Glycogen synthase kinase 3-β inhibition induces lymphangiogenesis through β-catenin-dependent and mTOR-independent pathways.
Lymphatic vessels play an important role in health and in disease. In this study, we evaluated the effects of GSK3-β inhibition on lung lymphatic endothelial cells in vitro. Pharmacological inhibition and silencing of GSK3-β resulted in increased lymphangiogenesis of lung lymphatic endothelial cells. To investigate mechanisms of GSK3-β-mediated lymphangiogenesis, we interrogated the mammalian/mechanistic target of rapamycin pathway and found that inhibition of GSK3-β resulted in PTEN activation and subsequent decreased activation of AKT, leading to decreased p-P70S6kinase levels, indicating inhibition of the mTOR pathway. In addition, consistent with a negative role of GSK3-β in β-catenin stability through protein phosphorylation, we found that GSK3-β inhibition resulted in an increase in β-catenin levels. Simultaneous silencing of β-catenin and inhibition of GSK3-β demonstrated that β-catenin is required for GSK3-β-induced lymphangiogenesis.
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|PubMed Central ID||
R01 HL130275 / HL / NHLBI NIH HHS / United States
R01 HL132991 / HL / NHLBI NIH HHS / United States
F32 HL140859 / HL / NHLBI NIH HHS / United States
T32 HL007633 / HL / NHLBI NIH HHS / United States