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- Title
AKAP13 couples GPCR signaling to mTORC1 inhibition.
- Authors
Zhang, Shihai; Wang, Huanyu; Melick, Chase H.; Jeong, Mi-Hyeon; Curukovic, Adna; Tiwary, Shweta; Lama-Sherpa, Tshering D.; Meng, Delong; Servage, Kelly A.; James, Nicholas G.; Jewell, Jenna L.
- Abstract
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. Author summary: 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.
- Subjects
UNITED States. Food &; Drug Administration; G protein coupled receptors; MTOR protein; CELLULAR signal transduction; SMALL molecules; CARRIER proteins; OVERALL survival; LUNGS
- Publication
PLoS Genetics, 2021, Vol 17, Issue 10, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1009832