InactivationofGsk3byAKTcausesaccumulationofbcatenin

Lipopolysaccharide (LPS) from XX bacteria induces a wide range of inflammatory responses, including the response of alveolar macrophages to bacteria in the lungs. CD14 and the Toll-like receptor TLR4 are activated by LPS, initiating a signaling cascade that activates PI3 kinase and increases synthesis of the inositol phosphate PIP3 (see Toll-like Receptor pathway). PIP3 activates the inositol phosphate dependent protein kinase PDK1, which activates AKT (protein kinase B, see AKT Signaling Pathway). One of the key actions of AKT is to block apoptosis. AKT phosphorylation of NF-kB promotes the survival and activation of macrophages responding to LPS. Another substrate of AKT is the protein kinase Gsk3-beta. AKT phosphorylates and deactivates Gsk3-beta. Non-phosphorylated Gsk3-beta is active and phosphorylates beta-catenin, leading to its degradation in the ubiquitin dependent proteosome pathway (see proteosome pathway). Stimulation by LPS causes the accumulation of beta-catenin in the nucleus and the activation of genes in concert with the transcription factor LEF1. This pathway is probably not restricted to alveolar pathway, but leads to the activation of beta-catenin dependent genes by LPS in other cells as well. Other pathways regulate this pathway also, such as the modulation of PI3 kinase activity by ceramide, and the inhibition of Gsk3-beta activity by the Wnt/frizzled/disheveled (DSH) pathway.

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