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Birgit Leitinger - One of the best experts on this subject based on the ideXlab platform.

  • Two-step release of kinase autoinhibition in Discoidin Domain receptor 1
    Proceedings of the National Academy of Sciences of the United States of America, 2020
    Co-Authors: Douglas Sammon, Erhard Hohenester, Birgit Leitinger
    Abstract:

    Discoidin Domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase with important functions in organogenesis and tissue homeostasis. Aberrant DDR1 activity contributes to the progression of human diseases, including fibrosis and cancer. How DDR1 activity is regulated is poorly understood. We investigated the function of the long intracellular juxtamembrane (JM) region of human DDR1 and found that the kinase-proximal segment, JM4, is an important regulator of kinase activity. Crystal structure analysis revealed that JM4 forms a hairpin that penetrates the kinase active site, reinforcing autoinhibition by the activation loop. Using in vitro enzymology with soluble kinase constructs, we established that release from autoinhibition occurs in two distinct steps: rapid autophosphorylation of the JM4 tyrosines, Tyr569 and Tyr586, followed by slower autophosphorylation of activation loop tyrosines. Mutation of JM4 tyrosines abolished collagen-induced DDR1 activation in cells. The insights may be used to develop allosteric, DDR1-specific, kinase inhibitors.

  • interaction of Discoidin Domain receptor 1 with a 14 3 3 beclin 1 akt1 complex modulates glioblastoma therapy sensitivity
    Cell Reports, 2019
    Co-Authors: Anne Vehlow, Erik Klapproth, Sha Jin, Ricarda Hannen, Maria Hauswald, Jörg-walter Bartsch, Christopher Nimsky, Achim Temme, Birgit Leitinger
    Abstract:

    Summary Glioblastoma (GBM) is highly refractory to therapy and associated with poor clinical outcome. Here, we reveal a critical function of the promitotic and adhesion-mediating Discoidin Domain receptor 1 (DDR1) in modulating GBM therapy resistance. In GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We demonstrate that inhibition of DDR1 in combination with radiochemotherapy with temozolomide in GBM models enhances sensitivity and prolongs survival superior to conventional therapy. We identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1 to be required for prosurvival Akt and mTOR signaling and regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance and provide a rationale target for the development of therapy-sensitizing agents.

  • Interaction of Discoidin Domain Receptor 1 with a 14-3-3-Beclin-1-Akt1 Complex Modulates Glioblastoma Therapy Sensitivity
    Elsevier, 2019
    Co-Authors: Anne Vehlow, Birgit Leitinger, Erik Klapproth, Sha Jin, Ricarda Hannen, Maria Hauswald, Jörg-walter Bartsch, Christopher Nimsky, Achim Temme, Nils Cordes
    Abstract:

    Summary: Glioblastoma (GBM) is highly refractory to therapy and associated with poor clinical outcome. Here, we reveal a critical function of the promitotic and adhesion-mediating Discoidin Domain receptor 1 (DDR1) in modulating GBM therapy resistance. In GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We demonstrate that inhibition of DDR1 in combination with radiochemotherapy with temozolomide in GBM models enhances sensitivity and prolongs survival superior to conventional therapy. We identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1 to be required for prosurvival Akt and mTOR signaling and regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance and provide a rationale target for the development of therapy-sensitizing agents. : Vehlow and Klapproth et al. identify the Discoidin Domain receptor 1 (DDR1) to assemble with a 14-3-3-Beclin-1-Akt1 protein complex, which mediates prosurvival Akt and mTOR signaling for regulating autophagy-associated glioblastoma cell sensitivity to therapy. Keywords: Discoidin Domain receptor 1, glioblastoma, radiochemotherapy, therapy resistance, autophagy, 14-3-3, Beclin-1, Akt1, mTOR, GBM stem-like cells, orthotopic GBM mouse mode

  • adam10 controls collagen signaling and cell migration on collagen by shedding the ectoDomain of Discoidin Domain receptor 1 ddr1
    Molecular Biology of the Cell, 2015
    Co-Authors: Yasuyuki Shitomi, Birgit Leitinger, Ida B Thogersen, Jan J Enghild, Yoshifumi Itoh
    Abstract:

    Discoidin Domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and transmits signals from various collagens in epithelial cells. However, how DDR1–dependent signaling is regulated has not been understood. Here we report that collagen binding induces ADAM10-dependent ectoDomain shedding of DDR1. DDR1 shedding is not a result of an activation of its signaling pathway, since DDR1 mutants defective in signaling were shed in an efficient manner. DDR1 and ADAM10 were found to be in a complex on the cell surface, but shedding did not occur unless collagen bound to DDR1. Using a shedding-resistant DDR1 mutant, we found that ADAM10-dependent DDR1 shedding regulates the half-life of collagen-induced phosphorylation of the receptor. Our data also revealed that ADAM10 plays an important role in regulating DDR1-mediated cell adhesion to achieve efficient cell migration on collagen matrices.

