Division of Matrixome Research and Application, Institute for Protein Research, Osaka University , Suita, Japan.
Department of Medical Physiology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
J Cell Biol. 2023 Sep 4;222(9). doi: 10.1083/jcb.202208047. Epub 2023 Jun 20.
Polydom is an extracellular matrix protein involved in lymphatic vessel development. Polydom-deficient mice die immediately after birth due to defects in lymphatic vessel remodeling, but the mechanism involved is poorly understood. Here, we report that Polydom directly binds to Tie1, an orphan receptor in the Angiopoietin-Tie axis, and facilitates migration of lymphatic endothelial cells (LECs) in a Tie1-dependent manner. Polydom-induced LEC migration is diminished by PI3K inhibitors but not by an ERK inhibitor, suggesting that the PI3K/Akt signaling pathway is involved in Polydom-induced LEC migration. In line with this possibility, Akt phosphorylation in LECs is enhanced by Polydom although no significant Tie1 phosphorylation is induced by Polydom. LECs also exhibited nuclear exclusion of Foxo1, a signaling event downstream of Akt activation, which was impaired in Polydom-deficient mice. These findings indicate that Polydom is a physiological ligand for Tie1 and participates in lymphatic vessel development through activation of the PI3K/Akt pathway.
多域蛋白是一种细胞外基质蛋白，参与淋巴管的发育。由于淋巴管重塑缺陷，Polydom 缺陷型小鼠在出生后立即死亡，但其中涉及的机制尚不清楚。在这里，我们报告 Polydom 可直接与 Tie1（血管生成素-Tie 轴中的孤儿受体）结合，并以 Tie1 依赖的方式促进淋巴管内皮细胞（LEC）的迁移。PI3K 抑制剂可减弱 Polydom 诱导的 LEC 迁移，但 ERK 抑制剂则不能，这表明 PI3K/Akt 信号通路参与了 Polydom 诱导的 LEC 迁移。与此一致，Polydom 可增强 LEC 中的 Akt 磷酸化，尽管 Polydom 不会诱导 Tie1 的显著磷酸化。LEC 中 Foxo1 的核排除也增强了 Akt 激活的信号事件，而在 Polydom 缺陷型小鼠中则受损。这些发现表明 Polydom 是 Tie1 的一种生理配体，并通过激活 PI3K/Akt 通路参与淋巴管的发育。
