Download M001 Signalling to the translation initiation machinery Nahum

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.