Cell Activation-Induced Phosphoinositide 3-Kinase Alpha/Beta Dimerization Regulates PTEN Activity

Abstract

The phosphoinositide 3-kinase (PI3K)/PTEN (phosphatase and tensin homolog) pathway is one of the central routes that enhances cell survival, division, and migration, and it is frequently deregulated in cancer. PI3K catalyzes formation of phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P₃] after cell activation; PTEN subsequently reduces these lipids to basal levels. Activation of the ubiquitous p110α isoform precedes that of p110β at several points during the cell cycle. We studied the potential connections between p110α and p110β activation, and we show that cell stimulation promotes p110α and p110β association, demonstrating oligomerization of PI3K catalytic subunits within cells. Cell stimulation also promoted PTEN incorporation into this complex, which was necessary for PTEN activation. Our results show that PI3Ks dimerize in vivo and that PI3K and PTEN activities modulate each other in a complex that controls cell PI(3,4,5)P₃ levels.

This article is related to:

Uncovering the PI3Ksome: Phosphoinositide 3-Kinases and Counteracting PTEN Form a Signaling Complex with Intrinsic Regulatory Properties

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00167-14.

ACKNOWLEDGMENTS

We thank T. Balla for the GFP-PH-Btk plasmid, S. Alvira, C. Hernández, and L. Sanz for technical support with gel filtration experiments, M. C. Moreno-Ortíz for technical support with flow cytometry, and C. Mark for editorial assistance.

V.P.-G. held a predoctoral FPI fellowship from the Spanish Ministry of Science and Innovation. This work was financed in part by grants from the Spanish Ministry of Science and Innovation (SAF2010-21019), the Network of Cooperative Research in Cancer (RD07/0020/2020 and RD12/0036/0059), and the Madrid regional government (BMD-2502).