mTORC1 signaling and the metabolic control of cell growth

Abstract

mTOR [mechanistic target of rapamycin] is a serine/threonine protein kinase that, as part of mTORC1 (mTOR complex 1), acts as an important molecular connection between nutrient signals and the metabolic processes indispensable for cell growth. While there has been pronounced interest in the upstream mechanisms regulating mTORC1, the full range of downstream molecular targets through which mTORC1 signaling stimulates cell growth is only recently emerging. It is now evident that mTORC1 promotes cell growth primarily through the activation of key anabolic processes. Through a diverse set of downstream targets, mTORC1 promotes the biosynthesis of macromolecules, including proteins, lipids, and nucleotides to build the biomass underlying cell, tissue, and organismal growth. Here, we focus on the metabolic functions of mTORC1 as they relate to the control of cell growth. As dysregulated mTORC1 underlies a variety of human diseases, including cancer, diabetes, autoimmune diseases, and neurological disorders, understanding the metabolic program downstream of mTORC1 provides insights into its role in these pathological states.

Figure 1. mTORC1 is a molecular switch between catabolic and anabolic processes

(A) A standard metabolic cycle. Anabolic processes convert nutrients and energy into macromolecules, and catabolic processes can convert macromolecules into their nutrient components and energy. (B) Through the sensing of exogenous growth factors and endogenous nutrients and energy, mTORC1 serves to tip the metabolic balance away from catabolic processes and toward anabolic processes to produce biomass.

Figure 2. The mTORC1 network senses cellular growth signals and relays their status to an array of downstream metabolic processes

The activation state of mTORC1 in response to growth factors and nutrients depends on regulatory inputs into small GTPases of the Rheb and Rag families. The TSC complex integrates a variety of growth signals and, under conditions of nutrient or growth factor withdrawal, functions as a GTPase-activating protein (GAP) to negatively regulate Rheb, which is an essential activator of mTORC1. A heterodimer of RagA or B bound to RagC or D is regulated by amino acids through the Gator1 and Ragulator complexes. In the presence of amino acids, the Rag proteins bind to mTORC1 and promote its activation by Rheb. When activated, mTORC1 regulates various cellular processes that promote macromolecular synthesis and cell growth. This occurs through parallel transcriptional, translational, and post-translational effects on downstream targets. This figure emphasized the metabolic outputs of mTORC1 signaling.

Figure 3. mTORC1 signaling stimulates de novo nucleotide synthesis through multiple downstream mechanisms

In response to growth signals, mTORC1 activation leads to S6K1 mediated-phosphorylation of CAD, the rate-limiting enzyme of the de novo pyrimidine synthesis pathway, thereby acutely stimulating an increase in pyrimidine synthesis. Through downstream effects on transcription factors that induce expression of key metabolic enzymes, mTORC1 activation also increases the de novo purine synthesis pathway. One such mechanism involves activation of ATF4 and its induction of serine synthesis and mTHF enzymes, which contribute one-carbon formyl units to the purine ring. Purine and pyrimidine nucleotides are depicted and color coded by the source of their carbon, nitrogen, and oxygen moieties assembled through the de novo synthesis pathways.