  • Discoidin Domain receptor 1 controls linear invadosome formation via a cdc42 tuba pathway
    Journal of Cell Biology, 2014
    Co-Authors: Birgit Leitinger, Amelie Juin, Julie Di Martino, Elodie Henriet, Annesophie Gary, Lisa Paysan
    Abstract:

    Accumulation of type I collagen fibrils in tumors is associated with an increased risk of metastasis. Invadosomes are F-actin structures able to degrade the extracellular matrix. We previously found that collagen I fibrils induced the formation of peculiar linear invadosomes in an unexpected integrin-independent manner. Here, we show that Discoidin Domain Receptor 1 (DDR1), a collagen receptor overexpressed in cancer, colocalizes with linear invadosomes in tumor cells and is required for their formation and matrix degradation ability. Unexpectedly, DDR1 kinase activity is not required for invadosome formation or activity, nor is Src tyrosine kinase. We show that the RhoGTPase Cdc42 is activated on collagen in a DDR1-dependent manner. Cdc42 and its specific guanine nucleotide-exchange factor (GEF), Tuba, localize to linear invadosomes, and both are required for linear invadosome formation. Finally, DDR1 depletion blocked cell invasion in a collagen gel. Altogether, our data uncover an important role for DDR1, acting through Tuba and Cdc42, in proteolysis-based cell invasion in a collagen-rich environment.

Dongsheng Zhu - One of the best experts on this subject based on the ideXlab platform.

Alex N Bullock - One of the best experts on this subject based on the ideXlab platform.

  • 2 amino 2 3 dihydro 1h indene 5 carboxamide based Discoidin Domain receptor 1 ddr1 inhibitors design synthesis and in vivo antipancreatic cancer efficacy
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Dongsheng Zhu, Huocong Huang, Daniel M Pinkas, Jinfeng Luo, Debolina Ganguly, Alice E Fox, Emily N Arner, Qiuping Xiang, Alex N Bullock
    Abstract:

    A series of 2-amino-2,3-dihydro-1H-indene-5-carboxamides were designed and synthesized as new selective Discoidin Domain receptor 1 (DDR1) inhibitors. One of the representative compounds, 7f, bound with DDR1 with a Kd value of 5.9 nM and suppressed the kinase activity with an half-maximal (50%) inhibitory concentration value of 14.9 nM. 7f potently inhibited collagen-induced DDR1 signaling and epithelial-mesenchymal transition, dose-dependently suppressed colony formation of pancreatic cancer cells, and exhibited promising in vivo therapeutic efficacy in orthotopic mouse models of pancreatic cancer.

  • tetrahydroisoquinoline 7 carboxamide derivatives as new selective Discoidin Domain receptor 1 ddr1 inhibitors
    ACS Medicinal Chemistry Letters, 2017
    Co-Authors: Zhen Wang, Yali Zhang, S G Bartual, Tingting Xu, Wenting Du, Zhengchao Tu, Rolf A Brekken, Alex N Bullock, Guang Liang
    Abstract:

    Acute lung injury (ALI) is a deadly symptom for serious lung inflammation. Discoidin Domain Receptor 1 (DDR1) is a new potential target for anti-inflammatory drug discovery. A new selective tetrahydroisoquinoline-7-carboxamide based DDR1 inhibitor 7ae was discovered to tightly bind the DDR1 protein and potently inhibit its kinase function with a Kd value of 2.2 nM and an IC50 value of 6.6 nM, respectively. The compound dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) release in mouse primary peritoneal macrophages (MPMs). In addition, 7ae also exhibited promising in vivo anti-inflammatory effects in a LPS-induced mouse ALI model. To the best of our knowledge, this is the first “proof of concept” investigation on the potential application of a small molecule DDR1 inhibitor to treat ALI.

Wolfgang Vogel - One of the best experts on this subject based on the ideXlab platform.

