title: Proprotein convertase PC7 enhances the activation of the EGF receptor pathway through processing of the EGF precursor.
abstract: Although the processing profile of the membrane-bound epidermal growth factor precursor (pro-EGF) is tissue-specific, it has not been investigated at the cellular level nor have the cognate proteinases been defined. Among the proprotein convertases (PCs), only the membrane-bound PC7, the most ancient and conserved basic amino acid-specific PC family member, induces the processing of pro-EGF into an ∼115-kDa transmembrane form (EGF-115) at an unusual VHPR(290)↓A motif. Because site-directed mutagenesis revealed that Arg(290) is not critical, the generation of EGF-115 by PC7 is likely indirect. This was confirmed by testing a wide range of protease inhibitors, which revealed that the production of EGF-115 is most probably achieved via the activation by PC7 of a latent serine and/or cysteine protease(s). EGF-115 is more abundant at the cell surface than pro-EGF and is associated with a stronger EGF receptor (EGFR) activation, as evidenced by higher levels of phosphorylated ERK1/2. This suggests that the generation of EGF-115 represents a regulatory mechanism of juxtacrine EGFR activation. Thus, PC7 is distinct from the other PCs in its ability to enhance the activation of the cell surface EGFR.
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Estelle
authors.initials: E
authors.lastname: Rousselet
authors.forename: Suzanne
authors.initials: S
authors.lastname: Benjannet
authors.forename: Edwidge
authors.initials: E
authors.lastname: Marcinkiewicz
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Asselin
authors.forename: Claude
authors.initials: C
authors.lastname: Lazure
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D013381:Subtilisins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D011480:Protease Inhibitors; D011498:Protein Precursors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C099101:PCSK7 protein, human; C490930:Pcsk7 protein, mouse; D013381:Subtilisins