Fig. 2

Ubiquitination on PI3K-AKT signal. Under the conditions of growth factor stimuli, such as insulin, activated RTKs recruit IRS1 (insulin receptor substrate 1) for binding and activation of p85-p110 heterodimers (PI3K). With the assistance of phosphatase PTPL1, free p85β is ubiquitinated by Fbxl2 and degraded through the proteasome system to block its competition with p85-p110 heterodimers binding to IRS1, thereby promoting activation of the PI3K-AKT signal. The p110 subunit of PI3K catalyzes the conversion of PIP2 to PIP3, which recruits AKT to the plasma membrane for activation through PDK1 and PDK2. In that process, activation of AKT is inhibited by PTEN through conversion of PIP3 to PIP2 to restraint the downstream events, i.e., K48-linked polyubiquitination on phosphorylated AKT is triggered by E3 ligases CHIP, BRCA1, MULAN or TTC3 for proteasome degradation, but K63-linked AKT is induced by NEDD4–1, Skp2 and TRAF6 to mediate its nuclear localization for further activation of the PI3K-AKT signal. However, TRAF4 is the main effector for AKT K63-linked ubiquitination and promotes EGF-induced AKT membrane recruitment in human lung cancer cells to induce tumorigenic properties. Deubiquitinating enzyme CYLD plays a tumor suppressor role in inhibiting AKT activity by removing AKT K63-linked ubiquitin chains and serves as a negative regulator for AKT-mediated tumorigenesis. Ubiquitinated PTEN with poly-ub chains is usually degraded by the proteasome system, while partial mono-ubiquitinated forms translocate into the nucleus to escape proteasome degradation, mediated by NEDD4–1, WWP2, XIAP and CHIP E3 ligase. However, this progress can be reversed by deubiquitinating enzymes USP7 and USP13 to deactivate the PI3K-AKT signal