2025-01-22
最先端研究セミナー
講演者： 田村-辻 潔美 （北海道大学 大学院歯学研究院 口腔医学部門 准教授）
演題： FOXO1 transcription factor promotes angiogenesis via myosin light chain 2 (MLC2) phosphorylation
日時： 2025年1月22日（水）12：00- 13：00
開催場所：発生医学研究所1階 カンファレンス室
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https://md.kumamoto-u.ac.jp/course/view.php?id=114380
Abstract：
Angiogenesis is an important therapeutic target because it is necessary for wound healing and tissue repair and is also involved in the progression of diseases such as tumors and diabetes. However, the process by which vascular endothelial cells transform into an elongated form (endothelial elongation), a key event in vascular network expansion, is not well understood. Therefore, we focused on endothelial morphogenesis during angiogenesis. FOXO1 transcription factor has been reported to play an important role in endothelial elongation. Using animal experiments in zebrafish and mice, and human normal endothelial cell cultures, we identified PPP1R14C (KEPI) as a target gene of FOXO1 and demonstrated that endothelial elongation is regulated by the FOXO1-PPP1R14C- Myosin light chain 2 (MLC2) pathway. MLC2 is phosphorylated by MLC kinase (MLCK) to form phosphorylated MLC2 (pMLC2), which is dephosphorylated by MLC phosphatase (MLCP). PPP1R14C is an endogenous inhibitor of protein phosphatase 1 (PP1), the catalytic subunit of MLCP. When PPP1R14C is increased by FOXO1, MLCP activity is inhibited and pMLC2 dephosphorylation is suppressed. This indirectly causes an increase in pMLC2. pMLC2 may activate actin-myosin interactions and induces changes in cell morphology, probably by generating intricately regulated tension and contractile forces in the cell. We believe that the identification of molecular mechanisms specific to endothelial morphological changes in this study will expand new potential targets for angiogenic and anti-angiogenic therapies.
Reference:
Kiyomi Tsuji-Tamura, Mari Sato, Masato Tamura (2024), Pharmacological control of angiogenesis by regulating phosphorylation of myosin light chain 2, Cell Signalling, vol. 120, 111223.
Kiyomi Tsuji-Tamura, Minetaro Ogawa (2023), FOXO1 promotes endothelial cell elongation and angiogenesis by up-regulating the phosphorylation of myosin light chain 2, Angiogenesis, 2023, vol. 26, p523-545.
Kiyomi Tsuji-Tamura, Minetaro Ogawa (2016), Inhibition of the PI3K-Akt and mTORC1 signaling pathways promotes the elongation of vascular endothelial cells, Journal of Cell Science, vol. 129, p1165-1178.
Kiyomi Tsuji, Keiji Uno, Gui Xia Zhang, Masato Tamura (2004), Periodontal ligament cells under intermittent tensile stress regulate mRNA expression of osteoprotegerin and tissue inhibitor of matrix metalloprotease-1 and -2, Journal of Bone and Mineral Metabolism, vol. 22, p94-103.
