Adam Meets Eph: An ADAM Substrate Recognition Module Acts as a Molecular Switch for Ephrin Cleavage In trans

Abstract

The Eph family of receptor tyrosine kinases and their ephrin ligands are mediators of cell-cell communication. Cleavage of ephrin-A2 by the ADAM10 membrane metalloprotease enables contact repulsion between Eph- and ephrin-expressing cells. How ADAM10 interacts with ephrins in a regulated manner to cleave only Eph bound ephrin molecules remains unclear. The structure of ADAM10 disintegrin and cysteine-rich domains and the functional studies presented here define an essential substrate-recognition module for functional interaction of ADAM10 with the ephrin-A5/EphA3 complex. While ADAM10 constitutively associates with EphA3, the formation of a functional EphA3/ephrin-A5 complex creates a new molecular recognition motif for the ADAM10 cysteine-rich domain that positions the proteinase domain for effective ephrin-A5 cleavage. Surprisingly, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells. Our data suggest a simple mechanism for regulating ADAM10-mediated ephrin proteolysis, which ensures that only Eph bound ephrins are recognized and cleaved.

ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A

“…The importance of the substrate's conformation for cleavage was nicely demonstrated for Ephrin-A5, which is cleaved by ADAM10, but only upon forming a complex with its receptor, EphA3 (ref. 23). Another plausible mechanism underlying Nrp1 shedding may involve alternative splicing.…”

“…Previous studies have uncovered important aspects of MP contribution to axon guidance. One major aspect is the catalysis of structural changes that are essential for the proper functioning of guidance receptors [21][22][23] . Another role, suggested by two previous studies, is the control of axonal sensitivity through regulation of receptor levels.…”

“…Consistent with this, some ADAMs have been shown to cleave axon guidance receptors 17 . As such, they have been implicated in overall control of receptor levels 18,19 ; activation of signalling upon ligand binding 20,21 ; and disassembly of receptor-ligand complexes 22,23 . However, whether metalloproteases regulate the levels of axon guidance receptors as part of a developmental switch in responsiveness is still unknown.…”

Expression of seven members of the ADAM family in developing chicken spinal cord

“…The process of motor axon outgrowth and pathfinding is controlled by a combination of different factors (Schneider and Granato, 2003), for example, by members of the Eph/ephrins family of molecules (Eberhart et al, 2000) and by NCAM (Landmesser, 1996;Stoker, 1996). It is of interest that ADAM10 can cleave ephrins in the Eph/ephrin binding-complex and regulate their functions (Janes et al, 2005). ADAM17 is involved in neurite outgrowth mediated by regulation of the proteolytic processing of NCAM (Kalus et al, 2006).…”

Transmembrane chemokines: Versatile ‘special agents’ in vascular inflammation

“…3).During transmigration and at the interface of leukocytes and endothelialcells, sheddingcould either occur in cis (sheddase and substrate aree xpressed on the same cell) or in trans (sheddase and substrate arelocated on opposed cells). Cleavage of transmembrane chemokines either in cis or trans would facilitate the detachment of boundcells allowingthem to further migratethrough the endothelium.While cleavage in cis wasconsideredmore likely, arecent study investigating the cleavage of ephrinA5 provided first evidencet hat cleavage in trans may occur (109).M oreover,w ithin the tissue ADAM10 and ADAM17 would generate accumulating amounts of soluble chemokines building up ac oncentration gradient and thereby furtherattracting transmigrated leukocytestothe siteofinflammation. Thus, whether leukocytesa re arrested to the vascular wall, transmigrate throughthe endothelium and finallymigrate into the underlying tissue is likelytobeinfluencedbythe activity of metalloproteinases such as ADAM17 and ADAM10.…”