GSK3 and Polo-like kinase regulate ADAM13 function during cranial neural crest cell migration.
Bottom Line: 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.
Affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003.Show MeSH
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Mentions: ADAM13 plays a central role in regulating cranial neural crest cell migration and induction in amphibian embryos (Alfandari et al., 2001; Wei et al., 2010; Cousin et al., 2011, 2012). The cytoplasmic domain is critical, as it controls both the level of ADAM13 protein present in the CNC and the transcriptional activity in these cells (Cousin et al., 2000; Cousin et al., 2011). Here we show that one of these controls is mediated by a phosphorylation cascade involving GSK3 and Polo-like kinase. We further demonstrate that these phosphorylations, although essential for CNC migration, are not critical for ADAM13 cleavage of its extracellular substrates but are essential for the nuclear function of ADAM13. Our results suggest a model in which ADAM13 is successively phosphorylated in vivo, first by GSK3 to phospho-prime for Plk, and second by Plk at the critical residue T833 (Figure 7).
Affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003.