Journal articles: 'MET signalling'

1

Comoglio, Paolo M. "Pathway specificity for Met signalling." Nature Cell Biology 3, no. 7 (July 2001): E161—E162. http://dx.doi.org/10.1038/35083116.

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Kermorgant, S., and P. J. Parker. "c-Met Signalling: Spatio-Temporal Decisions." Cell Cycle 4, no. 3 (February 2005): 352–55. http://dx.doi.org/10.4161/cc.4.3.1519.

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Bolanos-Garcia, Victor Martin. "MET meet adaptors: Functional and structural implications in downstream signalling mediated by the Met receptor." Molecular and Cellular Biochemistry 276, no. 1-2 (August 2005): 149–57. http://dx.doi.org/10.1007/s11010-005-3696-6.

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4

Skead, Garret, and Dhirendra Govender. "Gene of the month: MET." Journal of Clinical Pathology 68, no. 6 (April 22, 2015): 405–9. http://dx.doi.org/10.1136/jclinpath-2015-203050.

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The MET receptor tyrosine kinase and its ligand hepatocyte growth factor/scatter factor (HGF/SF) are potential therapeutic targets in many human malignancies, making this pathway an important focus of molecular and cancer research. MET mutations have been detected in various tumours. In addition, many tumour types demonstrate MET and HGF/SF overexpression and amplification. The MET signal transduction cascade is complex, and manifests in a broad spectrum of mitogenic and morphogenic functions, affecting cell proliferation, migration, differentiation, morphology and survival. Cancer cells commandeer the physiological functions of this signalling axis to facilitate invasion and metastasis. Significant progress has been made in the development of agents that inhibit MET-HGF/SF signalling. In this article, we outline the key features of the MET gene, its protein product and the ligand HGF/SF, to provide an overview of this important signalling pathway and offer a summary of the relevant pathological and clinical directions of research.

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Stakenborg, Michelle, Bram Verstockt, Elisa Meroni, Gera Goverse, Veronica De Simone, Sare Verstockt, Mario Di Matteo, et al. "Neutrophilic HGF-MET Signalling Exacerbates Intestinal Inflammation." Journal of Crohn's and Colitis 14, no. 12 (June 17, 2020): 1748–58. http://dx.doi.org/10.1093/ecco-jcc/jjaa121.

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Abstract Background and Aims Ulcerative colitis [UC] is associated with excessive neutrophil infiltration and collateral tissue damage, but the link is not yet completely understood. Since c-MET receptor tyrosine kinase [MET] is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor [HGF], we aimed to identify the function of HGF-MET signalling in neutrophils in UC patients and in mice during intestinal inflammation. Methods Serum and colonic biopsies from healthy controls and UC patients with active [Mayo endoscopic subscore 2–3] and inactive [Mayo endoscopic subscore 0–1] disease were collected to assess the level of serum and colonic HGF. Disease progression and immune cell infiltration were assessed during dextran sodium sulphate [DSS] colitis in wild-type and MRP8-Cre MET-LoxP mice. Results Increased mucosal HGF expression was detected in patients with active UC, and in mice during the inflammatory phase of DSS colitis. Similarly, serum HGF was significantly increased in active UC patients and positively correlated with C-reactive protein and blood neutrophil counts. Flow cytometric analysis also demonstrated an upregulation of colonic MET+ neutrophils during DSS colitis. Genetic ablation of MET in neutrophils reduced the severity of DSS-induced colitis. Concomitantly, there was a decreased number of TH17 cells, which could be due to a decreased production of IL-1β by MET-deficient neutrophils. Conclusions These data highlight the central role of neutrophilic HGF-MET signalling in exacerbating damage during intestinal inflammation. Hence, selective blockade of this pathway in neutrophils could be considered as a novel therapeutic approach in UC.

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Jeffers, M., S. Rong, and G. F. Vande Woude. "Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signalling in human cells concomitant with induction of the urokinase proteolysis network." Molecular and Cellular Biology 16, no. 3 (March 1996): 1115–25. http://dx.doi.org/10.1128/mcb.16.3.1115.

