Phosphoinositide 3-kinases p110α and p110β regulate cell cycle entry, exhibiting distinct activation kinetics in G1 Phase

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, The two ubiquitous PI3K isoforms (p110 alpha and p110 beta) 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 p110 alpha was activated first in G(0)/G(1), followed by a minor p110 beta activity peak. In late G(1), p110 alpha activation preceded that of p][100, which showed the maximum activity at this time. p110 beta activation required Ras activity, whereas p110 alpha was first activated by tyrosine kinases and then further induced by active Ras. Interference with p110 alpha and -beta activity diminished the activation of downstream effectors with different kinetics, with a selective action of p110a in blocking early G, events. We show that inhibition of either p110 alpha or p110 beta reduced cell cycle entry. These results reveal that PI3K alpha and -beta present distinct activation requirements and kinetics in G(1) phase, with a selective action of PI3K alpha at the G(0)/G(1) phase transition. Nevertheless, PI3K alpha and -beta both regulate S-phase entry.