Reactome: A Curated Pathway Database

ADAM10 cleaves EFNAs

Stable Identifier
R-HSA-3928660
Type
Reaction [BlackBoxEvent]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

After the initial adhesion, the EPH- and ephrin (EFN)-bearing cells break away due to a repulsive response. Repulsive signaling outcomes that promote cell-cell disengagement involve removal of the cell surface EPH:EFN complexes rather than dissociation of the bound proteins (Litterst et al. 2007). Removal of EPH:EFN complexes is mediated by a mechanism involving a metalloprotease enzyme bound to EFN or EPH receptors, which is activated after a time delay to cleave EFN or EPH. Through this mechanism, the mechanical adhesion between EFN and EPH on different cell surfaces is broken, resulting in the two cells moving apart. ADAMs (a disintegrin and a metalloprotease) are proteases responsible for the regulated ectodomain shedding of protein receptors like TGF-alpha, TNF-alpha, and the notch ligand Delta, a process that is critical to their signaling function. Similarly, EFNAs have been identified as substrates for membrane-bound ADAM10/Kuzbanian/KUZ. Flanagan and colleagues showed that ADAM10 is constitutively associated with EFNA2, and mediates the cleavage of EFNA2 ectodomain upon EPHA3:EFNA2 complex formation . This EFN cleavage mechanism was proposed to occur in cis (where both the proteinase and its substrate are within the same cell membrane) (Hattori et al. 2000). Janes et al. show the alternate model to that of the Flangan group. They showed that ADAM10 constitutively associates with the EPHA3 receptor, rather than EFNA and cleaves EFNA5 from its membrane tether only in trans (where the proteinase and its substrate are on opposing cell membrane) (Janes et al. 2005). In both models, EFN is cleaved from the membrane by ADAM10 only after the interaction of EFN with EPH receptors.

Participants
Participant Of
This entity is regulated by:
Title Physical Entity Activity
metallopeptidase activity of EPHAs:EFNAs:ADAM10 [plasma membrane] EPHAs:EFNAs:ADAM10 [plasma membrane] metallopeptidase activity (0008237)
Inferred From