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Mol Biol Cell. 2015 Feb 15;26(4):659-73. doi: 10.1091/mbc.E14-10-1463. Epub 2014 Dec 24.

ADAM10 controls collagen signaling and cell migration on collagen by shedding the ectodomain of discoidin domain receptor 1 (DDR1).

Author information

1
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
2
Department of Molecular Biology and Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark.
3
National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom.
4
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.

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.

PMID:
25540428
PMCID:
PMC4325837
DOI:
10.1091/mbc.E14-10-1463
[Indexed for MEDLINE]
Free PMC Article

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