Discoidin domain receptor 1 expression in activated T cells is regulated by the ERK MAP kinase signaling pathway

Chetoui, Nizar; Azreq, Mohammed-Amine El; Boisvert, Marc; Bergeron, Marie-Ève; Aoudjit, Fawzi

doi:10.1002/jcb.23300

Cited by 40 publications

(35 citation statements)

References 41 publications

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“…Consistent with previous reports on lymphocytes, 21 we found that DDR2 activation is not required for neutrophil adhesion to a 2D collagen I-coated surface (Figure 2A). Similarly, DDR2 inhibition does not alter neutrophil chemotaxis on a 2D collagencoated surface ( Figure 2B; supplemental Figure 2A for quantification; supplemental Video 1).…”

Section: Ddr2 Is Required For Neutrophil Migration In a 3d Collagen Lsupporting

confidence: 93%

Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices

Afonso

McCann

Kapnick

et al. 2013

Blood

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Key Points• DDR2 regulates the directional migration of neutrophils in 3D collagen matrices, but not on 2D surfaces. • DDR2 regulates directionality through increased metalloproteinase secretion and generation of collagen-derived chemotactic peptide gradients.Neutrophils express a variety of collagen receptors at their surface, yet their functional significance remains unclear. Although integrins are essential for neutrophil adhesion and migration on 2-dimensional (2D) surfaces, neutrophils can compensate for the absence of integrins in 3-dimensional (3D) lattices. In contrast, we demonstrate that the inhibition of the tyrosine-kinase collagen receptor discoidin domain receptor 2 (DDR2) has no impact on human primary neutrophil migration on 2D surfaces but is an important regulator of neutrophil chemotaxis in 3D collagen matrices. In this context, we show that DDR2 activation specifically regulates the directional migration of neutrophils in chemoattractant gradients. We further demonstrate that DDR2 regulates directionality through its ability to increase secretion of metalloproteinases and local generation of collagen-derived chemotactic peptide gradients. Our findings highlight the importance of collagen-derived extracellular signaling during neutrophil chemotaxis in 3D matrices. (Blood. 2013;121(9):1644-1650) IntroductionNeutrophils exhibit the ability to maintain robust migration under a wide array of distinct environmental conditions. For example, by increasing the rate of actin polymerization, neutrophils lacking integrins are able to retain normal migration speeds in 3D environments. 1,2 We set out to determine the role of another collagen receptor family, the discoidin domain receptors (DDRs), during neutrophil chemotaxis. The DDR family is composed of 2 members, DDR1 and DDR2. DDRs are homodimeric receptor tyrosine kinases that bind to triple-helical collagen fibers through a domain similar to discoidin 1 of the social amoeba Dictyostelium discoideum. 3,4 On binding to collagen, DDRs become activated and serve as docking sites for many signaling pathways. 5 A common outcome after DDR activation is the increase in metalloproteinase (MMP) secretion and collagen rearrangement. [6][7][8][9] As a consequence, DDR1 and DDR2 have both been associated with metastasis during tumor progression. 6 Similarly, DDR1 overexpression has been shown to enhance lymphocyte migration. 10,11 However, the mechanism underlying the enhanced leukocyte migration remains unknown.We show that circulating human primary neutrophils solely express DDR2 and establish that DDR2 regulates the ability of neutrophils to migrate directionally toward chemoattractants in a collagen I matrix. DDR2 activation induces increased MMP secretion, leading to the generation of collagen-derived chemotactic peptides that are poised to form local gradients and enhance neutrophil persistence. Methods Isolation of human blood neutrophilsBlood was collected from anonymous healthy donors enrolled in the National Institutes of Health Blood Bank research prog...

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Section: Ddr2 Is Required For Neutrophil Migration In a 3d Collagen Lsupporting

confidence: 93%

Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices

Afonso

McCann

Kapnick

et al. 2013

Blood

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“…We have previously shown that DDR1 expression is induced in human CD4 + T cells upon their activation through the T cell receptor [18, 25]. Here, we analyzed the expression of DDR1 and DDR2 in human Th17 effector cells.…”

