Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Monovalency Unleashes the Full Therapeutic Potential of the DN-30 Anti-Met Antibody

“…Receptor shedding is a physiologic cellular mechanism of protein degradation that leads to depletion of Met from the cell surface and to generation of a "decoy" receptor in the extracellular environment (13). This regulatory mechanism has conceivably evolved as part of a more general feedback system that holds in check the activity of Met, a master controller of key cellular functions.…”

“…We have previously reported the development of a monoclonal antibody directed against the extracellular portion of Met (DN-30) that binds to Met at subnanomolar affinity, resulting in proteolytic cleavage of the extracellular portion close to the cell membrane and release of a soluble receptor in the extracellular space (12). Following ectodomain shedding, operated by a metalloprotease of the ADAM family, the remaining transmembrane fragment becomes substrate of a second protease (␥-secretase) that detaches the kinase-containing portion from the membrane and rapidly addresses it toward the proteasome degradation pathway (13). Therefore, the net result of DN-30 binding to Met is (a) the generation of a soluble "decoy" Met that neutralizes HGF and forms heterodimers with bona fide Met (14) and (b) the proteolytic degradation of the Met kinase.…”

MET signalling: principles and functions in development, organ regeneration and cancer

“…The first step is a disintegrin and metalloprotease (ADAM)-mediated release (known as shedding) of the extracellular domain, which generates a soluble N-terminal fragment and a membrane-anchored cytoplasmic tail. Then, the surface-associated cytoplasmic remnant undergoes regulated proteolysis by γ-secretase, which yields a labile intracellular portion that is rapidly cleared by proteasome-mediated degradation 94 (Fig. 3d).…”

“…Unlike CBL-mediated endosomal degradation, regulated proteolysis of MET is ligand-and ubiquitin-independent and does not require the kinase activity of the receptor: the mechanism occurs basally and affords MET signalling with chronic, low-grade attenuation under steady-state conditions. The shedding of MET that is catalysed by ADAM metalloproteases can be acutely enhanced by various agents such as phorbol esters, suramin, lysophosphatidic acid and monoclonal antibodies (mAbs) against the MET ectodomain 94,95,96,97,98,99,100,101,102 . Importantly, the extracellular shedding of MET not only decreases the number of receptor molecules on the cell surface but also generates a decoy moiety that interacts with both HGF (by sequestering the ligand) and full-length MET (by impairing dimerization and transactivation of the native receptor) to further inhibit MET signalling 103,104 .…”

Le récepteur Met fête ses 30 ans

“…De façon intéressante, d'autres mAb dirigés contre le domaine extracellulaire de Met ont une action inhibitrice sans interférer avec l'interaction ligand/ récepteur. Par exemple, l'anticorps monoclonal DN30 favorise la dégradation de Met dans des modèles murins en activant son clivage par les métalloprotéases et le complexe γ-sécrétase, et réduit ainsi la croissance tumorale [44]. D'autres stratégies sont développées au niveau pré-clinique pour inhiber la signalisation HGF/SF-Met.…”