Fig. 3

Ubiquitination on mTOR signal affects the cross-talk between RAS-RAF-MEK and PI3K-AKT-mTOR pathways. TSC2 and mTORC1 as the downstream sensor receive many inputs from both RAS-RAF-ERK and PI3K-AKT signaling to activate S6K and 4E-BP1 for mRNA translation and protein synthesis, as well for inhibition of autophagy. Meanwhile, activated mTORC1 can enhance the RAF-ERK signaling through feedback inhibition of PI3K but not of AKT or mTORC2. In this pathway, Fbxw7 is responsible for recognizing mTOR and executing the ubiquitination (K48-Ub chains) for further proteasome degradation to reduce the activity of mTORC1 and mTORC2. Upon the stimulation of amino acid, K63-linked ubiquitin chains on mTOR are essential for activation of mTORC1, which is triggered by TRAF6 with the assistance of p62 and adaptor protein Raptor. However, Raptor, an essential component of mTORC1, can be poly-ubiquitinated and deubiquitinated by the DDB1-Cul4 complex and UCH-L1, respectively, thereby impairing the activity of mTORC1 and downstream signaling