Section: Resultsmentioning

confidence: 99%

Discoidin domain receptor 1 promotes Th17 cell migration by activating the RhoA/ROCK/MAPK/ERK signaling pathway

et al. 2016

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Effector T cell migration through the tissue extracellular matrix (ECM) is an important step of the adaptive immune response and in the development of inflammatory diseases. However, the mechanisms involved in this process are still poorly understood. In this study, we addressed the role of a collagen receptor, the discoidin domain receptor 1 (DDR1), in the migration of Th17 cells. We showed that the vast majority of human Th17 cells express DDR1 and that silencing DDR1 or using the blocking recombinant receptor DDR1:Fc significantly reduced their motility and invasion in three-dimensional (3D) collagen. DDR1 promoted Th17 migration by activating RhoA/ROCK and MAPK/ERK signaling pathways. Interestingly, the RhoA/ROCK signaling module was required for MAPK/ERK activation. Finally, we showed that DDR1 is important for the recruitment of Th17 cells into the mouse dorsal air pouch containing the chemoattractant CCL20. Collectively, our results indicate that DDR1, via the activation of RhoA/ROCK/MAPK/ERK signaling axis, is a key pathway of effector T cell migration through collagen of perivascular tissues. As such, DDR1 can contribute to the development of Th17-dependent inflammatory diseases.

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“…[29][30][31] DDR1 has been shown to contribute to oncogenesis by disrupting normal cell-matrix communications and initiating promigratory and proinvasive programs. [32][33][34][35] In this study, we show that LMP1, but not its physiological homolog CD40, can induce the expression of DDR1 in primary human GC B cells, the presumed progenitors of HRS cells. We also show that the overexpression of DDR1 protects collagentreated lymphoma cells from cell death.…”

Section: Introductionmentioning

confidence: 96%

The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1

Cader

Vockerodt

Bose

et al. 2013

Blood

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Key Points• Expression of the EBV oncogene LMP1 in primary human germinal center B cells, upregulates DDR1, a receptor tyrosine kinase activated by collagen • Primary HRS cells overexpress DDR1, and its activation significantly increases lymphoma cell survival in vitroThe malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma are surrounded by a tumor microenvironment that is composed of a variety of cell types, as well as noncellular components such as collagen. Although HRS cells harbor oncogenic Epstein-Barr virus (EBV) in approximately 50% of cases, it is not known if the tumor microenvironment contributes to EBV-driven lymphomagenesis. We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal center B cells, the presumed progenitors of HRS cells, upregulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We also show that HRS cells intimately associated with collagen frequently overexpress DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphomaderived cell lines. The ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75 Burkitt lymphoma cells, following etoposide treatment. Conversely, knockdown of DDR1 significantly decreased the survival of collagentreated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus, suggesting that DDR1 also influences baseline survival. Our results identify a hitherto unknown function for collagen in protecting Hodgkin lymphoma cells from apoptosis and suggest an important contribution of the tumor microenvironment in promoting the oncogenic effects of EBV. (Blood. 2013;122(26):4237-4245) IntroductionHodgkin lymphoma is characterized by the presence of a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by a prominent tumor microenvironment. This microenvironment is comprised of different cell populations, including T cells, macrophages, fibroblasts, and other cell types. Interactions between HRS cells and these nonmalignant cells are mediated by various receptorligand pairs, including for example CD40-CD40L, CD30-CD30L, and RANK-RANKL which contribute to HRS cell proliferation and survival.1,2 However, the Hodgkin lymphoma microenvironment also contains a collagen-rich extracellular matrix. Although collagen is known to contribute to the pathogenesis of other cancer types, including those of the breast, pancreas, and lung, [3][4][5] it is not known if it also contributes to the malignant phenotype of HRS cells.In approximately 50% of cases, HRS cells harbor the oncogenic Epstein-Barr virus (EBV). EBV-positive HRS cells express a limited number of viral genes which include the Epstein-Barr nuclear antigen 1 (EBNA1) and the latent membrane proteins (LMP1 and -2).6-10 LMP1 is reported to be an oncogene and can constitutively activate several cell signaling pathways known to be aberrantly expressed in Hodgkin lymphoma, including nuclear factor (NF)-kB, JNK, and pho...

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Discoidin domain receptor 1 expression in activated T cells is regulated by the ERK MAP kinase signaling pathway

Cited by 40 publications

References 41 publications

Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices

Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices

Discoidin domain receptor 1 promotes Th17 cell migration by activating the RhoA/ROCK/MAPK/ERK signaling pathway

The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1

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