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Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector of cells expressing the Met tyrosine kinase receptor. Although HGF/SF is synthesized by mesenchymal cells and acts predominantly on epithelial cells, we have recently demonstrated that human sarcoma cell lines often inappropriately express high levels of Met and respond mitogenically to HGF/SF. In the present report we show that HGF/SF-Met signalling in the human leiomyosarcoma cell line SK-LMS-1 enhances its in vivo tumorigenicity, an effect for which the mitogenicity of this signalling pathway is likely to play a role. In addition, we found that HGF/SF-Met signalling dramatically induces the in vitro invasiveness and in vivo metastatic potential of these cells. We have studied the molecular basis by which HGFSF-Met signalling mediates the invasive phenotype. A strong correlation has previously been demonstrated between the activation of the urokinase plasminogen activator (uPA) proteolysis network and the acquisition of the invasive-metastatic phenotype, and we show here that HGF/SF-Met signalling significantly increases the protein levels of both uPA and its cellular receptor in SK-LMS-1 cells. This results in elevated levels of cell-associated uPA and enhanced plasmin-generating ability by these cells. These studies couple HGF/SF-Met signalling to the activation of proteases that mediate dissolution of the extracellular matrix-basement membrane, and important property for cellular invasion-metastasis.

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Badreldin, W., T. Powles, L. Menard, C. Ho-Yen, and S. Kermorgant. "Understanding and targeting Met signalling in bladder cancer." Annals of Oncology 28 (September 2017): v16. http://dx.doi.org/10.1093/annonc/mdx361.055.

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Cecchi, Fabiola, Daniel C. Rabe, and Donald P. Bottaro. "Targeting the HGF/Met signalling pathway in cancer." European Journal of Cancer 46, no. 7 (May 2010): 1260–70. http://dx.doi.org/10.1016/j.ejca.2010.02.028.

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9

Thayaparan, Thivyan, James F. Spicer, and John Maher. "The role of the HGF/Met axis in mesothelioma." Biochemical Society Transactions 44, no. 2 (April 11, 2016): 363–70. http://dx.doi.org/10.1042/bst20150252.

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Malignant mesothelioma is an asbestos-related cancer that occurs most commonly in the pleural space and is incurable. Increasing evidence suggests that aberrant receptor tyrosine kinase (RTK)-directed signalling plays a key role in the pathogenesis of this cancer. In the majority of mesotheliomas, up-regulated expression or signalling by Met, the receptor for hepatocyte growth factor (HGF) can be demonstrated. Following binding of ligand, Met relays signals that promote cell survival, proliferation, movement, invasiveness, branching morphogenesis and angiogenesis. Here we describe the HGF/Met axis and review the mechanisms that lead to the aberrant activation of this signalling system in mesothelioma. We also describe the cross-talk that occurs between HGF/Met and a number of other receptors, ligands and co-receptor systems. The prevalent occurrence of HGF/Met dysregulation in patients with mesothelioma sets the scene for the investigation of pharmaceutical inhibitors of this axis. In light of the inter-relationship between HGF/Met and other ligand receptor, combinatorial targeting strategies may provide opportunities for therapeutic advancement in this challenging tumour.

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10

Baird, A. M., M. Jarzabek, L. Shiels, S. Raeppel, S. Finn, S. Cuffe, H. I. Pass, I. Schmitt-Opitz, A. T. Byrne, and S. G. Gray. "Targeting the RON/MET/TAM signalling network in mesothelioma." Annals of Oncology 28 (April 2017): ii56. http://dx.doi.org/10.1093/annonc/mdx093.003.

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Li, Guanlin, Liyang Ma, Huifen Lu, Guangming Cao, Xuan Shao, Yanlei Liu, Yu-xia Li, Ming Liu, Huixia Yang, and Yan-ling Wang. "Transactivation of Met signalling by semaphorin4D in human placenta." Journal of Hypertension 36, no. 11 (November 2018): 2215–25. http://dx.doi.org/10.1097/hjh.0000000000001808.

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12

Kemp, L. E., B. Mulloy, and E. Gherardi. "Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors." Biochemical Society Transactions 34, no. 3 (May 22, 2006): 414–17. http://dx.doi.org/10.1042/bst0340414.

