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Transcript
M001Signalling to the translation initiation machinery Nahum Sonenberg Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Canada In higher eukaryotes extracellular stimuli, modulate rates of protein synthesis. The effects of these stimuli are largely mediated via the phosphorylation of translation initiation factors. Recruitment of the mRNA by the 40S ribosomal subunit is facilitated by the translation initiation factor, eIF4E (the mRNA 5’ cap binding protein). Two major pathways signal to the translation machinery: The MAPK and the PI3K pathways. eIF4E is phosphorylated by Mnk-1, which is activated by both Erk and p38 MAPK. eIF4E activity is also controlled by phosphorylation of 4E-BPs (eIF4Ebinding proteins). 4E-BPs repress cap-dependent translation by binding to eIF4E. Upon their phosphorylation, 4E-BPs dissociate from eIF4E. The signalling pathway that leads to phosphorylation of 4E-BPs is the PI3K pathway. The mammalian target of rapamycin (mTOR) is a key effector of PI3K signalling in mammalian cells. mTOR forms two different complexes, mTORC1 and mTORC2. mTORC1 integrates growth factor and nutrient signals to control cell proliferation and cell growth . mTORC1 regulates these processes by modulating mRNA translation via phosphorylation of its two major downstream targets: the 4E-BPs and the S6Ks. 4E-BPs strongly inhibit cell proliferation, but not cell size. In contrast, the S6Ks effect cell size, but not cell proliferation. These findings support a model whereby control of cell size and cell cycle progression/proliferation are independent in mammalian cells.