While NEDD4 and WWP2 promote PTEN polyubiquitination, with the assistance of adaptor proteins NDFIPs and NUMB, and subsequent proteasomal degradation in the cytoplasm, NEDD4-mediated PTEN monoubiquination leads to its translocation into the nucleus where it controls the cell cycle and genomic stability. Furthermore, WWP1 mediates PTEN K27-linked polyubiquitination, ablating its dimerization and plasma membrane localization (Created with BioRender.com). C2, calcium-binding domain; PTEN, phosphatase and tensin homolog deleted on chromosome 10; NEDD4, neuronal precursor cell-expressed developmentally downregulated 4; WWP1, WW domain containing E3 ubiquitin protein ligase 1; WWP2, WW domain containing E3 ubiquitin protein ligase 2; NDFIPs, NEDD4 family interacting proteins; NUMB, NUMB endocytic adaptor protein; APC/CDH1, anaphase-promoting complex/CDC20 homolog 1; CENPC, centromere protein C; U, ubiquitin.