Papel de la oligomerización de las pl3k de clase ia p110 alfa y p110 beta en la regulación de la actividad de pten

Laburpena

One of the central pathways that enhances cell survival, division and migration, and is frequently deregulated in cancer is that of PI3K/PTEN (phosphoinositide 3- -kinase/phosphatase and tensin homolog). Although four genes encode PI3K p110 catalytic subunits and there are seven regulatory subunits, only the p110¿ and p110ß isoforms and the p85 regulatory subunits are expressed ubiquitously in body tissues. When cells are activated to enter the cell cycle, the PI3K catalyze formation of the phosphatidylinositol (PI)(3,4,5)P3, a second messenger that triggers a number of important signaling cascades; PTEN subsequently reduces PI(3,4,5)P3 to basal levels. Activation of p110¿ precedes that of p110ß at several points in the cell cycle, during G0/G1 and G1/S transitions and at mitosis entry; nonetheless, it is not known whether p110¿ and p110ß activation are linked. In addition, PI3K activation precedes that of PTEN, but its ability to regulate PTEN activation has not been studied. We explored the potential connections between p110¿, p110ß and PTEN activation, and found that serum stimulation of cells promotes p110¿ and p110ß association, which demonstrates oligomerization of PI3K catalytic subunits within the cells. Moreover, p110¿ regulates optimal p110ß activation by direct association of the two isoforms. p85 dimerization through N-terminal SH3-BcR domains is necessary for p110¿/p110ß complex formation. PTEN is also incorporated into the p110¿/p110ß complex, and its activation depends on its association to this oligomer. Our results show that PI3K and PTEN activities regulate one other within a multimolecular complex that controls cell PI(3,4,5)P3 levels.