AKAP13 couples GPCR signaling to mTORC1 inhibition.
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 s...
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Public Library of Science (PLoS)
2021
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oai:doaj.org-article:358b3427813548ef951b4b856085d7822021-12-02T20:03:30ZAKAP13 couples GPCR signaling to mTORC1 inhibition.1553-73901553-740410.1371/journal.pgen.1009832https://doaj.org/article/358b3427813548ef951b4b856085d7822021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009832https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The 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.Shihai ZhangHuanyu WangChase H MelickMi-Hyeon JeongAdna CurukovicShweta TiwaryTshering D Lama-SherpaDelong MengKelly A ServageNicholas G JamesJenna L JewellPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 10, p e1009832 (2021) |
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DOAJ |
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DOAJ |
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EN |
| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Shihai Zhang Huanyu Wang Chase H Melick Mi-Hyeon Jeong Adna Curukovic Shweta Tiwary Tshering D Lama-Sherpa Delong Meng Kelly A Servage Nicholas G James Jenna L Jewell AKAP13 couples GPCR signaling to mTORC1 inhibition. |
| description |
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. |
| format |
article |
| author |
Shihai Zhang Huanyu Wang Chase H Melick Mi-Hyeon Jeong Adna Curukovic Shweta Tiwary Tshering D Lama-Sherpa Delong Meng Kelly A Servage Nicholas G James Jenna L Jewell |
| author_facet |
Shihai Zhang Huanyu Wang Chase H Melick Mi-Hyeon Jeong Adna Curukovic Shweta Tiwary Tshering D Lama-Sherpa Delong Meng Kelly A Servage Nicholas G James Jenna L Jewell |
| author_sort |
Shihai Zhang |
| title |
AKAP13 couples GPCR signaling to mTORC1 inhibition. |
| title_short |
AKAP13 couples GPCR signaling to mTORC1 inhibition. |
| title_full |
AKAP13 couples GPCR signaling to mTORC1 inhibition. |
| title_fullStr |
AKAP13 couples GPCR signaling to mTORC1 inhibition. |
| title_full_unstemmed |
AKAP13 couples GPCR signaling to mTORC1 inhibition. |
| title_sort |
akap13 couples gpcr signaling to mtorc1 inhibition. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/358b3427813548ef951b4b856085d782 |
| work_keys_str_mv |
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