Figure 1. The PI3K family comprises multiple classes and isoforms.

PI3Ks are classified based on their substrate specificities and structures. In vivo, class IA and IB PI3Ks phosphorylate PtdIns(4,5)P₂, while class III PI3Ks phosphorylate PtdIns. Some evidence suggests that class II PI3Ks may also preferentially phosphorylate PtdIns in vivo^8-10. Class IA PI3Ks are heterodimers of a p110 catalytic subunit and a p85 regulatory subunit. Class IA catalytic isoforms (p110α, p110β, and p110δ) possess a p85-binding domain (p85-BD), RAS-binding domain (RBD), helical domain, and catalytic domain. Class IA p85 regulatory isoforms (p85α, p85β, p55α, p55γ, and p50α) possess an inter-SH2 (iSH2) domain that binds class IA catalytic subunits, flanked by SH2 domains that bind phosphorylated YXXM motifs. The longer isoforms, p85α and p85β, additionally possess N-terminal SH3 and breakpoint cluster homology (BH) domains. Class IB PI3Ks are heterodimers of a p110γ catalytic subunit and a p101 or p87 regulatory subunit. p110γ possesses an RBD, helical domain, and catalytic domain. The domain structures of p101 and p87 are not fully known, but a C-terminal region of p101 has been identified as binding G_βγ subunits¹²⁰. The monomeric class II isoforms (PI3K-C2α, PI3K-C2β, and PI3K-C2γ) possess an RBD, helical domain, and catalytic domain. VPS34, the only class III PI3K, possesses helical and catalytic domains. VPS34 forms a constitutive heterodimer with the myristoylated, membrane-associated VPS15 protein. Other indicated domains include proline-rich (P) domains and membrane-interacting C2 domains. Modified with permission from Reference 2.