Discoidin Domain Receptor 1

Abstract

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and is activated by collagens. Transcriptional profiling of cirrhosis in human liver using a DNA array and quantitative PCR detected elevated mRNA expression of DDR1 compared with that in nondiseased liver. The present study characterized DDR1 expression in cirrhotic and nondiseased human liver and examined the cellular effects of DDR1 expression. mRNA expression of all five isoforms of DDR1 was detected in human liver, whereas DDR1a demonstrated differential expression in liver with hepatitis C virus and primary biliary cirrhosis compared with nondiseased liver. In addition, immunoblot analysis detected shed fragments of DDR1 more readily in cirrhotic liver than in nondiseased liver. Inasmuch as DDR1 is subject to protease-mediated cleavage after prolonged interaction with collagen, this differential expression may indicate more intense activation of DDR1 protein in cirrhotic compared with nondiseased liver. In situ hybridization and immunofluorescence localized intense DDR1 mRNA and protein expression to epithelial cells including hepatocytes at the portal-parenchymal interface and the luminal aspect of the biliary epithelium. Overexpression of DDR1a altered hepatocyte behavior including increased adhesion and less migration on extracelular matrix substrates. DDR1a regulated extracellular expression of matrix metalloproteinases 1 and 2. These data elucidate DDR1 function pertinent to cirrhosis and indicate the importance of epithelial cell-collagen interactions in chronic liver injury.

Discoidin domain receptor tyrosine kinases: new players in cancer progression

“…In macrophages, DDR1 supports monocyte chemotactic protein (MCP)-1 induced adhesion to and invasion through collagen IV, which may contribute to macrophage infiltration and accumulation during atherogenesis [150]. In cancer, DDR1 plays a role in adhesion to collagen of a variety of malignant cells including pituitary adenoma [102], glioma [100], and hepatoma cells [151], which may support tumor cell migration. In the case of DDR2, its contribution to cell adhesion is still unclear.…”

“…Knockdown of DDR1 in MDCK cells or expression of dominant negative DDR1 in the porcine kidney epithelial cells, LLC-PK1, dramatically increases migration towards collagen I [59]. In the hepatoma cell line, Huh7, DDR1a overexpression reduces migration toward collagen I, fibronectin, and Matrigel [151]. In non-malignant human mammary epithelial cells, Wnt-5a inhibits migration possibly through activation of DDR1 [38] while in the breast cancer cell lines MCF7 and MDA-MB-231, DDR1 apparently suppresses migration only when co-expressed with its interacting partner, the phosphoprotein DARPP32 [49].…”

Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer

“…For example, in MCF7 cells, DDR1 promotes cell migration when it is associated with myosin IIa [32]; on the other hand, when DDR1 is associated with phospho-DARP32, it suppresses cell migration [101]. Furthermore, DDR1 overexpression decreased cell migration in Huh7 cells [102] and in Hs587T breast cancer cells [91].…”

Interactions between the discoidin domain receptor 1 and β1 integrin regulate attachment to collagen

“…DDR1 is activated by many types of collagens and appears to act as a sensor that triggers the degradation and turnover of extracellular matrix proteins ( Franco et al, 2002 ; Leitinger, 2011 ). The biological importance of DDR1 in physiological matrix turnover is supported by experiments using genetic disruption that demonstrate a role for DDR1 in variety of fibrotic conditions of kidney ( Flamant et al, 2006 ; Gross et al, 2010 ), liver ( Song et al, 2011 ), lung ( Avivi-Green et al, 2006 ) and blood vessels ( Franco et al, 2010 ).…”