Open AccessGlycogen synthase kinase 3-β inhibition induces lymphangiogenesis through β-catenin-dependent and mTOR-independent pathways
Author(s) -
Benjamin Stump,
Shikshya Shrestha,
Anthony M. Lamattina,
Pierce H. Louis,
Woohyun Cho,
Mark A. Perrella,
Xingbin Ai,
Iván O. Rosas,
Florence F. Wagner,
Carmen Priolo,
Jonathan W. Astin,
Souheil ElChemaly
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0213831
Subject(s) - lymphangiogenesis , gsk 3 , pi3k/akt/mtor pathway , catenin , protein kinase b , gene silencing , cancer research , phosphorylation , microbiology and biotechnology , pten , signal transduction , biology , chemistry , wnt signaling pathway , biochemistry , cancer , metastasis , genetics , gene
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.