cytoplasmic relaxation of active eph controls ephrin shedding by adam10细胞质的活跃弗管制放松ephrin adam10脱落.pdfVIP

Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10 1. 1,2,3,¤. 2 1 Peter W. Janes , Sabine H. Wimmer-Kleikamp , Achilleas S. Frangakis , Kane Treble , Bettina 1 3 3 4 5 2,3 Griesshaber , Ola Sabet , Markus Grabenbauer , Alice Y. Ting , Paul Saftig , Philippe I. Bastiaens *, Martin Lackmann1* 1 Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia, 2 European Molecular Biology Laboratory, Heidelberg, Germany, 3 Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany, 4 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 5 Biochemical Institute, Christian-Albrecht-University, Kiel, Germany Abstract Release of cell surface-bound ligands by A-Disintegrin-And-Metalloprotease (ADAM) transmembrane metalloproteases is essential for signalling by cytokine, cell adhesion, and tyrosine kinase receptors. For Eph receptor ligands, it provides the switch between cell-cell adhesion and repulsion. Ligand shedding is tightly controlled by intrinsic tyrosine kinase activity, which for Eph receptors relies on the release of an inhibitory interaction of the cytoplasmic juxtamembrane segment with the kinase domain. However, a mechanism linking kinase and sheddase activities had remained elusive. We demonstrate that it is a membrane-proximal localisation of the latent kinase domain that prevents ephrin ligand shedding in trans.