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The receptor tyrosine kinase Met and its ligand HGF/SF (hepatocyte growth factor/scatter factor) are essential in the signalling pathways required for embryogenesis and tissue regeneration. Aberrant signalling of this complex is also a feature of many tumours and appears to contribute to the growth, invasiveness and metastasis of both carcinomas and sarcomas. HGF/SF, like many other angiogenic growth factors, employs heparan sulphate as co-receptor. The role of this interaction has not been completely defined but appears to be physiologically relevant. Thus the presence of heparin increases the potency of HGF/SF in experiments with cells in culture leading to elevated downstream signalling effects and, although not vital for the Met–HGF/SF interaction, heparin or heparan sulphate is essential for the activity of certain isoforms of HGF/SF, such as NK1 and NK2. Here, we summarize the progress made in understanding the interaction between heparin and heparan sulphate and NK1, NK2 and HGF/SF and we discuss their role in HGF/SF–Met signalling.

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13

Boon, E. M. J., M. Kovarikova, P. W. B. Derksen, and R. van der Neut. "MET signalling in primary colon epithelial cells leads to increased transformation irrespective of aberrant Wnt signalling." British Journal of Cancer 92, no. 6 (March 2005): 1078–83. http://dx.doi.org/10.1038/sj.bjc.6602405.

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14

Boon, EMJ, M. Kovarikova, P. Derksen, and R. van der Neut. "MET signalling in primary colon epithelial cells leads to increased transformation irrespective of aberrant Wnt signalling." European Journal of Gastroenterology & Hepatology 18, no. 1 (January 2006): A35. http://dx.doi.org/10.1097/00042737-200601000-00125.

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15

Barrow, R., L. Menard, and S. Kermorgant. "454 c-Met endosomal signalling and breast cancer cell migration." European Journal of Cancer Supplements 8, no. 5 (June 2010): 116. http://dx.doi.org/10.1016/s1359-6349(10)71255-6.

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16

Leirião, Patrícia, Sónia S. Albuquerque, Simona Corso, Geert-Jan Van Gemert, Robert W. Sauerwein, Ana Rodriguez, Silvia Giordano, and Maria M. Mota. "HGF/MET signalling protects Plasmodium-infected host cells from apoptosis." Cellular Microbiology 7, no. 4 (January 28, 2005): 603–9. http://dx.doi.org/10.1111/j.1462-5822.2004.00490.x.

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17

Zhang, Siqi, Qiaoling Song, Xueting Wang, Zhiqiang Wei, Rilei Yu, Xin Wang, and Tao Jiang. "Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways." International Journal of Molecular Sciences 20, no. 10 (May 20, 2019): 2489. http://dx.doi.org/10.3390/ijms20102489.

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c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.

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18

Genestine, M., E. Caricati, A. Fico, S. Richelme, H. Hassani, C. Sunyach, F. Lamballe, et al. "Enhanced neuronal Met signalling levels in ALS mice delay disease onset." Cell Death & Disease 2, no. 3 (March 2011): e130-e130. http://dx.doi.org/10.1038/cddis.2011.11.

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19

Chen, Shan, Jingying Li, Hong Liang, Xia-Hui Lin, Juan Li, and Huang-Hao Yang. "Light-Induced Activation of c-Met Signalling by Photocontrolled DNA Assembly." Chemistry - A European Journal 24, no. 60 (October 4, 2018): 15988–92. http://dx.doi.org/10.1002/chem.201803868.

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20

Trusolino, Livio, Andrea Bertotti, and Paolo M. Comoglio. "MET signalling: principles and functions in development, organ regeneration and cancer." Nature Reviews Molecular Cell Biology 11, no. 12 (November 23, 2010): 834–48. http://dx.doi.org/10.1038/nrm3012.

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21

Kermorgant, Stéphanie, Daniel Zicha, and Peter J. Parker. "PKC controls HGF-dependent c-Met traffic, signalling and cell migration." EMBO Journal 23, no. 19 (September 23, 2004): 3721–34. http://dx.doi.org/10.1038/sj.emboj.7600396.

