Review Volume 7, Issue 12 pp 1032—1049

Figure 3. PTEN's cytoplasmic and nuclear functions. In the cytoplasm, PI3K is activated downstream of receptors that include receptor tyrosine kinases, G protein–coupled receptors, cytokine receptors, and integrins. PI3K activation converts PIP₂ to PIP₃, thereby leading to AKT activation, which enhances cell growth, proliferation, and survival. PTEN dephosphorylates PIP₃ and consequently suppresses the PI3K pathway. NEDD4-1 is an E3 ligase of PTEN that mediates PTEN ubiquitination. Polyubiquitination of PTEN leads to its degradation in the plasma, whereas monoubiquitination of PTEN increases its nuclear localization. PTEN can translocate into the nucleus through various mechanisms, including passive diffusion, Ran- or major vault protein–mediated import, and a monoubiquitination-driven mechanism. In the nucleus, PTEN promotes p300-mediated P53 acetylation in response to DNA damage to control cellular proliferation. Nuclear PTEN is also involved in maintaining genomic integrity by binding to centromere protein C (CENPC) and in DNA repair by upregulating RAD51 recombinase (RAD51).