PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCFSKP2

The PTEN tumor suppressor acts as a phosphatase for phosphatidylinositol-3, 4,5-trisphosphate (PIP3) [1, 2], We have shown previously that PTEN negativ ely controls the G1/S cell cycle transition and regulates the levels of p27 (KIP1), a CDK inhibitor [3, 4], Recently, we and others have identified an ubiquitin E3 ligase, the SCFSKP2 complex, that mediates p27 ubiquitin-depen dent proteolysis [5-7], Here we report that PTEN and the PI 3-kinase pathwa y regulate p27 protein stability. PTEN-deficiency in mouse embryonic stem ( ES) cells causes a decrease of p27 levels with concomitant increase of SKP2 , a key component of the SCFSKP2 complex. Conversely, in human glioblastoma cells, ectopic PTEN expression leads to p27 accumulation, which is accompa nied by a reduction of SKP2, We found that ectopic expression of SKP2 alone is sufficient to reverse PTEN-induced p27 accumulation, restore the kinase activity of cyclin E/CDK2, and partially overcome the PTEN-induced G1 cell cycle arrest. Consistently, recombinant SCFSKP2 complex or SKP2 protein al one can rescue the defect in p27 ubiquitination in extracts prepared from c ells treated with a PI 3-kinase inhibitor. Our findings suggest that SKP2 f unctions as a critical component in the PTEN/PI 3-kinase pathway for the re gulation of p27(KIP1) and cell proliferation.