mTOR: from growth signal integration to cancer, diabetes and ageing

Abstract

The mammalian target of rapamycin (mTOR) is a highly conserved kinase that belongs to the phosphoinositide 3-kinase-related protein kinases (PIKK) family. mTOR participates in two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. mTORC1 integrates energy, nutrients, stress and growth factors and, in response to these stimuli, it drives the growth of cells, organs and whole organisms. mTORC2, which is activated by growth factors, promotes cell proliferation and survival. mTOR signalling maximizes energy storage and consumption. Upon chronic activation, mTORC1 drives insulin resistance by suppressing insulin receptor signalling and promoting fat accumulation. mTORC1 and mTORC2 are tightly linked with signalling pathways that lead to cancer. mTORC1 drives tumorigenesis by boosting translation of oncogenes, promoting anabolism and angiogenesis and suppressing autophagy. mTORC2 activates Akt and other AGC family kinases that promote cell proliferation and survival. Therapeutic strategies that are based on novel catalytic mTOR inhibitors have shown promising preclinical results. Our increasing knowledge of the molecular mechanisms underlying ageing is revealing a major role for mTOR in this process. Thus, understanding mTORC1 and mTORC2 biology is crucial for the development of novel drugs that can stave off ageing and age-related diseases.