Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from growth factors and nutrients to control biosynthetic processes, including protein, lipid, and nucleic acid synthesis. Dysregulation in the mTORC1 network underlies a wide array of pathological states, including metabolic diseases, neurological disorders, and cancer. Tumor cells are characterized by uncontrolled growth and proliferation due to a reduced dependency on exogenous growth factors. The genetic events underlying this property, such as mutations in the PI3K-Akt and Ras-Erk signaling networks, lead to constitutive activation of mTORC1 in nearly all human cancer lineages. Aberrant activation of mTORC1 has been shown to play a key role for both anabolic tumor growth and resistance to targeted therapeutics. While displaying a growth factor-independent mTORC1 activity and proliferation, tumors cells remain dependent on exogenous nutrients such as amino acids (AAs). AAs are an essential class of nutrients that are obligatory for the survival of any cell. Known as the building blocks of proteins, AAs also act as essential metabolites for numerous biosynthetic processes such as fatty acids, membrane lipids and nucleotides synthesis, as well as for maintaining redox homeostasis. In most tumor types, mTORC1 activity is particularly sensitive to intracellular AA levels. This dependency, therefore, creates a targetable vulnerability point as cancer cells become dependent on AA transporters to sustain their homeostasis. The following review will discuss the role of AA transporters for mTORC1 signaling in cancer cells and their potential as therapeutic drug targets.
Highlights
MTORC1 and Nutrient SensingThe mechanistic target of rapamycin complex 1 is the master regulator protein kinase of anabolic cell growth and proliferation in eukaryotic cells
In the absence of stress, growth promoting signals lead to the Aktand/or Erk-dependent phosphorylation of TSC2 resulting in the immediate release of the tuberous sclerosis complex (TSC) complex from the lysosome allowing the accumulation of Rheb-GTP and mechanistic target of rapamycin complex 1 (mTORC1) activation (Figure 1)
ASCT2 was shown to drive an increase in the intracellular concentration of glutamine, which is secondarily used as an efflux substrate by LAT1 to promote the uptake of extracellular leucine and the activation of mTORC1
Summary
The mechanistic target of rapamycin complex 1 (mTORC1) is the master regulator protein kinase of anabolic cell growth and proliferation in eukaryotic cells. AAs are sensed via a complex upstream network composed of recruited to the lysosome where it decreases Rheb-GTP levels and turns off mTORC1 signaling. (Panel C) When AAs are absent, the Rag heterodimer is converted to its inactive conformation RagA/B-GDP and RagC/D-GTP which promotes the release of mTORC1 into the cytoplasm (C) Signals from both AAs and growth factors/hormones are required to promote a full activation of mTORC1. During cellular stress or withdrawal of growth factors, the TSC complex is recruited, through an unknown mechanism, to the lysosomal surface where it decreases Rheb-GTP levels and turns off mTORC1 signaling (Figure 1). In the absence of stress, growth promoting signals lead to the Aktand/or Erk-dependent phosphorylation of TSC2 resulting in the immediate release of the TSC complex from the lysosome allowing the accumulation of Rheb-GTP and mTORC1 activation (Figure 1). Of the review we discuss the role of AA transporters for mTORC1 signaling both in normal and cancer cells and their potential as drug targets for cancer therapy
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