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22

Gherardi, E., S. Sandin, M. V. Petoukhov, J. Finch, M. E. Youles, L. G. Ofverstedt, R. N. Miguel, et al. "Structural basis of hepatocyte growth factor/scatter factor and MET signalling." Proceedings of the National Academy of Sciences 103, no. 11 (March 6, 2006): 4046–51. http://dx.doi.org/10.1073/pnas.0509040103.

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23

Judson, M., K. Eagleson, and P. Levitt. "[P179]: Met signalling modulates cortical pyramidal cell dendritic development in vivo." International Journal of Developmental Neuroscience 24, no. 8 (November 16, 2006): 571–72. http://dx.doi.org/10.1016/j.ijdevneu.2006.09.239.

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Barrow-McGee, Rachel, and Stéphanie Kermorgant. "Met endosomal signalling: In the right place, at the right time." International Journal of Biochemistry & Cell Biology 49 (April 2014): 69–74. http://dx.doi.org/10.1016/j.biocel.2014.01.009.

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Grzelakowska-Sztabert, B., M. Dudkowska, and M. Manteuffel-Cymborowska. "Nuclear and membrane receptor-mediated signalling pathways modulate polyamine biosynthesis and interconversion." Biochemical Society Transactions 35, no. 2 (March 20, 2007): 386–90. http://dx.doi.org/10.1042/bst0350386.

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Polyamines play an important role in cell growth and differentiation, while their overproduction has potentially oncogenic consequences. Polyamine homoeostasis, a critical determinant of cell fate, is precisely tuned at the level of biosynthesis, degradation and transport. The enzymes ODC (ornithine decarboxylase), AdoMetDC (S-adenosylmethionine decarboxylase) and SSAT (spermidine/spermine N1-acetyltransferase) are critical for polyamine pool maintenance. Our experiments were designed to examine the expression of these enzymes in testosterone-induced hypertrophic and antifolate-induced hyperplastic mouse kidney, characterized by activation of AR (androgen receptor) and HGF (hepatocyte growth factor) membrane receptor c-Met respectively. The expression of these key enzymes was up-regulated by antifolate CB 3717 injury-evoked activation of HGF/c-Met signalling. In contrast, activation of the testosterone/AR pathway remarkably induced a selective increase in ODC expression without affecting other enzymes. Studies in catecholamine-depleted kidneys point to a synergistic interaction between the signalling pathways activated via cell membrane catecholamine receptors and AR, as well as c-Met. We found that this cross-talk modulated the expression of ODC and AdoMetDC, enzymes limiting polyamine biosynthesis, but not SSAT. This is in contrast with the antagonistic cross-talk between AR- and c-Met-mediated signalling which negatively regulated the expression of ODC, but affected neither AdoMetDC nor SSAT.

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Hov, Håkon, Erming Tian, Anders Waage, Magne Børset, and Anders Sundan. "IL-6 and IGF-1 Act in Synergy with HGF in Myeloma Cells by Modulating the Ras-MAPK Pathway." Blood 110, no. 11 (November 16, 2007): 4793. http://dx.doi.org/10.1182/blood.v110.11.4793.4793.

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Abstract Multiple myeloma is an incurable malignancy of plasma cells homing to the bone marrow. Myeloma cells are dependent on factors in their microenvironment for survival and expansion. HGF may be produced both by myeloma cells and the bone marrow microenvironment and serum levels of HGF are known to be a prognostic factor in multiple myeloma. Both IL-6 and IGF-1 are known growth factors for myeloma cells. In the human myeloma cell line (HMCL) INA-6, HGF alone had low effect, but together with IL-6 and IGF-1 it became a potent growth factor increasing thymidin incorporation two- to three-fold above the levels obtained with IL-6 or IGF-1 alone. Similar results were obtained for the myeloma cell line OH-2. The ANBL-6 cell line harbours an autocrine growth promoting HGF-loop. When inhibiting this autocrine HGF loop with a specific c-Met receptor tyrosine kinase inhibitor (PHA-665752), IL-6- and IGF-1-induced proliferation was reduced by 80% and 50% respectively. Thus, in the prescence of HGF, both IL-6 and IGF-1 are dependent on the HGF-receptor c-Met for full effect on cell proliferation. There seems to be two interconnected explanations for the synergy between HGF- and either IL-6- or IGF-1-signalling in myeloma cells. IL-6 and IGF-1 treatment increased the expression of c-Met in INA-6 cells Secondly, we found that HGF was unique among the three growth factors in activating both Ras and p44/42 MAPK in INA-6 cells. Also in ANBL-6 cells, IGF and IL-6 was dependent on functional c-Met signalling to fully activate this pathway. Thus, the reason for synergy between HGF and IL-6 or IGF-1 seemed to be that full activation of the Ras-Mapk pathway through Gab1 and SHP-2 by these cytokines was dependent on operating c-Met signalling. Taken together, HGF and c-Met signalling would be attractive targets for therapy of multiple myeloma.

