Figure 2 Figure 2a. The members of the phosphoinositide 3-kinase (PI3K) family. PI3Ks have been divided into three classes according to their structural characteristics and substrate specificity. Class IA PI3Ks are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit. In mammals, there are three genes, PIK3CA, PIK3CB and PIK3CD, encoding p110 catalytic isoforms: p110α, p110β and p110δ, respectively. While the expression of p110δ is largely restricted to the immune system, p110α and p110β are ubiquitously expressed, . The p110 catalytic isoforms are highly homologous and share five distinct domains: an N-terminal p85-binding domain (p85BD) that interacts with the p85 regulatory subunit, a Ras-binding domain (RasBD) that mediates activation by members of the Ras family of small GTPases, a putative membrane-binding domain C2, the helical domain, and the C-terminal kinase catalytic domain. There are also three genes, PIK3R1, PIK3R2 and PIK3R3, encoding p85α (and its splicing variants p55α and p50 α), p85β and p55γ regulatory subunits, respectively, collectively called p85. These regulatory subunits share three core domains including a p110-binding domain (denoted as inter-SH2 or iSH2) flanked by two Src-homology 2 (SH2) domains (N-terminal nSH2 and C-terminal cSH2). The two longer isoforms, p85α and p85β, have a Src-homology 3 (SH3) domain and a BCR homology (BH) domain located in their extended N-terminal regions. In the basal state, p85 binds to the N-terminus of the p110 subunit via its iSH2 domain, inhibiting its catalytic activity, . Class IB PI3K is a heterodimer composed of a catalytic subunit p110γ and a regulatory subunit p101. p110γ is mainly expressed in leukocytes and can be activated directly by GPCRs. Class II PI3Ks are monomers with only a single catalytic subunit.There are three class II PI3K isoforms, PI3KC2α, PI3KC2β and PI3KC2γ, each of which has a divergent N-terminus followed by a Ras binding domain (RasBD), C2 domain, helical domain, and catalytic domain with PX and C2 domains at the C-termini (reviewed in REF, ). Class III PI3Ks consists of a single catalytic subunit Vps34 (homolog of the yeast vacuolar protein-sorting defective 34). Figure 2b. The level of phosphatidylinositol-3,4,5-triphosphate, PI(3,4,5)P3, is regulated by Class I phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homologue (PTEN). PI(3,4,5)P3 is an important lipid second messenger that regulates multiple cellular processes. Class I PI3Ks phosphorylates the inositol ring of phosphatidylinositol-4,5-triphosphate, PI(4,5)P2 on the 3-position, to generate PI(3,4,5)P3. PTEN is a lipid phosphatase that removes phosphate on the 3-position of PI(3,4,5)P3 and converts it back to PI(4,5)P2.