Quantitation of class IA PI3Ks in mice reveals p110-free-p85s and isoform-selective subunit associations and recruitment to receptors

Significance The class IA PI3Ks, comprised of regulatory (p85α/p85β/p55γ) and catalytic (p110α/β/δ) subunits, which make the signaling lipid PIP 3 , constitute a key node in signaling. Many factors underlie their numerous cellular roles and large investments in the creation of PI3K-inhibitors. The existence of heterodimeric-isoforms (at least nine) with distinct distributions and properties and the often-debated existence of “p110-free-regulatory-subunits” as modulators provide the system with flexibility, redundancy and isoform-selective functions. Despite the scale of this endeavour, many of the system’s “rules of engagement” are unknown. Here we demonstrate preferential subunit associations, clarify the existence of “p110-free-regulatory-subunits”, show that they have properties that could allow them to modulate pathway activity, and reveal mechanisms that allow selective activation of PI3Kα and β by receptors.