title: Nemo-like kinase 1 (Nlk1) and paraxial protocadherin (PAPC) cooperatively control Xenopus gastrulation through regulation of Wnt/planar cell polarity (PCP) signaling.
abstract: The Wnt/planar cell polarity (PCP) pathway directs cell migration during vertebrate gastrulation and is essential for proper embryonic development. Paraxial protocadherin (PAPC, Gene Symbol pcdh8.2) is an important activator of Wnt/PCP signaling during Xenopus gastrulation, but how PAPC activity is controlled is incompletely understood. Here we show that Nemo-like kinase 1 (Nlk1), an atypical mitogen-activated protein (MAP) kinase, physically associates with the C-terminus of PAPC. This interaction mutually stabilizes both proteins by inhibiting polyubiquitination. The Nlk1 mediated stabilization of PAPC is essential for Wnt/PCP signaling, tissue separation and gastrulation movements. We identified two conserved putative phosphorylation sites in the PAPC C-terminus that are critical for Nlk1 mediated PAPC stabilization and Wnt/PCP regulation. Intriguingly, the kinase activity of Nlk1 itself was not essential for its cooperation with PAPC, suggesting an indirect regulation for example by impeding a different kinase that promotes protein degradation. Overall these results outline a novel, kinase independent role of Nlk1, wherein Nlk1 regulates PAPC stabilization and thereby controls gastrulation movements and Wnt/PCP signaling during development.
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Ciprianidis
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Theiß
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Steinbeißer
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany. Electronic address: lilian.kaufmann@med.uni-heidelberg.de.
authors.forename: Lilian T
authors.initials: LT
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000235:genetics*; D054262:Gastrulation / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D060066:Protein Interaction Maps / Q000235:genetics; D000091363:Protocadherins; D060449:Wnt Signaling Pathway / Q000235:genetics*; D029867:Xenopus Proteins / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000235:genetics / Q000254:growth & development
chemical_list: D015820:Cadherins; C117635:Pcdh8 protein, Xenopus; D000091363:Protocadherins; D029867:Xenopus Proteins; D020928:Mitogen-Activated Protein Kinases; C462720:nemo like kinase, Xenopus
keywords: Gastrulation movements; Nemo-like kinase; Paraxial protocadherin; Ubiquitination; Wnt/PCP; Xenopus laevis