Cadherins are calcium-dependent cell adhesion molecules involved in embryonic morphogenesis, determining cell and tissue architecture, and controlling dynamic changes in cell shape and position. Loss of E-cadherin is also strongly correlated with both the initiation and progression of tumours, and proteolytic cleavage of E-cadherin has been associated with rapid changes in cell adhesion. Maretzky et al. have identified the metalloprotease ADAM10 as a key mediator of E-cadherin proteolytic processing with important consequences for cell adhesion and motility.

Cleavage of E-cadherin is known to regulate adhesion, but the actual protease that delivers the fatal chop has remained elusive. Cleavage of the extracellular domain of E-cadherin generates a 38-KDa C-terminal fragment (CTF1), which can be used as a marker of E-cadherin processing. Three findings from Maretzky et al. suggest that ADAM10 specifically cleaves E-cadherin: First, assessment of CTF1 levels by western blot revealed that both constitutive and induced E-cadherin cleavage was greatly reduced in ADAM10-deficient fibroblasts. Second, the levels of CTF1 decreased in a dose-dependent manner when ADAM10-expressing keratinocytes were treated with the ADAM10 inhibitor, GI254023X. Third, depletion of ADAM10 by siRNA decreased CTF1 levels by 95% compared with mock-transfected keratinocytes, further proving the role of ADAM10 in E-cadherin shedding.

Intercellular adhesions are stabilized by -catenin binding to the cytoplasmic domain of E-cadherin. As E-cadherin cleavage has been previously shown to disrupt cell adhesion and induce the translocation of -catenin from the cell surface to the cytoplasm, Maretzky et al. sought to ascertain whether ADAM10 was important for this process. Interestingly, when E-cadherin cleavage was blocked by addition of the ADAM10 inhibitor, the translocation of -catenin was prevented, suggesting that ADAM10 mediates -catenin re-localization upon E-cadherin cleavage. Furthermore, examination of ADAM10-transfected keratinocytes and ADAM10-deficient embryos revealed that ADAM10 can regulate the transcription of -catenin downstream genes such as cyclin-D1, c-myc and c-jun in vivo, highlighting a novel role for ADAM10 in -catenin signal transduction.

To investigate the effects of ADAM10 on adhesion and cell motility, wound healing and adhesion assays were carried out. Whereas inhibition of ADAM10 led to an increase in adhesiveness, transient transfection of ADAM10 enhanced epithelial cell migration. Finally, examination of the levels of E-cadherin and CTF1 in ADAM10-deficient embryos revealed a dramatic increase in E-cadherin levels and loss of its cleavage, further cementing the need for ADAM10 in E-cadherin processing in vivo.

In summary, Maretzky et al. identify ADAM10 as a critical regulator of both constitutive and regulated E-cadherin shedding in vitro and in vivo. By cleaving E-cadherin, ADAM10 not only disrupts cell adhesion, which leads to an increase in cell motility, but also regulates -catenin signal transduction. It still remains to be determined whether other ADAM10 substrates also mediate these effects, and whether ADAM10-mediated E-cadherin cleavage contributes to tumour progression.

Author: Monica Hoyos-Flight