p87 and p101 Subunits Are Distinct Regulators Determining Class IB Phosphoinositide 3-Kinase (PI3K) Specificity

Class IB phosphoinositide 3-kinase gamma (PI3K gamma) comprises a single catalytic p110 gamma subunit, which binds to two non-catalytic subunits, p87 or p101, and controls a plethora of fundamental cellular responses. The non-catalytic subunits are assumed to be redundant adaptors for G beta gamma enabling G-protein-coupled receptor-mediated regulation of PI3K gamma. Growing experimental data provide contradictory evidence. To elucidate the roles of the non-catalytic subunits in determining the specificity of PI3K gamma, we tested the impact of p87 and p101 in heterodimeric p87-p110 gamma and p101-p110 gamma complexes on the modulation of PI3K gamma activity in vitro and in living cells. RT-PCR, biochemical, and imaging data provide four lines of evidence: (i) specific expression patterns of p87 and p101, (ii) up-regulation of p101, providing the basis to consider p87 as a protein forming a constitutively and p101 as a protein forming an inducibly expressed PI3K gamma, (iii) differences in basal and stimulated enzymatic activities, and (iv) differences in complex stability, all indicating apparent diversity within class IB PI3K gamma. In conclusion, expression and activities of PI3K gamma are modified differently by p87 and p101 in vitro and in living cells, arguing for specific regulatory roles of the non-catalytic subunits in the differentiation of PI3K gamma signaling pathways.