title: Mammalian EGF receptor activation by the rhomboid protease RHBDL2.
abstract: The epidermal growth factor receptor (EGFR) has several functions in mammalian development and disease, particularly cancer. Most EGF ligands are synthesized as membrane-tethered precursors, and their proteolytic release activates signalling. In Drosophila, rhomboid intramembrane proteases catalyse the release of EGF-family ligands; however, in mammals this seems to be primarily achieved by ADAM-family metalloproteases. We report here that EGF is an efficient substrate of the mammalian rhomboid RHBDL2. RHBDL2 cleaves EGF just outside its transmembrane domain, thereby facilitating its secretion and triggering activation of the EGFR. We have identified endogenous RHBDL2 activity in several tumour cell lines.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Adrain
authors.forename: Kvido
authors.initials: K
authors.lastname: Strisovsky
authors.forename: Markus
authors.initials: M
authors.lastname: Zettl
authors.forename: Landian
authors.initials: L
authors.lastname: Hu
authors.forename: Marius K
authors.initials: MK
authors.lastname: Lemberg
authors.forename: Matthew
authors.initials: M
authors.lastname: Freeman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006801:Humans; D016086:Lentivirus; D051379:Mice; D008856:Microscopy, Fluorescence; D010649:Phenylalanine / Q000031:analogs & derivatives; D012697:Serine Endopeptidases; D057057:Serine Proteases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013379:Substrate Specificity; D013876:Thiophenes; D014161:Transduction, Genetic
chemical_list: D013876:Thiophenes; D049452:Green Fluorescent Proteins; D010649:Phenylalanine; D004815:Epidermal Growth Factor; C080985:batimastat; D066246:ErbB Receptors; D057057:Serine Proteases; D012697:Serine Endopeptidases; C545655:RHBDL2 protein, human