  • expression and mutation analysis of the Discoidin Domain receptors 1 and 2 in non small cell lung carcinoma
    British Journal of Cancer, 2007
    Co-Authors: Caroline E Ford, Tommy Andersson, Mingsound Tsao, Wolfgang Vogel
    Abstract:

    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=0.0005) and DDR2 significantly downregulated to an equivalent extent (P=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=0.22–0.83, P=0.014) and disease-free survival (HR=0.56, 95% CI=0.33–0.94, P=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.

  • Discoidin Domain receptor 1 deficient mice are resistant to bleomycin induced lung fibrosis
    American Journal of Respiratory and Critical Care Medicine, 2006
    Co-Authors: Carmel Avivigreen, Mayank Singal, Wolfgang Vogel
    Abstract:

    Rationale: Discoidin Domain receptor 1 (DDR1) is a tyrosine kinase activated by native collagens. Based on previous findings showing increased DDR1 expression in bronchoalveolar lavage cells from patients with idiopathic pulmonary fibrosis, we hypothesized that DDR1 mediates disease progression after lung injury.Objectives: To investigate the inflammatory and fibrotic responses of DDR1 knockout and wild-type mice to bleomycin-induced lung injury.Methods: Age- and sex-matched DDR1 knockout and wild-type C57BL/6 mice received a single intratracheal instillation of 2 U/kg bleomycin or saline, respectively. After 2 wk, lung inflammation and fibrosis were assessed using immunohistochemistry, real-time polymerase chain reaction, TUNEL assay, ELISA, fluorescence-activated cell sorting, and Western blot analysis.Measurements and Main Results: Compared with wild-type animals, DDR1-null mice were largely protected against bleomycin-induced injury. Bleomycin-induced increases in collagen protein levels and tenascin-...

  • sensing extracellular matrix an update on Discoidin Domain receptor function
    Cellular Signalling, 2006
    Co-Authors: Wolfgang Vogel, Rahim Abdulhussein, Caroline E Ford
    Abstract:

    Discoidin Domain Receptors (DDRs) have recently emerged as non-integrin-type receptors for collagen. The two mammalian gene products Discoidin Domain Receptor 1 and -2 constitute a subfamily of tyrosine kinase receptors that are selectively expressed in a number of different cell types and organs. Upon collagen activation, DDRs regulate cell adhesion, proliferation and extracellular matrix remodeling. Here we review the various signaling pathways and cellular responses evoked by activated DDRs. Additionally, we give an overview of the more recent advances in understanding the role of DDRs in various human diseases, in particular during tumor progression, atherosclerosis, inflammation and tissue fibrosis. Furthermore, we discuss potential roles of genes homologous to mammalian DDRs identified in flies, worms and sponges. We show that the structural organization of these DDR-related genes is highly conserved throughout evolution suggesting that invertebrate DDRs may also function as receptors for collagen. By highlighting current questions about these unusual collagen receptors, we hope to attract new research on DDRs from a variety of different fields.

  • expression and signaling activity of wnt 5a Discoidin Domain receptor 1 and syk plays distinct but decisive roles in breast cancer patient survival
    Clinical Cancer Research, 2005
    Co-Authors: Janna Dejmek, Karin Leandersson, Stefan O Emdin, Jonas Manjer, Anders Bjartell, Wolfgang Vogel, Göran Landberg, Tommy Andersson
    Abstract:

    Expression and signaling activity of Wnt-5a/Discoidin Domain receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival.

  • tyrosine kinase activity of Discoidin Domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression
    Circulation Research, 2002
    Co-Authors: Wolfgang Vogel, Michelle P Bendeck
    Abstract:

    Smooth muscle cell (SMC) interactions with collagen mediate cell migration during the pathogenesis of atherosclerosis and restenosis. Discoidin Domain receptors (DDRs) have been identified as novel collagen receptors. We used aortic SMCs from wild-type and DDR1−/− mice to evaluate the function of the DDR1 in regulating migration. DDR1−/− SMCs exhibited impaired attachment to and migration toward a type I collagen substrate. Matrix metalloproteinase-2 (MMP-2) and MMP-9 activities were concomitantly reduced in these cells. Transfection of a full-length cDNA for DDR1b rescued these deficits, whereas kinase-dead mutants of DDR1 restored attachment but not migration and MMP production. These results suggest that active DDR1 kinase is a central mediator of SMC migration.

Anne Vehlow - One of the best experts on this subject based on the ideXlab platform.

