Fig. 2

The interplay between the RPL11-MDM2-p53 and PI3K/AKT/mTOR pathways can be regulated by neddylation. The binding of RPL11 to MDM2 inhibits MDM2’s E3 ligase activity, preventing p53 degradation, but neddylation can hinder this binding, indirectly causing p53 degradation and affecting the expression of various target genes. On the other hand, the PI3K/AKT/mTOR pathway activation initiates when growth factors or hormones bind to cell surface receptors like RTKs or GPCRs, leading to the recruitment and activation of PI3K, which then turns PIP2 into PIP3. PIP3 acts as a docking site for proteins such as AKT and PDK1, allowing PDK1 to activate AKT. Activated AKT inhibits the TSC, a negative regulator of mTORC1, thus enabling Rheb to activate mTORC1. This pathway can be negatively regulated by PTEN, which dephosphorylates PIP3 back to PIP2, removing AKT’s activation signal. Neddylation can enhance PTEN’s nuclear translocation, strengthening the pathway’s signal transduction, while deneddylation of PTEN, dependent on NEDP1, can inhibit the PI3K/AKT/mTOR pathway. MDM2, mouse double minute 2 homolog; RPL11, ribosomal Protein L11; Ub, ubiquitin; NEDD8, neural precursor cell expressed developmentally downregulated protein 8; RTKs, receptor tyrosine kinases; GPCRs, G protein-coupled receptors; PI3K, phosphoinositide 3-kinases; PIP2, Phosphatidylinositol 4,5-bisphosphate; PIP3, Phosphatidylinositol 3,4,5-trisphosphate; TSC, tuberous sclerosis complex; mTORC1, mTOR complex 1; AKT, AKT serine/threonine kinase; PDK1, 3-Phosphoinositide Dependent Protein Kinase-1; Rheb, Ras homolog enriched in brain. Created with BioRender.com