Question

The protein mTOR is observed to be overactive in many cancers. Explain why this is the case. Name three events that cause mTORC1 to become activated, three events that cause mTORC1 to become inactivated, and explain the molecular signals that lead to each outcome.

Answer 1

mTOR which stands for mammalian target of Rapamycin, is a protein kinase that plays a key role in regulating the translation machinary of a cell via controlling ribogenesis, protein sysnthesis and cell growth. mTOR also plays a role in cell signalling. mTOR phoshorylates and activates S6K protein (involved in cell growth) and inactivates 4EBP1 via phosphorylation, which is an mRNA translation repressor.

In cancers, there is disruption in regulation of cell growth, which happens in response to various stimuli and growth factors.mTOR is activated downstream of signalling via MAPK,PI3K, AMPK and mediates protein synthesis,cell growth and cell division. These three pathways converge via inhibiting formation of TSC complex (TSC1/TSC2 heterodimer) or tuberous sclerosis complex. The TSC complex's GAP activity converts active GTP-Rheb (which inturn activates mTOR) to inactive GDP-Rheb

mTOR is activated by insulin hormone, and growth factors,nutrient supply, oxygen levels of the cells.In absence of growth factors, lack of oxygen or hypoxia , less nutrient supply or lower amino acid supply leads to inactivation of mTOR, protein synthesis and cell division which cannot be carried out since cell is under stress.

mTOR inactivation is a target of drugs like rapamycin to treat cancer.