Deciphering the Molecular Mechanisms by which PKA inhibits mTORC1

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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 human disease including cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. 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. G-protein coupled receptors (GPCRs) paired to Gαs proteins activate Protein Kinase A (PKA) by increasing intracellular cyclic adenosine 3’5’ monophosphate (cAMP) levels. PKA phosphorylates the mTORC1 component Raptor and potently inhibits mTORC1 activity. Importantly, GPCRs are the largest family of drug targets and many compounds have been approved by the FDA to regulate GPCR signaling. Our preliminary data reveals further mechanistic detail and identifies new components involved in mTORC1 inhibition by PKA (Specific Aims 1-2). Moreover, we will determine the role of PKA signaling in mTORC1-mediated biology and disease (Specific Aim 3). Therefore, the overall objective of this proposal is to decipher the molecular mechanisms by which PKA inhibits mTORC1 and regulates mTORC1-mediated biology. We anticipate that the proposed studies will yield new insights into mTORC1 regulation by PKA and will uncover therapeutic targets to perturb mTORC1- mediated disease.