Sensing extracellular matrix: An update on discoidin domain receptor function

Vogel, Wolfgang F.; Abdulhussein, Rahim; Ford, Caroline

doi:10.1016/j.cellsig.2006.02.012

Cited by 315 publications

(321 citation statements)

References 74 publications

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“…In normal conditions, DDR1 is expressed in the kidney. [1][2][3] However, current evidence does not support a key role for DDR1 in renal development and physiology, in particular because transgenic mice lacking DDR1 present a close to normal renal phenotype in basal conditions. 11,19 In contrast, DDR1 has been established as an important contributor to a broad variety of pathologic processes, especially in cancer and inflammation, by promoting cell migration, invasion, and survival.…”

Section: Discussionmentioning

confidence: 88%

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Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Guerrot

Kerroch

Placier

et al. 2011

The American Journal of Pathology

100

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The interactions between tubulointerstitial infiltrating cells and the extracellular matrix play an important role in regulating renal fibrosis. Discoidin domain receptor 1 (DDR1) is a nonintegrin tyrosine kinase receptor for collagen implicated in cell adhesion, proliferation, and extracellular matrix remodeling. We have previously demonstrated that transgenic mice lacking DDR1 are protected from hypertension-associated renal fibrosis. The purpose of this study was to determine the role of DDR1 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After 12 days of unilateral ureteral obstruction (UUO), kidney histopathologic and real-time quantitative PCR analyses were performed in DDR1 ؊/؊ and wild-type mice. DDR1 expression was strongly increased in the obstructed kidney. Wild-type mice developed important perivascular and interstitial inflammation and fibrosis. In comparison, DDR1 ؊/؊ mice displayed reduced accumulation of fibrillar collagen and transforming growth factor ␤ expression. F4/80 ؉ cell count and proinflammatory cytokines were remarkably blunted in DDR1 ؊/؊ obstructed kidneys. Leukocyte rolling and adhesion evaluated by intravital microscopy were not different between DDR1 ؊/؊ and wild-type mice. Importantly, macrophages isolated from DDR1 ؊/؊ mice presented similar M1/M2 polarization but displayed impaired migration in response to monocyte chemoattractant protein-1. Together, these data suggest that DDR1 plays an important role in the pathogenesis of renal disease via enhanced inflammation. Inhibition of DDR1 expression or activity may represent a novel therapeutic target against the progression of renal diseases. Renal fibrosis is the consequence of the accumulation of extracellular matrix (ECM) components, including collagen, in the kidney. In chronic kidney diseases, irrespective of the initiating cause, fibrotic lesions autoaggravate, leading to a progressive decrease in renal function. Despite growing interest, the pathophysiologic pathways responsible for the progression of renal fibrosis remain elusive. A better understanding of specific mechanisms that promote inflammation and ECM synthesis is of critical importance in this setting because such pathways are susceptible to being at the cornerstone of the initiation and the progression of fibrogenesis.Discoidin domain receptor 1 (DDR1) is a tyrosine kinase transmembrane receptor for collagen constitutively expressed in several cell types and organs, including the gastrointestinal tract, lung, and kidney. 1 In the mammalian kidney, DDR1 is predominantly expressed by vascular smooth muscle cells, mesangial cells, and epithelial cells in normal conditions. 2,3 On activation by binding to collagen I to VI and VIII, DDR1 regulates cell differentiation, adhesion, proliferation, and ECM remodeling. 4 -6 A number of studies have shown that DDR1 is implicated in carcinogenesis, inflammation, atherosclerosis, and fibrogenesis. [7][8][9][10][11][12] Consistent with an important pathogenetic role in vascular diseases, 8,[1...

