title: GSK3 and Polo-like kinase regulate ADAM13 function during cranial neural crest cell migration.
abstract: ADAMs are cell surface metalloproteases that control multiple biological processes by cleaving signaling and adhesion molecules. ADAM13 controls cranial neural crest (CNC) cell migration both by cleaving cadherin-11 to release a promigratory extracellular fragment and by controlling expression of multiple genes via its cytoplasmic domain. The latter activity is regulated by γ-secretase cleavage and the translocation of the cytoplasmic domain into the nucleus. One of the genes regulated by ADAM13, the protease calpain8, is essential for CNC migration. Although the nuclear function of ADAM13 is evolutionarily conserved, it is unclear whether the transcriptional regulation is also performed by other ADAMs and how this process may be regulated. We show that ADAM13 function to promote CNC migration is regulated by two phosphorylation events involving GSK3 and Polo-like kinase (Plk). We further show that inhibition of either kinase blocks CNC migration and that the respective phosphomimetic forms of ADAM13 can rescue these inhibitions. However, these phosphorylations are not required for ADAM13 proteolysis of its substrates, γ-secretase cleavage, or nuclear translocation of its cytoplasmic domain. Of significance, migration of the CNC can be restored in the absence of Plk phosphorylation by expression of calpain-8a, pointing to impaired nuclear activity of ADAM13.
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Abbruzzese
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cousin
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Salicioni
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003 alfandar@vasci.umass.edu.
authors.forename: Dominique
authors.initials: D
authors.lastname: Alfandari
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D002465:Cell Movement; D002467:Cell Nucleus / Q000201:enzymology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000201:enzymology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009432:Neural Crest / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D029867:Xenopus Proteins / Q000378:metabolism* / Q000502:physiology*; D014982:Xenopus laevis / Q000196:embryology / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D051722:ADAM Proteins; D018797:Cell Cycle Proteins; D038362:Glycogen Synthase Kinase 3; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D029867:Xenopus Proteins; D000097869:Polo-Like Kinase 1; C581760:GSK3B protein, Xenopus; C104937:ADAM33 protein, Xenopus