Kanzaki Noriyuki, Ogita Hisakazu, Komura Hitomi, Ozaki Misa, Sakamoto Yasuhisa, Majima Takashi, Ijuin Takeshi, Takenawa Tadaomi, Takai Yoshimi
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Osaka, Japan.
J Cell Sci. 2008 Jun 15;121(Pt 12):2008-17. doi: 10.1242/jcs.024620. Epub 2008 May 27.
The nectin-afadin complex is involved in the formation of cell-cell junctions, such as adherens junctions (AJs) and tight junctions (TJs). Nectins are Ca(2+)-independent immunoglobulin-like cell-cell adhesion molecules, whereas afadin is an intracellular nectin-binding protein that connects nectins to the cadherin-catenin system at AJs and to the claudin-zona-occludens (ZO) protein system at TJs. Afadin(-/-) mice show embryonic lethality, resulting from impaired migration and improper differentiation of cells due to disorganization of cell-cell junctions during gastrulation. However, it remains to be elucidated whether disruption of afadin affects apoptosis. In the present study, we first found that embryoid bodies derived from afadin-knockout embryonic stem (ES) cells contained many more apoptotic cells than those derived from wild-type ES cells. We also revealed that apoptosis induced by serum starvation or Fas-ligand stimulation was increased in cultured NIH3T3 cells when afadin or nectin-3 was knocked down. The nectin-afadin complex was involved in the platelet-derived growth factor (PDGF)-induced activation of phosphatidylinositol 3-kinase (PI3K)-Akt signaling for cell survival. This complex was associated with PDGF receptor on the plasma membrane at cell-cell adhesion sites. Thus, the nectin-afadin complex is involved in PDGF-induced cell survival, at least through the PI3K-Akt signaling pathway.
NECTIN-afadin复合物参与细胞间连接的形成，如黏着连接（AJs）和紧密连接（TJs）。NECTIN是一种不依赖Ca(2+)的免疫球蛋白样细胞间黏附分子，而afadin是一种细胞内NECTIN结合蛋白，它在AJs处将NECTIN与钙黏蛋白-连环蛋白系统相连，在TJs处与claudin-紧密连接蛋白（ZO）系统相连。Afadin(-/-)小鼠表现出胚胎致死性，这是由于原肠胚形成过程中细胞间连接紊乱导致细胞迁移受损和分化异常所致。然而，afadin的破坏是否影响细胞凋亡仍有待阐明。在本研究中，我们首先发现，源自afadin基因敲除胚胎干细胞（ES细胞）的拟胚体比源自野生型ES细胞的拟胚体含有更多的凋亡细胞。我们还发现，当afadin或NECTIN-3被敲低时，血清饥饿或Fas配体刺激诱导的培养NIH3T3细胞凋亡增加。NECTIN-afadin复合物参与血小板衍生生长因子（PDGF）诱导的磷脂酰肌醇3激酶（PI3K）-Akt信号通路激活以促进细胞存活。该复合物在细胞间黏附位点与质膜上的PDGF受体相关联。因此，NECTIN-afadin复合物至少通过PI3K-Akt信号通路参与PDGF诱导的细胞存活。