  • ddr1 Discoidin Domain receptor tyrosine kinase 1 drives glioblastoma therapy resistance by modulating autophagy
    Autophagy, 2019
    Co-Authors: Anne Vehlow, Nils Cordes
    Abstract:

    Therapy resistance of tumor cells is a major obstacle for efficient anticancer treatment approaches and has been attributed to tumor heterogeneity as well as genetic and epigenetic changes. Accumulating evidence demonstrates that tumor cell adhesion to the extracellular matrix acts as an additional essential factor conferring tumor cell resistance to both radio- and chemotherapeutic intervention. Our recent study demonstrates that DDR1 (Discoidin Domain receptor tyrosine kinase 1) elicits therapy resistance of glioblastoma multiforme (GBM) stem-like and bulk cells through its adhesion to extracellular matrix and the subsequent modulation of macroautophagy/autophagy. Mechanistically, DDR1 associates with a YWHA/14-3-3-BECN1-AKT1 multiprotein complex favoring pro-survival/anti-autophagic and resistance-mediating AKT-MTOR signaling. In turn, inhibition of DDR1 sensitizes glioblastoma cells to radio- and chemotherapy by inducing autophagy. Collectively, our study suggests that DDR1 may be a potential target for sensitizing glioblastoma cells to combination therapies through its efficient induction of autophagic cell death. Abbreviations: AKT1: AKT serine/threonine kinase 1; ATG14: autophagy related 14; BECN1: Beclin 1; DDR1: Discoidin Domain receptor tyrosine kinase 1; ECM: extracellular matrix; GBM: glioblastoma multiforme; MTOR: mechanistic target of rapamycin kinase; PDGFR: platelet derived growth factor receptor; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; RPTOR: regulatory associated protein of MTOR complex 1; RICTOR: RPTOR independent companion of MTOR complex 2.

  • interaction of Discoidin Domain receptor 1 with a 14 3 3 beclin 1 akt1 complex modulates glioblastoma therapy sensitivity
    Cell Reports, 2019
    Co-Authors: Anne Vehlow, Erik Klapproth, Sha Jin, Ricarda Hannen, Maria Hauswald, Jörg-walter Bartsch, Christopher Nimsky, Achim Temme, Birgit Leitinger
    Abstract:

    Summary Glioblastoma (GBM) is highly refractory to therapy and associated with poor clinical outcome. Here, we reveal a critical function of the promitotic and adhesion-mediating Discoidin Domain receptor 1 (DDR1) in modulating GBM therapy resistance. In GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We demonstrate that inhibition of DDR1 in combination with radiochemotherapy with temozolomide in GBM models enhances sensitivity and prolongs survival superior to conventional therapy. We identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1 to be required for prosurvival Akt and mTOR signaling and regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance and provide a rationale target for the development of therapy-sensitizing agents.

  • Interaction of Discoidin Domain Receptor 1 with a 14-3-3-Beclin-1-Akt1 Complex Modulates Glioblastoma Therapy Sensitivity
    Elsevier, 2019
    Co-Authors: Anne Vehlow, Birgit Leitinger, Erik Klapproth, Sha Jin, Ricarda Hannen, Maria Hauswald, Jörg-walter Bartsch, Christopher Nimsky, Achim Temme, Nils Cordes
    Abstract:

    Summary: Glioblastoma (GBM) is highly refractory to therapy and associated with poor clinical outcome. Here, we reveal a critical function of the promitotic and adhesion-mediating Discoidin Domain receptor 1 (DDR1) in modulating GBM therapy resistance. In GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We demonstrate that inhibition of DDR1 in combination with radiochemotherapy with temozolomide in GBM models enhances sensitivity and prolongs survival superior to conventional therapy. We identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1 to be required for prosurvival Akt and mTOR signaling and regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance and provide a rationale target for the development of therapy-sensitizing agents. : Vehlow and Klapproth et al. identify the Discoidin Domain receptor 1 (DDR1) to assemble with a 14-3-3-Beclin-1-Akt1 protein complex, which mediates prosurvival Akt and mTOR signaling for regulating autophagy-associated glioblastoma cell sensitivity to therapy. Keywords: Discoidin Domain receptor 1, glioblastoma, radiochemotherapy, therapy resistance, autophagy, 14-3-3, Beclin-1, Akt1, mTOR, GBM stem-like cells, orthotopic GBM mouse mode