Discoidin Domain Receptor 1 Mediates Myosin-Dependent Collagen Contraction

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Nuno M. Coelho, Pamma D. Arora, Sander van Putten, Stellar Boo, Petar Petrovic, Alyna Xue Lin, Boris Hinz, Christopher A. McCulloch
Discoidin domain receptor 1 (DDR1) is a tyrosine kinase collagen adhesion receptor that mediates cell migration through association with non-muscle myosin IIA (NMIIA). Because DDR1 is implicated in cancer fibrosis, we hypothesized that DDR1 interacts with NMIIA to enable collagen compaction by traction forces. Mechanical splinting of rat dermal wounds increased DDR1 expression and collagen alignment. In periodontal ligament of DDR1 knockout mice, collagen mechanical reorganization was reduced >30%. Similarly, cultured cells with DDR1 knockdown or expressing kinase-deficient DDR1d showed 50% reduction of aligned collagen. Tractional remodeling of collagen was dependent on DDR1 clustering, activation, and interaction of the DDR1 C-terminal kinase domain with NMIIA filaments. Collagen remodeling by traction forces, DDR1 tyrosine phosphorylation, and myosin light chain phosphorylation were increased on stiff versus soft substrates. Thus, DDR1 clustering, activation, and interaction with NMIIA filaments enhance the collagen tractional remodeling that is important for collagen compaction in fibrosis.

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Teaser

Coelho et al. show a role for DDR1 in mechanical realignment of collagen by cell-mediated traction forces, consistent with increased expression of DDR1 in different fibrotic conditions. DDR1 clustering and activation control the interactions with collagen and myosin IIA and ultimately determine the kinetics of collagen remodeling by traction forces.


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