Mechanical signaling through the discoidin domain receptor 1 plays a central role in tissue fibrosis

Abstract

The preservation of tissue and organ architecture and function depends on tightly regulated interactions of cells with the extracellular matrix (ECM). These interactions are maintained in a dynamic equilibrium that balances intracellular, myosin-generated tension with extracellular resistance conferred by the mechanical properties of the extracellular matrix. Disturbances of this equilibrium can lead to the development of fibrotic lesions that are associated with a wide repertoire of high prevalence diseases including obstructive cardiovascular diseases, muscular dystrophy and cancer. Mechanotransduction is the process by which mechanical cues are converted into biochemical signals. At the core of mechanotransduction are sensory systems, which are frequently located at sites of cell-ECM and cell-cell contacts. As integrins (cell-ECM junctions) and cadherins (cell-cell contacts) have been extensively studied, we focus here on the properties of the discoidin domain receptor 1 (DDR1), a tyrosine kinase that mediates cell adhesion to collagen. DDR1 expression is positively associated with fibrotic lesions of heart, kidney, liver, lung and perivascular tissues. As the most common end-point of all fibrotic disorders is dysregulated collagen remodeling, we consider here the mechanical signaling functions of DDR1 in processing of fibrillar collagen that lead to tissue fibrosis.

Keywords: Cell signaling; Collagen; DDR1; Fibrosis; Myosin IIA; cell adhesion; cell adhesive proteins; cell biology; cytoskeleton; extracellular matrix; kinases; mechanic forces; mechanoreceptor; mechanotrasduction.

Figure 1.

DDR1 isoforms. Discoidin domain (DS); discoidin-like domain (DS-like); transmembrane domain (TM); N terminal (NT); C terminal (CT).

Figure 2.

Collagen-induced DDR1 activation. a-c – Adhesion to fibrillar collagen induces initially, DDR1 clustering, which promotes activation of DDR1 kinase domain (phosphorylation at the tyrosine 792) and its association with myosin IIA. d -DDR1 activation reinforces DDR1 binding to collagen by increasing receptor clustering and enhances the association of DDR1 with NMIIA filaments, thereby optimizing the transmission of contractile forces to collagen.