Regulated cleavage of a contact-mediated axon repellent.
Contact-mediated axon repulsion by ephrins raises an unresolved question: these cell surface ligands form a high-affinity multivalent complex with their receptors present on axons, yet rather than being bound, axons can be rapidly repelled. We show here that ephrin-A2 forms a stable complex with the metalloprotease Kuzbanian, involving interactions outside the cleavage region and the protease domain. Eph receptor binding triggered ephrin-A2 cleavage in a localized reaction specific to the cognate ligand. A cleavage-inhibiting mutation in ephrin-A2 delayed axon withdrawal. These studies reveal mechanisms for protease recognition and control of cell surface proteins, and, for ephrin-A2, they may provide a means for efficient axon detachment and termination of signaling.
Hattori
M
M
Department of Cell Biology and Program in Neuroscience, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Osterfield
M
M
Flanagan
J G
JG
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology*; D002448:Cell Adhesion; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins; D036383:Ephrin-A2; D015870:Gene Expression; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D020439:Growth Cones / Q000502:physiology; D006801:Humans; D008024:Ligands; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009420:Nervous System / Q000196:embryology / Q000201:enzymology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D036121:Receptor, EphA3; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D019483:Disintegrins; D029721:Drosophila Proteins; D036383:Ephrin-A2; D017261:Glycosylphosphatidylinositols; D008024:Ligands; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C491718:EPHA3 protein, human; C491717:Epha3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D036121:Receptor, EphA3; C100953:KUZ protein, Drosophila; D008666:Metalloendopeptidases