title: 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.
authors.affiliation: Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN 37232, United States; The Center of Matrix Biology, Vanderbilt University, Nashville, TN 37232, United States. Electronic address: corina.borza@vanderbilt.edu.
authors.forename: Corina M
authors.initials: CM
authors.lastname: Borza
authors.affiliation: Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN 37232, United States; The Center of Matrix Biology, Vanderbilt University, Nashville, TN 37232, United States; Department of Medicine, Veterans Affairs Hospital, Nashville, TN 37232, United States. Electronic address: ambra.pozzi@vanderbilt.edu.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D000070819:Discoidin Domain Receptor 1; D000070818:Discoidin Domain Receptors; D005109:Extracellular Matrix / Q000235:genetics / Q000473:pathology; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011975:Receptors, Mitogen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D011975:Receptors, Mitogen; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: Cancer; Fibrosis; Inflammation; Kidney; Matrix; Signaling