Abstract
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.
Highlights
Co-ordinated cell migration is fundamental to various biological processes including morphogenesis, wound healing and cancer metastasis
In this study we demonstrated that Paraxial protocadherin (PAPC) is down-regulated in the axial mesoderm during gastrulation, at the transcriptional level and at the protein level, by ubiquitin-mediated degradation
Our results show that phosphorylation of PAPC by GSK3 serves as a signal for ubiquitination of PAPC by β-TrCP, and this process is necessary for PAPC to enter the normal regulation cycle
Summary
Co-ordinated cell migration is fundamental to various biological processes including morphogenesis, wound healing and cancer metastasis. In gastrulating Xenopus embryos, for example, lateral and chordal mesodermal cells are polarized and aligned mediolaterally, and simultaneously migrate towards the midline and intercalate each other to narrow and elongate the body axis, a process known as convergent extension (CE) [1]. Cells are maintained as a cohesive tissue while individual cells break the cell-cell boundary by wedging between neighbouring cells, it is proposed that regulation of cell adhesion/deadhesion is a prerequisite for such cell behaviour [2]. Paraxial protocadherin (PAPC) belongs to the protocadherin family, and has six cadherin ectodomains, a single-pass transmembrane domain and a cytoplasmic tail [3]. Prior to the onset of gastrulation, PAPC is expressed in the Spemann organizer in Xenopus and the dorsal.
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