Kai Masatake, Ueno Naoto, Kinoshita Noriyuki
Department of Developmental Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji-cho, Okazaki, Aichi 444-8585, Japan.
Department of Developmental Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji-cho, Okazaki, Aichi 444-8585, Japan; Department of Molecular Biomechanics, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigonaka, Myodaiji-cho, Okazaki, Aichi 444-8585, Japan.
PLoS One. 2015 Jan 12;10(1):e0115111. doi: 10.1371/journal.pone.0115111. eCollection 2015.
Paraxial protocadherin (PAPC) has been shown to be involved in gastrulation cell movements during early embryogenesis. It is first expressed in the dorsal marginal zone at the early gastrula stage and subsequently restricted to the paraxial mesoderm in Xenopus and zebrafish. Using Xenopus embryos, we found that PAPC is also regulated at the protein level and is degraded and excluded from the plasma membrane in the axial mesoderm by the late gastrula stage. Regulation of PAPC requires poly-ubiquitination that is dependent on phosphorylation. PAPC is phosphorylated by GKS3 in the evolutionarily conserved cytoplasmic domain, and this in turn is necessary for poly-ubiquitination by an E3 ubiquitin ligase β-TrCP. We also show that precise control of PAPC by phosphorylation/ubiquitination is essential for normal Xenopus gastrulation cell movements. Taken together, our findings unveil a novel mechanism of regulation of a cell adhesion protein and show that this system plays a crucial role in vertebrate embryogenesis.
近轴原钙黏蛋白（PAPC）已被证明在早期胚胎发育过程中的原肠胚形成细胞运动中发挥作用。它最初在原肠胚早期的背侧边缘区表达，随后在非洲爪蟾和斑马鱼中局限于近轴中胚层。利用非洲爪蟾胚胎，我们发现PAPC在蛋白质水平上也受到调控，到原肠胚晚期，它在轴中胚层中被降解并从质膜中排除。PAPC的调控需要依赖磷酸化的多聚泛素化。PAPC在进化上保守的细胞质结构域中被糖原合酶激酶3（GSK3）磷酸化，而这反过来又是E3泛素连接酶β-TrCP进行多聚泛素化所必需的。我们还表明，通过磷酸化/泛素化对PAPC进行精确调控对于非洲爪蟾正常的原肠胚形成细胞运动至关重要。综上所述，我们的研究结果揭示了一种细胞黏附蛋白的新型调控机制，并表明该系统在脊椎动物胚胎发育中起着关键作用。
