Discover how the latest breakthrough reveals Epinephrine’s role in regulating PI3Kα through the intricate Hippo kinase pathway, a potential game-changer in gastroenterological treatments and cancer research.
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Epinephrine inhibits PI3Kα via the Hippo kinases.
Lin et al., Cell Rep 2023
DOI: 10.1016/j.celrep.2023.113535
Novelty & Importance: This study identifies a new regulatory mechanism of the phosphoinositide 3-kinase p110α (PI3K p110α), which is crucial for insulin signaling and glucose metabolism. The research reveals that Hippo kinases, specifically MST1/2, can phosphorylate p110α at threonine 1061 (T1061), leading to its inhibition. This finding connects the stress hormone epinephrine and insulin signaling, providing insights into the cross-talk between stress responses and metabolic control.
Contribution to Literature: The research expands the understanding of PI3K regulation by uncovering the role of Hippo kinases in modulating its activity. It demonstrates that phosphorylation at T1061 induces a conformational change in p110α, affecting its membrane association and downstream insulin signaling pathways. This contributes to the broader knowledge of how hormonal signals like epinephrine can influence metabolic processes such as glycolysis and glycogen synthesis.
Results Summary: Activation of MST1/2 kinases by forskolin or epinephrine leads to phosphorylation of p110α at T1061, which inhibits its activity. This results in impaired insulin signaling and reduced glycolysis and glycogen synthesis in human hepatocytes, cancer cell lines, and rodent tissues. The inhibitory effects are reversed when MST1/2 are deleted or inhibited, or when T1061 is mutated to alanine, highlighting the specificity of this regulatory interaction.