Discoidin domain receptors in disease

Abstract

Discoidin domain receptors, DDR1 and DDR2, lie at the intersection of two large receptor families, namely the extracellular matrix and tyrosine kinase receptors. As such, DDRs are uniquely positioned to function as sensors for extracellular matrix and to regulate a wide range of cell functions from migration and proliferation to cytokine secretion and extracellular matrix homeostasis/remodeling. While activation of DDRs by extracellular matrix collagens is required for normal development and tissue homeostasis, aberrant activation of these receptors following injury or in disease is detrimental. The availability of mice lacking DDRs has enabled us to identify key roles played by these receptors in disease initiation and progression. DDR1 promotes inflammation in atherosclerosis, lung fibrosis and kidney injury, while DDR2 contributes to osteoarthritis. Furthermore, both DDRs have been implicated in cancer progression. Yet the mechanisms whereby DDRs contribute to disease progression are poorly understood. In this review we highlight the mechanisms whereby DDRs regulate two important processes, namely inflammation and tissue fibrosis. In addition, we discuss the challenges of targeting DDRs in disease. Selective targeting of these receptors requires understanding of how they interact with and are activated by extracellular matrix, and whether their cellular function is dependent on or independent of receptor kinase activity.

Keywords: Cancer; Fibrosis; Inflammation; Kidney; Matrix; Signaling.

Figure 1

Crosstalk between DDRs and transmembrane receptors and/or soluble factors can regulate various processes, including cell differentiation, adhesion, motility, survival as well as potentiate DDR phosphorylation and activation.

Figure 2

DDR expression and/or activation plays a role in both physiological (e.g., development) and pathological (e.g., cancer, inflammation, fibrosis) conditions by controlling key cellular processes, including protease production, cytokine secretion, cell migration, immune cell recruitment, and matrix production.

Figure 3

Illustration of how expression and/or activation of DDRs can be targeted in disease. For details see main text.