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Landry, Mélissa, Véronique Pomerleau, and Caroline Saucier. "Non-canonical dynamic mechanisms of interaction between the p66Shc protein and Met receptor." Biochemical Journal 473, no. 11 (May 27, 2016): 1617–27. http://dx.doi.org/10.1042/bcj20160249.

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The present study identifies a novel and unexpected mechanism underscoring the diversification of p66Shc among other Shc (Src homology and collagen homology) proteins, with respect to its mode of interaction with the receptor Met and impacts on key binding effectors of Met-regulated signalling.

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Ciuculete, Diana M., Sarah Voisin, Lara Kular, Nipuni Welihinda, Jörgen Jonsson, Maja Jagodic, Jessica Mwinyi, and Helgi B. Schiöth. "Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression." Epigenetics 15, no. 6-7 (December 19, 2019): 646–63. http://dx.doi.org/10.1080/15592294.2019.1700628.

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29

Sigurdardottir, A. G., A. Winter, A. Sobkowicz, M. Fragai, D. Chirgadze, D. B. Ascher, T. L. Blundell, and E. Gherardi. "Exploring the chemical space of the lysine-binding pocket of the first kringle domain of hepatocyte growth factor/scatter factor (HGF/SF) yields a new class of inhibitors of HGF/SF-MET binding." Chemical Science 6, no. 11 (2015): 6147–57. http://dx.doi.org/10.1039/c5sc02155c.

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30

Nath, D., N. J. Williamson, R. Jarvis, and G. Murphy. "Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase." Journal of Cell Science 114, no. 6 (March 15, 2001): 1213–20. http://dx.doi.org/10.1242/jcs.114.6.1213.

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A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as ‘ectodomain shedding’, under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.

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31

Leo, Christian, Valentina Sala, Mara Morello, Amedeo Chiribiri, Ilan Riess, Daniele Mancardi, Stefano Schiaffino, Carola Ponzetto, and Tiziana Crepaldi. "Activated Met Signalling in the Developing Mouse Heart Leads to Cardiac Disease." PLoS ONE 6, no. 2 (February 9, 2011): e14675. http://dx.doi.org/10.1371/journal.pone.0014675.

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Song, Yinhong, Min Su, Pranau Panchatsharam, Debra Rood, and Laijun Lai. "c-Met signalling is required for efficient postnatal thymic regeneration and repair." Immunology 144, no. 2 (January 6, 2015): 245–53. http://dx.doi.org/10.1111/imm.12365.

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Thompson, Scott M., Danielle E. Jondal, Kim A. Butters, Bruce E. Knudsen, Jill L. Anderson, Matthew P. Stokes, Xiaoying Jia, et al. "Heat stress induced, ligand-independent MET and EGFR signalling in hepatocellular carcinoma." International Journal of Hyperthermia 34, no. 6 (November 6, 2017): 812–23. http://dx.doi.org/10.1080/02656736.2017.1385859.

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Kern, Michael André, Michael Friese, Eva Grundstrom, Laura Korhonen, Anders Wallin, Sten-Magnus Aquilonius, Håkan Askmark, Peter Schirmacher, and Dan Lindholm. "AMYOTROPHIC LATERAL SCLEROSIS: EVIDENCE FOR INTACT HEPATOCYTE GROWTH FACTOR/MET SIGNALLING AXIS." Cytokine 15, no. 6 (September 2001): 315–19. http://dx.doi.org/10.1006/cyto.2001.0941.

