Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

Figure 1 Protein kinase B signaling pathway. Stimulation of receptor tyrosine kinases or G-protein-coupled-receptors activates phosphatidylinositol (3,4,5)-trisphosphate (PIP₃) which phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP₂) at the plasma membrane to generate PIP₃. Inactive Akt in the cytosol gets recruited to the plasma membrane where it gets phosphorylated at T308 in the kinase domain by phosphoinositide dependent kinase 1 and at S473 in the regulatory domain by mTORC2 resulting in full activation; Signal termination is achieved by PTEN where it dephosphorylates PIP₃ to PIP₂; Additionally, PP2A and PHLPP have shown to regulate Akt kinase activity by direct dephosphorylation; Activation of Akt is known to regulate crucial transcription factors such as nuclear factor-kB (NF- kB), CREB, FOXO, and Nrf-2, each of which regulates a variety of target genes that regulate cell survival, proliferation, differentiation, migration, and metabolism; Akt is known to phosphorylate IkB kinase which phosphorylates IkB-a releasing NF-kB to translocate into the nucleus and transcribe genes; Activation of Akt might increase or suppress NF-kB regulated genes (IL-8, IL-18) depending on the stimulus. Both FOXO and CREB are known to regulate apoptosis and phosphorylation of these transcription factors by Akt, has shown to control cell survival. Nrf-2 activation by Akt increases the production of antioxidant genes such as HO-1 and NQO-1 that counteracts oxidative stress and inflammation. RTK: Receptor tyrosine kinase; GPCR: G-protein-coupled receptor; PI3K: Phosphoinositide-3-kinase; PIP₂: Phosphatidylinositol 4,5-bisphosphate; Akt: Protein kinase B; PDK1: Phosphoinositide dependent kinase 1; mTORC2: Mammalian target of rapamycin; PTEN: Phosphatase and tensin homolog; PHLPP: PH domain and leucine rich repeat protein phosphatases; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; CREB: cAMP response element binding protein; FOXO: Forkhead family of transcription factors; Nrf-2: Nuclear factor erythroid 2 related factor-2; PP2A: Protein phosphatase 2; HO-1: Heme oxygenase; NQO-1: NADPH quinone dehydrogenase 1.