Translocation of the Cytoplasmic Domain of ADAM13 to the Nucleus Is Essential for Calpain8-a Expression and Cranial Neural Crest Cell Migration

SummaryADAMs are transmembrane metalloproteases that control cell behavior by cleaving both cell adhesion and signaling molecules. The cytoplasmic domain of ADAMs can regulate the proteolytic activity by controlling the subcellular localization and/or the activation of the protease domain. Here, we show that the cytoplasmic domain of ADAM13 is cleaved and translocates into the nucleus. Preventing this translocation renders the protein incapable of promoting cranial neural crest (CNC) cell migration in vivo, without affecting its proteolytic activity. In addition, the cytoplasmic domain of ADAM13 regulates the expression of multiple genes in CNC, including the protease Calpain8-a. Restoring the expression of Calpain8-a is sufficient to rescue CNC migration in the absence of the ADAM13 cytoplasmic domain. This study shows that the cytoplasmic domain of ADAM metalloproteases can perform essential functions in the nucleus of cells and may contribute substantially to the overall function of the protein.

► The ADAM13 cytoplasmic domain is cleaved and translocates into the nucleus ► Nuclear ADAM13 participates in cranial neural crest (CNC) cell migration ► The ADAM13 cytoplasmic domain increases Calpain8 expression in CNC cells ► Calpain8 expression rescues migration in CNC lacking the ADAM13 cytoplasmic domain