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Rosen, E. M., S. K. Nigam, and I. D. Goldberg. "Scatter factor and the c-met receptor: a paradigm for mesenchymal/epithelial interaction." Journal of Cell Biology 127, no. 6 (December 15, 1994): 1783–87. http://dx.doi.org/10.1083/jcb.127.6.1783.

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Epithelia and mesenchyme interact during various physiologic and pathologic processes. Scatter factor is a mesenchyme-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. Recent studies suggest that scatter factor and its receptor (c-met) mediate mesenchyme/epithelia signalling and even interconversion. In this mini-review, we will discuss how scatter factor and c-met may mediate interactions between mesenchyme and epithelia during embryogenesis, organ repair, and neoplasia.

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Aghaizu, Nozie D., Hanqing Jin, and Paul J. Whiting. "Dysregulated Wnt Signalling in the Alzheimer’s Brain." Brain Sciences 10, no. 12 (November 24, 2020): 902. http://dx.doi.org/10.3390/brainsci10120902.

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The Wnt signalling system is essential for both the developing and adult central nervous system. It regulates numerous cellular functions ranging from neurogenesis to blood brain barrier biology. Dysregulated Wnt signalling can thus have significant consequences for normal brain function, which is becoming increasingly clear in Alzheimer’s disease (AD), an age-related neurodegenerative disorder that is the most prevalent form of dementia. AD exhibits a range of pathophysiological manifestations including aberrant amyloid precursor protein processing, tau pathology, synapse loss, neuroinflammation and blood brain barrier breakdown, which have been associated to a greater or lesser degree with abnormal Wnt signalling. Here we provide a comprehensive overview of the role of Wnt signalling in the CNS, and the research that implicates dysregulated Wnt signalling in the ageing brain and in AD pathogenesis. We also discuss the opportunities for therapeutic intervention in AD via modulation of the Wnt signalling pathway, and highlight some of the challenges and the gaps in our current understanding that need to be met to enable that goal.

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Ettl, Tobias, Sandra Viale-Bouroncle, Matthias G. Hautmann, Martin Gosau, Oliver Kölbl, Torsten E. Reichert, and Christian Morsczeck. "AKT and MET signalling mediates antiapoptotic radioresistance in head neck cancer cell lines." Oral Oncology 51, no. 2 (February 2015): 158–63. http://dx.doi.org/10.1016/j.oraloncology.2014.11.005.

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Muller, P. A. J., A. G. Trinidad, P. Timpson, J. P. Morton, S. Zanivan, P. V. E. van den Berghe, C. Nixon, et al. "Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion." Oncogene 32, no. 10 (May 14, 2012): 1252–65. http://dx.doi.org/10.1038/onc.2012.148.

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Szturz, P., E. Raymond, C. Abitbol, S. Albert, A. de Gramont, and S. Faivre. "Understanding c-MET signalling in squamous cell carcinoma of the head & neck." Critical Reviews in Oncology/Hematology 111 (March 2017): 39–51. http://dx.doi.org/10.1016/j.critrevonc.2017.01.004.

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40

Umitsu, Masataka, Katsuya Sakai, Keiko Tamura-Kawakami, Kunio Matsumoto, and Junichi Takagi. "The constitutive high-affinity Met-binding site in the kringle domain is dispensable for the signalling activity of hepatocyte growth factor." Journal of Biochemistry 167, no. 6 (January 14, 2020): 577–86. http://dx.doi.org/10.1093/jb/mvaa006.

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Abstract Activation of a tyrosine kinase receptor Met by hepatocyte growth factor (HGF) requires binding of proteolytically activated, two-chain (tc) HGF, but the biochemical detail of this ligand–receptor interaction specificity remains elusive because biologically inactive single chain (sc) HGF can also bind to Met with high affinity. We found that this proteolysis-independent Met binding can be eliminated by mutagenesis introduced in the kringle domain without losing the ability to bind and activate cellular Met receptor after proteolytic activation, arguing against this site’s involvement in the physiological signalling. This non-signal producing Met–HGF interaction can also be eliminated by addition of a heparin mimetic sucrose octasulphate (SOS). By including SOS in the running buffer, we succeeded in detecting cleavage-dependent tcHGF–Met complex formation by size exclusion chromatography.

