The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis and Renal Disease

Dorison, Aude; Dussaule, Jean–Claude; Chatziantoniou, Christos

doi:10.1159/000479119

Cited by 39 publications

(35 citation statements)

References 49 publications

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“…Another strategy to perturb DDR1 function is the use of inhibitors of receptor tyrosine kinases such as imatinib or nilotinib. Both have given mixed results so far, most likely due to their lack of selectivity and secondary effects [152]. In vitro studies showed that nilotinib reduces the association of DDR1 with myosin IIA and blocks collagen contraction [13].…”

Section: Targeting Ddr1 In Anti-fibrotic Therapiesmentioning

confidence: 99%

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

Coelho

McCulloch

2018

Cell Adhesion & Migration

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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.

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Section: Targeting Ddr1 In Anti-fibrotic Therapiesmentioning

confidence: 99%

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

Coelho

McCulloch

2018

Cell Adhesion & Migration

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“…7 DDR1 expression is upregulated in fibrosed organs including the kidney and it contributes to disease progression by regulating inflammatory and fibrotic responses. 13 We showed that DDR1 promotes collagen IV production, a major ECM upregulated in fibrotic diseases. This effect requires collagen binding to DDR1 and receptor kinase domain activation; however, the molecular mechanisms whereby DDR1 increases ECM synthesis and contributes to fibrosis initiation and/or progression is poorly defined.…”

mentioning

confidence: 91%

The Extracellular Matrix Receptor Discoidin Domain Receptor 1 Regulates Collagen Transcription by Translocating to the Nucleus

Chiusa

Liao

et al. 2019

JASN

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BackgroundThe discoidin domain receptor 1 (DDR1) is activated by collagens, upregulated in injured and fibrotic kidneys, and contributes to fibrosis by regulating extracellular matrix production, but how DDR1 controls fibrosis is poorly understood. DDR1 is a receptor tyrosine kinase (RTK). RTKs can translocate to the nucleus via a nuclear localization sequence (NLS) present on the receptor itself or a ligand it is bound to. In the nucleus, RTKs regulate gene expression by binding chromatin directly or by interacting with transcription factors.MethodsTo determine whether DDR1 translocates to the nucleus and whether this event is mediated by collagen-induced DDR1 activation, we generated renal cells expressing wild-type or mutant forms of DDR1 no longer able to bind collagen. Then, we determined the location of the DDR1 upon collagen stimulation. Using both biochemical assays and immunofluorescence, we analyzed the steps involved in DDR1 nuclear translocation.ResultsWe show that although DDR1 and its natural ligand, collagen, lack an NLS, DDR1 is present in the nucleus of injured human and mouse kidney proximal tubules. We show that DDR1 nuclear translocation requires collagen-mediated receptor activation and interaction of DDR1 with SEC61B, a component of the Sec61 translocon, and nonmuscle myosin IIA and β-actin. Once in the nucleus, DDR1 binds to chromatin to increase the transcription of collagen IV, a major collagen upregulated in fibrosis.ConclusionsThese findings reveal a novel mechanism whereby activated DDR1 translates to the nucleus to regulate synthesis of profibrotic molecules.

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“…Discoidin Domain Receptor 1 (DDR1) is a cell-surface tyrosine kinase receptor that binds to, and is activated by, collagens [16][17][18][19] . DDR1 is predominantly expressed in normal epithelial cells and its aberrant expression is associated with multiple solid cancer types.…”

Section: Introductionmentioning

confidence: 99%

“…Under various physiopathological conditions such as hypertensive nephropathy, collagen-triggered DDR1 activation is known to induce an inflammatory response, which in turn leads to excessive collagen synthesis and exaggerated fibrosis 19 (Figure 2c). Expression of Col3a1 and a-smooth muscle actin (a-SMA), another hallmark for accumulation of tumor-associated stromal cells 32 , followed the same trend, albeit not statistically significant (Figure 2c).…”

mentioning

confidence: 99%

“…Furthermore, obesity-associated fibrosis is an increasingly recognized hallmark of adipose dysfunction that is tightly associated with other adiposity-related changes such as inflammation 37 . As a known collagen receptor, DDR1 is a key player in a collagen-initiated positive feedback loop that ultimately results in excessive ECM accumulation in various non-cancer disease models 19 . Our in vitro and in vivo data suggest that the same positive feedback loop most likely also manifests in the mammary tumor microenvironment.…”

mentioning

confidence: 99%

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Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice

Sun

Gupta

et al. 2018

Journal of Biological Chemistry

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Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communications with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear, however. Here, we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1-KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1-KO adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVF-produced IL-6 is important for SVF-stimulated tumor cell invasion in vitro, and using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth.

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The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis and Renal Disease

Cited by 39 publications

References 49 publications

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

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

The Extracellular Matrix Receptor Discoidin Domain Receptor 1 Regulates Collagen Transcription by Translocating to the Nucleus

Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice

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