title: Distinct Intracellular Domain Substrate Modifications Selectively Regulate Ectodomain Cleavage of NRG1 or CD44.
abstract: Ectodomain cleavage by A-disintegrin and -metalloproteases (ADAMs) releases many important biologically active substrates and is therefore tightly controlled. Part of the regulation occurs on the level of the enzymes and affects their cell surface abundance and catalytic activity. ADAM-dependent proteolysis occurs outside the plasma membrane but is mostly controlled by intracellular signals. However, the intracellular domains (ICDs) of ADAM10 and -17 can be removed without consequences for induced cleavage, and so far it is unclear how intracellular signals address cleavage. We therefore explored whether substrates themselves could be chosen for proteolysis via ICD modification. We report here that CD44 (ADAM10 substrate), a receptor tyrosine kinase (RTK) coreceptor required for cellular migration, and pro-NRG1 (ADAM17 substrate), which releases the epidermal growth factor (EGF) ligand neuregulin required for axonal outgrowth and myelination, are indeed posttranslationally modified at their ICDs. Tetradecanoyl phorbol acetate (TPA)-induced CD44 cleavage requires dephosphorylation of ICD serine 291, while induced neuregulin release depends on the phosphorylation of several NRG1-ICD serines, in part mediated by protein kinase Cδ (PKCδ). Downregulation of PKCδ inhibits neuregulin release and reduces ex vivo neurite outgrowth and myelination of trigeminal ganglion explants. Our results suggest that specific selection among numerous substrates of a given ADAM is determined by ICD modification of the substrate.
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany Harvard Institutes of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Liseth M
authors.initials: LM
authors.lastname: Parra
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Hartmann
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Salome
authors.initials: S
authors.lastname: Schubach
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Herrlich
authors.affiliation: Harvard Institutes of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA aherrlich@partners.org.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrlich
mesh_terms: D000595:Amino Acid Sequence; D018920:Coculture Techniques; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D020890:Neuregulin-1 / Q000737:chemistry / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction; D012668:Trigeminal Ganglion / Q000166:cytology
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta