Phosphoinositide 3-Kinases p110α and p110β Regulate Cell Cycle Entry, Exhibiting Distinct Activation Kinetics in G 1 Phase

Abstract

Phosphoinositide 3-kinase (PI3K) is an early signaling molecule that regulates cell growth and cell cycle entry. PI3K is activated immediately after growth factor receptor stimulation (at the G 0 /G 1 transition) and again in late G 1 . The two ubiquitous PI3K isoforms (p110α and p110β) are essential during embryonic development and are thought to control cell division. Nonetheless, it is presently unknown at which point each is activated during the cell cycle and whether or not they both control S-phase entry. We found that p110α was activated first in G 0 /G 1 , followed by a minor p110β activity peak. In late G 1 , p110α activation preceded that of p110β, which showed the maximum activity at this time. p110β activation required Ras activity, whereas p110α was first activated by tyrosine kinases and then further induced by active Ras. Interference with p110α and -β activity diminished the activation of downstream effectors with different kinetics, with a selective action of p110α in blocking early G 1 events. We show that inhibition of either p110α or p110β reduced cell cycle entry. These results reveal that PI3Kα and -β present distinct activation requirements and kinetics in G 1 phase, with a selective action of PI3Kα at the G 0 /G 1 phase transition. Nevertheless, PI3Kα and -β both regulate S-phase entry. Copyright © 2008, American Society for Microbiology. All Rights Reserved.