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Mol Biol Cell December 15, 2014; 25 (25): 4072-82.

GSK3 and Polo-like kinase regulate ADAM13 function during cranial neural crest cell migration.

Abbruzzese G , Cousin H , Salicioni AM , Alfandari D .

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.

PubMed ID: 25298404
PMC ID: PMC4263450
Article link: Mol Biol Cell
Grant support: [+]

Species referenced: Xenopus
Genes referenced: adam10 adam17 adam19 adam33 adam9 cadm1 cdh11 gsk3a gsk3b itgb1 pcdh8.2 plk1 plk2 plk3 plk4 snai2 sox10 twist1
Antibodies: Adam33 Ab1 Adam33 Ab2 Adam33 Ab3 Adam33 Ab4 Gsk3a/b Ab1 Itgb1 Ab1 Pcdh8.2 Ab1 phospho-Adam33 Ab5
Morpholinos: adam19 MO2 adam33 MO3

Article Images: [+] show captions
References [+] :
Abu-Elmagd, Frizzled7 mediates canonical Wnt signaling in neural crest induction. 2006, Pubmed, Xenbase