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DUDKOWSKA, Magdalena, Agnieszka STACHURSKA, Wanda CHMURZYŃSKA, Barbara GRZELAKOWSKA-SZTABERT, and Małgorzata MANTEUFFEL-CYMBOROWSKA. "Cross-talk between steroid-receptor-mediated and cell-membrane-receptor-mediated signalling pathways results in the in vivo modulation of c-Met and ornithine decarboxylase gene expression in mouse kidney." Biochemical Journal 353, no. 2 (January 8, 2001): 317–23. http://dx.doi.org/10.1042/bj3530317.

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The cross-talk in vivo between two signalling pathways activated by testosterone via intracellular androgen receptor, and induced by damage to renal tubules evoked by anti-folate [N10-propargyl-5,8-dideazafolic acid (CB 3717)] or folate is reported. We show that CB 3717/folate induces the expression of the hepatocyte growth factor (HGF)/c-Met signalling system in injured kidneys in which a significant, but transient, elevation of the HGF mRNA level occurs. It is followed by a severalfold increase in the c-Met transmembrane receptor message that persists for up to 24h. The c-Met expression is also positively controlled by testosterone, which induces a significant increase in its mRNA level that is abolished by an anti-androgen, casodex. However, when testosterone and anti-folate/folate are administered sequentially, a substantial (3.5Ő4.0-fold) decrease in the increase of c-Met expression caused by CB 3717/folate alone occurs. Similarly, testosterone-induced ornithine decarboxylase (ODC) mRNA level and activity are decreased 2.8Ő7.7-fold when the androgen is applied together with CB 3717. Antagonism between these pathways is also visible under physiological conditions in the kidneys of male mice in which, owing to elevated endogenous testosterone levels, neither the ODC activity nor the mRNA level is induced by anti-folate/folate, whereas the c-Met message response to these drugs is significantly decreased. Our results document a substantial negative regulation of c-Met and ODC gene expression as a result of the cross-talk between testosterone-activated and HGF-activated pathways and suggest a sex-differentiated response to injury of mouse kidneys.

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Pettit, E. J., and M. B. Hallett. "Early Ca2+ signalling events in neutrophils detected by rapid confocal laser scanning." Biochemical Journal 310, no. 2 (September 1, 1995): 445–48. http://dx.doi.org/10.1042/bj3100445.

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Characterization of early Ca2+ signalling events is crucial for understanding the mechanisms which lead to cell signalling. Rapid confocal laser scanning of Fluo3-loaded neutrophils was used to provide spatially resolved cytosolic free Ca2+ measurements from neutrophils stimulated with formyl-Met-Leu-Phe with a time resolution of 12.5 ms. Heterogeneity of the magnitude and timing of the response was observed between individual neutrophils. There was always a delay between contact with the stimulus and onset of the Ca2+ signal, with a minimum delay of 75 ms and a mean delay of 530 ms (n = 150). There was no delay in the cytosolic free Ca2+ rise induced by ionomycin. The earliest Ca2+ event detected following stimulation with formyl-Met-Leu-Phe (1 microM) was a localized rise in cytosolic free Ca2+ from a location within the cell, pointing to Ca2+ store release as the initial event for triggering whole-cell Ca2+ changes in these cells.

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Webb, C. P., K. Lane, A. P. Dawson, G. F. Vande Woude, and R. M. Warn. "C-Met signalling in an HGF/SF-insensitive variant MDCK cell line with constitutive motile/invasive behaviour." Journal of Cell Science 109, no. 9 (September 1, 1996): 2371–81. http://dx.doi.org/10.1242/jcs.109.9.2371.

