mTOR signalling: jack-of-all-trades

Abstract

The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that senses and integrates environmental information into cellular regulation and homeostasis. Accumulating evidence has suggested a master role of mTOR signalling in many fundamental aspects of cell biology and organismal development. mTOR deregulation is implicated in a broad range of pathological conditions, including diabetes, cancer, neurodegenerative diseases, myopathies, inflammatory, infectious, and autoimmune conditions. Here, we review recent advances in our knowledge of mTOR signalling in mammalian physiology. We also discuss the impact of mTOR alteration in human diseases and how targeting mTOR function can treat human diseases.

Novel therapeutic roles of MC‐4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways

“…An important and promising target for metastatic RCC to date is mTOR, which is a pivotal regulator of the metabolic pathway of a cell. mTOR receives input from sensors of energy, nutrients, and stress and produces output that regulates protein synthesis and cell growth . The activation of class I PI3K could lead to activation of Akt‐mTOR signaling pathway, which in turn inhibits autophagy .…”

“…Although several types of vascular endothelial growth factor‐ and mechanistic target of rapamycin (mTOR)‐targeted drugs have been approved as first‐line therapies for the treatment of metastatic RCC, more than 40% of patients do not respond to these agents . In particular, mTOR signaling pathway is a pivotal regulator of cellular growth, differentiation, survival, metabolism, and stress response . mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E‐BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis.…”

“…mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E‐BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis. mTORC2 phosphorylates serum/glucocorticoid regulated kinase 1 (SGK1), Akt, Ras‐related C3 botulinum toxin substrate 1 (Rac1), and protein kinase Cα (PKCα) to regulate cell survival, glycolytic enzymes, pentose phosphate pathway enzymes, glutaminase, and cytoskeletal organization . Due to feedback between mTORC1 and mTORC2, crosstalk with other pathways leading to the compensatory activation of extracellular signal‐regulated kinase (ERK)/mitogen‐activated protein kinase pathway (MAPK), and a higher risk of side effects, the therapeutic efficacy of FDA‐approved mTORC1 inhibitors such as everolimus is limited …”

“…3 In particular, mTOR signaling pathway is a pivotal regulator of cellular growth, differentiation, survival, metabolism, and stress response. [4][5][6][7] mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis. mTORC2 phosphorylates serum/glucocorticoid regulated kinase 1 (SGK1), Akt, Ras-related C3 botulinum toxin substrate 1 (Rac1), and protein kinase Cα (PKCα) to regulate cell survival, glycolytic enzymes, pentose phosphate pathway enzymes, glutaminase, and cytoskeletal organization.…”

“…mTORC2 phosphorylates serum/glucocorticoid regulated kinase 1 (SGK1), Akt, Ras-related C3 botulinum toxin substrate 1 (Rac1), and protein kinase Cα (PKCα) to regulate cell survival, glycolytic enzymes, pentose phosphate pathway enzymes, glutaminase, and cytoskeletal organization. [4][5][6][7] Due to feedback between mTORC1 and mTORC2, crosstalk with other pathways leading to the compensatory activation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway (MAPK), 8,9 and a higher risk of side effects, the therapeutic efficacy of FDA-approved mTORC1 inhibitors such as everolimus is limited. 10 Several studies have demonstrated the importance of natural products as sources of new anticancer drugs.…”