Papel de la oligomerización de las PI3K de Clase IA p110α y p110β en la regulación de la actividad de PTEN
Author
Pérez García, VicenteAdvisor
Carrera Ramírez, Ana ClaraEntity
UAM. Departamento de Biología Molecular; CSIC. Centro Nacional de Biotecnología (CNB)Date
2014-07-16Subjects
Proteínas de supresión tumoral - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 16-07-2014Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
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.
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