User:AB20IF/MTORC

Article body
mTORC1 activates transcription and translation through its interactions with p70-S6 Kinase 1 (S6K1) and 4E-BP1, the eukaryotic initiation factor 4E (eIF4E) binding protein 1, primarily via phosphorylation and dephosphorylation of its downstream targets. S6K1 and 4E-BP1 modulate translation in eukaryotic cells. Their signaling will converge at the translation initiation complex on the 5' end of mRNA, and thus activate translation.

4E-BP1
Activated mTORC1 will phosphorylate translation repressor protein 4E-BP1, thereby releasing it from eukaryotic translation initiation factor 4E (eIF4E). eIF4E is now free to join the eukaryotic translation initiation factor 4G (eIF4G) and the eukaryotic translation initiation factor 4A (eIF4A). This complex then binds to the 5' cap of mRNA and will recruit the helicase eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B (eIF4B). The helicase is required to remove hairpin loops that arise in the 5' untranslated regions of mRNA, which prevent premature translation of proteins. Once the initiation complex is assembled at the 5' cap of mRNA, it will recruit the 40S small ribosomal subunit that is now capable of scanning for the AUG start codon start site, because the hairpin loop has been degraded by the eIF4A helicase. Once the ribosome reaches the AUG codon, translation can begin.

S6K
Previous studies suggest that S6K signaling is mediated by mTOR in a rapamycin-dependent manner wherein S6K is displaced from the eIF3 complex upon binding of mTOR with eIF3. Hypophosphorylated S6K is located on the eIF3 scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.

mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on a threonine residue (T389). This event stimulates the subsequent phosphorylation of S6K1 by PDPK1. Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the ribosome) and eIF4B, causing them to be recruited to the pre-initiation complex.

Active S6K can bind to the SKAR scaffold protein that can get recruited to exon junction complexes (EJC). Exon junction complexes span the mRNA region where two exons come together after an intron has been spliced out. Once S6K binds to this complex, increased translation on these mRNA regions occurs.

S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites thr-2446 and ser-2448; phosphorylation at these sites appears to stimulate mTOR activity.

S6K also can phosphorylate programmed cell death 4 (PDCD4), which marks it for degradation by ubiquitin ligase Beta-TrCP (BTRC). PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex.