Nutrient Regulation of the mTOR Complex 1 Signaling Pathway

Abstract

The mammalian target of rapamycin (mTOR) is an evolutionally conserved kinase which exists in two distinct structural and functional complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Of the two complexes, mTORC1 couples nutrient abundance to cell growth and proliferation by sensing and integrating a variety of inputs arising from amino acids, cellular stresses, energy status, and growth factors. Defects in mTORC1 regulation are implicated in the development of many metabolic diseases, including cancer and diabetes. Over the past decade, significant advances have been made in deciphering the complexity of the signaling processes contributing to mTORC1 regulation and function, but the mechanistic details are still not fully understood. In particular, how amino acid availability is sensed by cells and signals to mTORC1 remains unclear. In this review, we discuss the current understanding of nutrient-dependent control of mTORC1 signaling and will focus on the key components involved in amino acid signaling to mTORC1.

Coupling between Nutrient Availability and Thyroid Hormone Activation

“…2, K and L), indicating that this is an insulin/IGF-1-mediated mechanism. mTOR, which is downstream of insulin/IGF-1 signaling, also plays a central role in defining the balance between anabolic and catabolic processes (51). Downstream targets of mTORC2 include the AGC kinases (i.e.…”

Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

“…mTORC1 is defined by its binding partner Raptor, whereas in mTORC2, Rictor and mSIN are found in the complex instead of Raptor. Activation of mTORC1 regulates ribosome biogenesis and mRNA translation via phosphoregulation of p70 ribosomal protein S6 kinase and 4EPB1 (10). Activation of mTORC2 leads to phosphorylation of AKT at Ser 473 resulting in its full activation (11).…”

Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production

“…4,5 Under conditions of caloric restriction, a state of reduced nutrient availability without causing malnutrition, TORC1 function is down-regulated causing decreased protein translation and increased autophagy. [6][7][8] At the cellular level, decreased availability of critical molecules, such as essential amino acids, 9,10 also leads to inhibition of TORC1 function, decreased rates of protein translation and increased autophagy. The inhibition of TORC1 function has been documented to significantly increase lifespan in a number of model organisms and non-human primates, as well as significantly reducing the development of age-related pathologies, such as cardiovascular disease, diabetes and cancer.…”