AKAP13 couples GPCR signaling to mTORC1 inhibition.

Shihai Zhang,Shweta Tiwary,Kelly A Servage,Huanyu Wang,Delong Meng,Nicholas G James,Mi-Hyeon Jeong,Chase H Melick,Jenna L Jewell,Tshering D Lama-Sherpa,Adna Curukovic,Estela Jacinto

doi:10.1371/journal.pgen.1009832

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.

Highlights

The mammalian target of rapamycin is an evolutionarily conserved Ser/Thr kinase, that is often referred to as the “master regulator” of cell growth because it promotes anabolic events and inhibits catabolic processes [1,2,3]. mTOR is the catalytic component of a complex referred to as mTOR complex 1, which includes regulatory-associated protein of mTOR (Raptor) and mammalian lethal with Sec13 protein 8
A-kinase anchoring protein 13 (AKAP13) expression correlates with mTOR complex 1 (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 G-protein coupled receptor (GPCR), and targeting this pathway may be beneficial for human diseases with hyperactivated mTORC1

Summary

Introduction

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr kinase, that is often referred to as the “master regulator” of cell growth because it promotes anabolic events and inhibits catabolic processes [1,2,3]. mTOR is the catalytic component of a complex referred to as mTOR complex 1 (mTORC1), which includes regulatory-associated protein of mTOR (Raptor) and mammalian lethal with Sec protein 8 (mLST8, known as GβL). The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr kinase, that is often referred to as the “master regulator” of cell growth because it promotes anabolic events and inhibits catabolic processes [1,2,3]. MTOR is the catalytic component of a complex referred to as mTOR complex 1 (mTORC1), which includes regulatory-associated protein of mTOR (Raptor) and mammalian lethal with Sec protein 8 (mLST8, known as GβL). Raptor recognizes mTORC1 substrates and mLST8 acts a positive regulator of mTOR activity. Rapamycin and analogs (referred to as rapalogs) are used clinically to inhibit mTORC1 activity. These drugs have been shown to have multiple limitations. Understanding the molecular mechanisms involved in mTORC1 regulation is important for the development of new therapeutic approaches

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