Mammalian Target of Rapamycin - Physiological Significance (KO Phenotypes)

Physiological Significance (KO Phenotypes)

The mTORC2 signaling pathway is less clearly defined than the mTORC1 signaling pathway. Therefore, performing knockout experiments is a good way to shed light on more specific molecules and their roles in this pathway. Protein function inhibition using knockdowns and knockouts were found to produce the following phenotypes:

• NIP7: knockdown reduced mTORC2 activity which is indicated by decreased phosphorylation of mTORC2 substrates.
• RICTOR: overexpression leads to metastasis and knockdown inhibits growth factor induced PKC-phosphorylation.
• mTOR: inhibition of mTORC1 and mTORC2 by PP242 pyrimidin-3-yl)-1H-indol-5-ol] leads to autophagy or apoptosis; inhibition of mTORC2 alone by PP242 prevents phosphorylation of Ser-473 site on AKT and arrests the cells in G1 phase of the cell cycle.
• PDK1: knockout is lethal; hypomorphic allele results in smaller organ volume and organism size, but normal AKT activation.
• AKT: knockout mice experience spontaneous apoptosis (AKT1), severe diabetes (AKT2), small brains (AKT3), and growth deficiency (AKT1/AKT2)
• TOR1, the S. cerevisiae orthologue of mTORC1, is a regulator of both carbon and nitrogen metabolism; TOR1 KO strains regulate response to nitrogen as well as carbon availability, indicating that it is a key nutritional transducer in yeast.