Targeting this signaling pathway may be beneficial for human diseases with hyperactivated mTORC1.
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影响因子：
21.3
作者：
通讯作者：
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影响因子：
16
作者：
Gold, Matthew G.;Lygren, Birgitte;Barford, David
通讯作者：
Barford, David
影响因子：
2.5
作者：
Hinde, Elizabeth;Digman, Michelle A.;Gratton, Enrico
通讯作者：
Gratton, Enrico
DOI：
10.1038/nrm3522
发表时间：
2013-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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影响因子：
46.9
作者：
通讯作者：
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