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Section: Discussionmentioning

confidence: 88%

“…1 In the mammalian kidney, DDR1 is predominantly expressed by vascular smooth muscle cells, mesangial cells, and epithelial cells in normal conditions. 2,3 On activation by binding to collagen I to VI and VIII, DDR1 regulates cell differentiation, adhesion, proliferation, and ECM remodeling.…”

mentioning

confidence: 99%

Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Guerrot

Kerroch

Placier

et al. 2011

The American Journal of Pathology

100

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“…Furthermore we have shown that DDR1 is an independent favourable prognostic marker for early-stage NSCLC patients, and that mutations in DDR1 and DDR2 appear less frequently than previously reported. The collagen-binding RTKs, DDR1 and DDR2, have previously been linked to various human diseases including fibrosis (Alves et al, 1995;Mao et al, 2002;Lee et al, 2004;Avivi-Green et al, 2006), atherosclerosis (Hou et al, 2001;Hou et al, 2002;Ferri et al, 2004), and cancer (Johnson et al, 1993;Alves et al, 1995;Barker et al, 1995;Nemoto et al, 1997;Weiner et al, 2000;Dejmek et al, 2003;Ongusaha et al, 2003;Heinzelmann-Schwarz et al, 2004;Ram et al, 2006;Vogel et al, 2006). The mechanism by which DDRs may contribute to oncogenesis is as yet unknown.…”

Section: Discussionmentioning

confidence: 99%

Expression and mutation analysis of the discoidin domain receptors 1 and 2 in non-small cell lung carcinoma

et al. 2007

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The discoidin domain receptors, (DDR)1 and DDR2, have been linked to numerous human cancers. We sought to determine expression levels of DDRs in human lung cancer, investigate prognostic determinates, and determine the prevalence of recently reported mutations in these receptor tyrosine kinases. Tumour samples from 146 non-small cell lung carcinoma (NSCLC) patients were analysed for relative expression of DDR1 and DDR2 using quantitative real-time PCR (qRT-PCR). An additional 23 matched tumour and normal tissues were tested for differential expression of DDR1 and DDR2, and previously reported somatic mutations. Discoidin domain receptor 1 was found to be significantly upregulated by 2.15-fold (P ¼ 0.0005) and DDR2 significantly downregulated to an equivalent extent (P ¼ 0.0001) in tumour vs normal lung tissue. Discoidin domain receptor 2 expression was not predictive for patient survival; however, DDR1 expression was significantly associated with overall (hazard ratio (HR) 0.43, 95% CI ¼ 0.22 -0.83, P ¼ 0.014) and disease-free survival (HR ¼ 0.56, 95% CI ¼ 0.33 -0.94, P ¼ 0.029). Multivariate analysis revealed DDR1 is an independent favourable predictor for prognosis independent of tumour differentiation, stage, histology, and patient age. However, contrary to previous work, we did not observe DDR mutations. We conclude that whereas altered expression of DDRs may contribute to malignant progression of NSCLC, it is unlikely that this results from mutations in the DDR1 and DDR2 genes that we investigated.

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“…8 10 Discoidin domains (also known as the F5/8 type C domains) are found in a family of extracellular cell surface proteins and are involved in cell adhesion and signalling. 75 The discoidin domain receptors, for example, which are transmembrane tyrosine kinase receptors, interact through their discoidin domains with collagens and regulate cell adhesion and extracellular matrix remodelling. 75 Other proteins containing a discoidin domain include blood coagulation factors 5 and 8, milk fat globule protein, neuropilins 1 and 2 and neurexin IV.…”

Section: Molecular Geneticsmentioning

confidence: 99%

“…75 The discoidin domain receptors, for example, which are transmembrane tyrosine kinase receptors, interact through their discoidin domains with collagens and regulate cell adhesion and extracellular matrix remodelling. 75 Other proteins containing a discoidin domain include blood coagulation factors 5 and 8, milk fat globule protein, neuropilins 1 and 2 and neurexin IV. 76 The cysteine residues within the retinoschisis discoidin domain are critical for folding and the formation of functional retinoschisin dimers and ultimately octamers.…”

Section: Molecular Geneticsmentioning

confidence: 99%