Environmental Sensing by mTORC1

Abstract

The mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr kinase that can sense multiple upstream stimuli to regulate cell growth, metabolism, and autophagy. mTOR is the key component of a multi-protein complex termed mTOR complex 1 (mTORC1). Increased mTORC1 activation is common in many human diseases such as cancer. Small molecules like rapamycin that target and inhibit mTORC1, are currently used in the clinic with limited success. Thus, deciphering the molecular mechanisms involved in mTORC1 regulation is crucial in order to treat mTORC1-mediated disease. The majority of research has focused on stimuli that activate mTORC1, like growth factors and amino acids. In contrast, less is known about signaling pathways that can directly inhibit mTORC1 activity. We recently discovered that G-protein coupled receptor (GPCR) signaling potently inhibits mTORC1. GPCRs paired to Gas proteins activate Protein Kinase A (PKA) by increasing intracellular cyclic adenosine 3’5’ monophosphate (cAMP) levels. PKA phosphorylates the mTORC1 component Raptor resulting in decreased mTORC1 activity. Importantly, GPCRs are the largest family of drug targets and many compounds have been approved by the FDA to regulate GPCR signaling. We have identified an A-kinase anchoring protein as a crucial scaffold involved in GPCR-Gassignaling to mTORC1. Targeting this signaling pathway may be beneficial for human diseases with hyperactivated mTORC1.