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 diseases 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.

Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

“…Here, DDR1 and DDR2, in particular, have demonstrated important functions in tissue homeostasis and cancers (243,385), in which lack or inhibition of DDR1 attenuated fibrogenesis (35,97,120,272,276), whereas DDR2 deficiency promoted experimental liver fibrosis (101).…”

Extracellular matrix component signaling in cancer

“…In addition, they contribute to ECM remodelling by controlling the expression and activity of matrix metalloproteinases. Dysregulation of DDR function and/or expression contributes to disease progression of a wide variety of human disorders, including organ fibrosis, arthritis and a long list of cancers [81,83,84]. Both DDRs are considered valid therapeutic targets, but mechanistic insight into their roles in various diseases is largely at an early stage.…”

Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein

“…Given the absence of enzymatic activity and the recognised functional and biological importance of the DSDs in a range of other proteins [6,7,8] we reasoned that increased understanding of the putative role of the DSD in CPX-1 would help direct future studies investigating the biological function of CPX-1. To this end, we have employed a complementary range of computational, cellular and biochemical approaches that show that CPX-1 is a secreted, collagen-binding glycoprotein.…”

“…They typically serve as binding domains, binding to a diverse array of molecules including growth factors, phospholipids and lipids, galactose and collagen, and are implicated in a range of physiological and pathophysiological processes [6,7,8].…”