title: ADAM10 controls collagen signaling and cell migration on collagen by shedding the ectodomain of discoidin domain receptor 1 (DDR1).
abstract: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and transmits signals from various collagens in epithelial cells. However, how DDR1-dependent signaling is regulated has not been understood. Here we report that collagen binding induces ADAM10-dependent ectodomain shedding of DDR1. DDR1 shedding is not a result of an activation of its signaling pathway, since DDR1 mutants defective in signaling were shed in an efficient manner. DDR1 and ADAM10 were found to be in a complex on the cell surface, but shedding did not occur unless collagen bound to DDR1. Using a shedding-resistant DDR1 mutant, we found that ADAM10-dependent DDR1 shedding regulates the half-life of collagen-induced phosphorylation of the receptor. Our data also revealed that ADAM10 plays an important role in regulating DDR1-mediated cell adhesion to achieve efficient cell migration on collagen matrices.
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shitomi
authors.affiliation: Department of Molecular Biology and Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark.
authors.forename: Ida B
authors.initials: IB
authors.lastname: Thøgersen
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ito
authors.affiliation: National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Birgit
authors.initials: B
authors.lastname: Leitinger
authors.affiliation: Department of Molecular Biology and Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Enghild
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom yoshi.itoh@kennedy.ox.ac.uk.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Itoh
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000072197:ADAM10 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism*; D000070819:Discoidin Domain Receptor 1; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D003094:Collagen; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human