Figure 2. Signaling by class I, II, and III PI3K isoforms.

(A) Upon receptor tyrosine kinase (RTK) or G-protein coupled receptor (GPCR) activation, class I PI3Ks are recruited to the plasma membrane by interaction with phosphorylated YXXM motifs on RTKs or their adaptors, or with GPCR-associated G_βγ subunits. There they phosphorylate PtdIns(4,5)P₂ (PIP2) to generate PtdIns(3,4,5)P₃ (PIP₃), a second messenger which activates a number of AKT-dependent and –independent downstream signaling pathways regulating diverse cellular functions including growth, metabolism, motility, survival, and transformation. The phosphatase and tensin homolog (PTEN) lipid phosphatase removes the 3′ phosphate from PtdIns(3,4,5)P₃ to inactivate class I PI3K signaling. Modified with permission from Reference 2.

(B) Class II PI3Ks are not well understood, but may be activated by a number of different stimuli, including hormones, growth factors, chemokines, cytokines, phospholipids, and calcium (Ca²⁺). Although in vitro class II PI3Ks can phosphorylate both PtdIns and PtdIns(4)P, in vivo this class may preferentially phosphorylate PtdIns (PI) to generate PtdIns(3)P (PIP)^8-10. Class II PI3Ks regulate cellular functions including glucose transport, endocytosis, cell migration, and survival. Myotubularin (MTM) family phosphatases remove the 3′ phosphate from PtdIns(3)P to inactivate class II PI3K signaling.

(C) The class III VPS34-VPS15 heterodimer is found in distinct multiprotein complexes, which perform specific cellular functions. VPS34 may be activated by stimuli including amino acids, glucose, and other nutrients, and phosphorylates PtdIns (PI) to generate PtdIns(3)P (PIP). It plays critical roles in autophagy, endosomal trafficking, and phagocytosis. MTM family phosphatases remove the 3′ phosphate from PtdIns(3)P to inactivate class III PI3K signaling.