Figure 3

Schematic depiction of PTEN functions in nucleus and cytosol with regard to its posttranslational modifications. The classic pathway takes place in the cytosol underneath the plasma membrane whereby the phosphatase activity decreases the level of PIP3. The inhibition of Akt/PKB results in decreased cell proliferation and increased apoptosis. Further, a decrease of the nuclear E3 ubiquitin ligase MDM2 acting on p53 is observed. Nuclear PTEN forms a complex genome protection network by activation of Rad51/52 (DNA double strand repair), binding to CENP-C (chromosomal stability) and APC/C (slowdown of the cell cycle). It undergoes complex interactions with p53 family members. PTEN and p53 act on each other affecting acetylation and transcription. As net effect, p21, p27 and maspin are upregulated, acting as tumor suppressors in this context. PTEN sumoylation is achieved by the E3 SUMO ligase PIASxα, desumoylation most likely by a member of the SENP family. PIASxα crosstalks with the ubiquitinylation pathway. NEDD4-1 is the main E3 ubiquitin ligase regulated by cofactors p34 and NDFIP1. De-ubiquitinylation is achieved by USP7 or USP13. Poly-ubiquitinylated PTEN, p53 and MDM2 proteins are targeted for proteasome mediated degradation. Both PTEN and p53 may also be acetylated and phosphorylated to a substantial degree in the nucleus. The PTEN Long variant is secreted into the extracellular space. Cytosolic p27 is oncogenic in contrast to the nuclear moiety by e.g. retention of open conformation PTEN (PTEN-OC) in the cytoplasm targeted for proteasome degradation.