Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers

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Abstract

The collagen-binding receptor tyrosine kinase DDR1 (discoidin domain receptor 1) is a drug target for a wide range of human diseases, but the molecular mechanism of DDR1 activation is poorly defined. Here we co-expressed different types of signalling-incompetent DDR1 mutants (‘receiver’) with functional DDR1 (‘donor’) and demonstrate phosphorylation of receiver DDR1 by donor DDR1 in response to collagen. Making use of enforced covalent DDR1 dimerisation, which does not affect receptor function, we show that receiver dimers are phosphorylated in trans by the donor; this process requires the kinase activity of the donor but not that of the receiver. The receiver ectodomain is not required, but phosphorylation in trans is abolished by mutation of the transmembrane domain. Finally, we show that mutant DDR1 that cannot bind collagen is recruited into DDR1 signalling clusters. Our results support an activation mechanism whereby collagen induces lateral association of DDR1 dimers and phosphorylation between dimers.

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Victoria Juskaite

National Heart and Lung Institute, Imperial College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
David S Corcoran

National Heart and Lung Institute, Imperial College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Birgit Leitinger

National Heart and Lung Institute, Imperial College London, London, United Kingdom

For correspondence
b.leitinger@imperial.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2426-1179

Funding

Medical Research Council (MRC Doctoral Training Partnership PhD Studentship)

Victoria Juskaite

National Heart and Lung Institute (NHLI Foundation studentship)

David S Corcoran

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.