Complex Roles of ADAM Cell Surface Metalloproteases During Cranial Neural Crest Cell Migration

Objective/Background ADAMs are cell surface metalloproteases that shed a variety of substrate from the plasma membrane and contribute to multiple signaling cascades. Our objective was to determine the role of this protease during cranial neural crest cell migration. Methods We have used replacement of the endogenous ADAM proteins with proteins encoding truncated and mutated forms to test their ability to promote neural crest cell migration. Migration was assessed by following fluorescently labeled cells in vivo and in vitro. Results We found that meltrins (ADAM9, 13 and 19) play a complex role to promote cranial neural crest cell migration. ADAM9 and 13 cleave Cadherin‐11 to release an extracellular fragment that promotes cell migration by signaling via receptor tyrosine kinases. In addition ADAM13 cleaves multiple protocadherins and extracellular matrix proteins that may contribute to its activity during CNC migration. Finally, the cytoplasmic domain of ADAM13 undergoes multiple phosphorylation and cleavage that result in its translocation into the nucleus where it regulates the expression of multiple genes including cytoplasmic (calpain8) and extracellular proteases (MMP13). Conclusions While the proteolytic activity of ADAM is certainly critical as confirmed by our study, our result also uncovered an independent role for the cytoplasmic domains that has been conserved during evolution. Support or Funding Information NIH RO1‐DE016289, NIH F31‐DE023275