The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair

Abstract

IntroductionAtherosclerosis and restenosis are characterized by the development of a thickened neointimal layer in the blood vessel wall. Smooth muscle cells (SMCs) are activated after arterial injury and contribute to neointimal lesion development through proliferation, migration, and ECM synthesis. Recent research suggests that the ECM is not simply an inert scaffold, but instead there are dynamic interactions between cells and matrix that contribute to SMC responses. After arterial injury, SMCs synthesize the fibrillar type I and III collagens (1, 2) and the short-chain type VIII collagen (3-6). Recently, the discoidin domain receptor tyrosine kinases (DDRs) were shown to function as collagen receptors and to increase matrix metalloproteinase (MMP) production in a fibrosarcoma cell line (7,8). The MMPs (including MMP-1, MMP-2, MMP-3, MMP-9, and MT1-MMP) are upregulated after injury and facilitate SMC migration in the vessel wall (9-12). Given the role of the DDRs in mediating interactions with collagen and stimulating MMP synthesis, we posit here that the DDRs are important mediators of the SMC response to injury.The DDRs are distinguished by an extracellular domain of 160 amino acids that is homologous to the Dictyostelium discoideum protein discoidin-I (13). There are two distinct gene products, DDR1 and DDR2, and DDR1 appears in three alternative splice variants, 1a, 1b, and 1c (13). DDR1 is widely expressed during embryonic development and in adult tissues, particularly in the epithelium of skin, kidney, gut, and brain, and the splice variant DDR1b increases considerably during postnatal development. DDR2 is restricted to skeletal muscle, heart, and connective tissues (13). Strikingly high levels of DDR1 and 2 are seen in fastgrowing invasive mammary, ovarian, and lung tumors (14), in keeping with the increased proliferative rates and MMP production in these tumors. To date, one abstract has reported DDR1 and DDR2 expression in atherosclerotic lesions of nonhuman primates fed a high-cholesterol diet (15); however, nothing is known about the function of DDRs in the vascular system. In the current study we have examined DDR1, the most widely expressed DDR in adult mammals.The arterial collagens that are upregulated after injury can be classified broadly into two categories based on their structure; fibril-forming (type I and III) and short-chain (type VIII) collagens. Tissue-culture studies show that type I collagen affects SMC growth and migration (16)(17)(18). Type VIII collagen is a shortchain collagen expressed during active remodeling in angiogenesis (19), embryonic development of the heart (20), and glomerulonephritis (21). We and others have shown that it is dramatically upregulated following experimental arterial injury (3-5) and in human atherosclerotic plaques (6), and we have shown The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair Collagens act as important signaling molecules regulating vascular smooth muscle cell responses during arterial wound repair. Discoidin domain...

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

“…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,[13][14][15] we have demonstrated that DDR1-deficient mice were protected against renal vascular lesions induced by a long-term infusion of angiotensin II, a model in which hemodynamic alterations and vascular remodeling play a major role. 11 Whether DDR1 may contribute to the initiating mechanisms and the progression of renal fibrosis irrespective of the initial cause remains unclear.…”

“…The generation and genotyping of mice were described previously. 13,16 The original background of the DDR1-null mice was a mix of 129/Sv with CD1. These mice have been backcrossed seven times to 129/Sv.…”

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

“…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.…”

Collagens in the progression and complications of atherosclerosis

“…Using DDR1-null mice, we determined that DDR1 played a critical role mediating neointimal hyperplasia after arterial injury. 25 Furthermore, Ddr1 -/-SMCs exhibited reduced proliferation, migration, and MMP activity in response to type I or type VIII collagen in vitro, 25 and overexpression of DDR1 rescued these deficits. 30 In agreement with this, overexpression of DDR1 or DDR2 in human SMCs increased MMP-1 expression and decreased procollagen α 1 (I) mRNA expression.…”