The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.

The eukaryotic 5′ untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control of translation efficiency and shaping the cellular proteome. The ribosomal initiation complex is assembled on the mRNA via a cap-dependent or cap-independent mechanism. We describe various mechanisms controlling ribosome scanning and initiation codon selection by 5′ upstream open reading frames, translation initiation factors, and primary and secondary structures of the 5′UTR, including particular sequence motifs. We also discuss translational control via phosphorylation of eukaryotic initiation factor 2, which is implicated in learning and memory, neurodegenerative diseases, and cancer.

Proliferation Control: The protein complex mTORC1, which contains the protein kinase known as mammalian target of rapamycin, is an important regulator of cell proliferation and cell size. Among many targets, mTORC1 phosphorylates the eukaryotic translation initiation factor eIF4E–binding proteins (4E-BPs), thus controlling translation of proteins that regulate proliferation. Dowling et al. (p. 1172 ) used mice lacking expression of the 4E-BPs to show that these proteins contribute to mTORC1's activation of cell proliferation, but are dispensable for the effects of mTORC1 on cell growth. The latter required another mTORC1 target—the ribosomal protein S6 kinase. mTORC1 inhibitors are being explored as potential anticancer agents, and the presence of 4E-BPs was necessary for mTORC1 inhibitors to reduce the number and size of colonies formed by transformed mouse cells.