Papel de la oligomerización de las PI3K de Clase IA p110α y p110β en la regulación de la actividad de PTEN

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 16-07-2014
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 p110α and p110β 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 p110α precedes that of p110β at several points in the cell cycle, during G0/G1 and G1/S transitions and at mitosis entry; nonetheless, it is not known whether p110α and p110β 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 p110α, p110β and PTEN activation, and found that serum stimulation of cells promotes p110α and p110β association, which demonstrates oligomerization of PI3K catalytic subunits within the cells. Moreover, p110α regulates optimal p110β activation by direct association of the two isoforms. p85 dimerization through N-terminal SH3-BcR domains is necessary for p110α/p110β complex formation. PTEN is also incorporated into the p110α/p110β 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.