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The Met protein is a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF), a multifunctional growth factor with mitogenic, motogenic and morphogenic properties. A morphologically altered variant of the MDCK cell line, MDCK-1, spontaneously exhibits a number of features associated with a partial HGF/SF-Met induced phenotype (less adhesive colonies in culture, enhanced invasion and motility, nascent tubule formation), but paradoxically does not respond to HGF/SF treatment. Although the overall cell surface expression and distribution of Met were found to be similar in parental MDCK cells and the MDCK-1 cell line, p145met autophosphorylation (+/ HGF/SF) was significantly reduced in MDCK-1 cells in vitro and in vivo when compared with parental MDCK cells. In contrast, EGF induced cell proliferation and EGF receptor autophosphorylation to similar levels in both cell lines. The basal levels of protein tyrosine phosphorylation were higher in MDCK-1 cells when compared with parental MDCK cells, including that of two prominent proteins with molecular masses of approximately 185 kDa and 220 kDa. Moreover, both p185 and p220 are present and tyrosine phosphorylated in Met immunoprecipitates from MDCK-1 cells (+/-HGF/SF), but not parental MDCK cells. In addition, Met immunocomplexes from MDCK-1 cells exhibited an approximately 3-fold increased tyrosine kinase activity in vitro when compared with MDCK cells, correlating with the higher basal levels of total phosphotyrosine. Treatment of MDCK-1 cells with the tyrosine kinase inhibitor herbimycin A reverted the cell phenotype to a more MDCK-like morphology in culture, with a concomitant reduction in the tyrosine phosphorylation predominantly of p220. Taken together these data suggest that aberrations in Met activity and associated signalling render MDCK-1 cells insensitive to HGF/SF, and may also mediate alterations in MDCK-1 cell behaviour.

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Ma, Patrick C., Lara Costa, Angelo Cardoso, Takashi Kijima, Priya Madhawala, Dac Nuygen, Lily Zhong, Martin Sattler, Gautam Maulik, and Ravi Salgia. "P-327 Role of HGF/c-Met signalling in lung cancer tumor-stromal interactions." Lung Cancer 41 (August 2003): S174. http://dx.doi.org/10.1016/s0169-5002(03)92295-1.

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Kaldenbach, Michaela, Arne Giebeler, Darjus F. Tschaharganeh, Stephanie Erschfeld, Hermann E. Wasmuth, Laurent Dolle, Juergen Floege, Christian Trautwein, and Konrad L. Streetz. "Hepatocyte growth factor/c-Met signalling is important for the selection of transplanted hepatocytes." Gut 61, no. 8 (January 27, 2012): 1209–18. http://dx.doi.org/10.1136/gutjnl-2011-301345.

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Hosonuma, M., T. Isozaki, H. Furuya, Y. Yamazaki, Y. Ikari, S. Nishimi, S. Ishii, et al. "AB0065 HGF/C-MET SIGNALING PROMOTE ANGIOGENESIS THROUGH CXCL16 IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1063.2–1063. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3491.

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Background:Hepatocyte growth factor (HGF) binds to the receptor tyrosine kinase c-Met and is a multifunctional cytokine that promotes processes such as cell proliferation, survival, differentiation, migration and angiogenesis [1]. We previously reported that HGF is produced by inflammation in the RA synovium, and activates monocyte migration to the synovium and promotes bone destruction through its own chemotactic effect and enhanced chemokine production in the synovium [2].Objectives:Therefore, we next aimed to determine the role of HGF in RA angiogenesis.Methods:The expression of HGF / c-Met in the serum and synovial tissues (STs) of RA patients and controls and human umbilical vein endothelial cells (HUVECs) was evaluated by ELISA and immunostaining. The effect of HGF/c-Met signaling on the promotion of CXCL16 production from HUVECs and RA fibroblast-like synoviocytes (FLSs) was determined by ELISA. To examine the role of HGF in angiogenesis, we performed in vitro Matrigel assays using HUVECs treated with HGF.Results:HGF in serum in treatment-naive RA patients was significantly higher than that in controls and HGF in serum in treatment-resistant RA showed a significant positive correlation with CXCL16. c-Met were expressed on vascular endothelial cells of RA STs and HUVECs. Stimulation of HUVECs with HGF dose-dependently increased CXCL16 production. c-Met signal inhibition by SU11274 suppressed TNF-α stimulation-enhanced CXCL16 production by RA FLSs in a dose-dependent manner. Furthermore, HGF induced HUVEC tube formation by 1.8-fold.Conclusion:HGF is produced by inflammation in the RA synovium, and activates angiogenesis through its own potent angiogenic effect and enhanced production of CXCL16 in the synovium. These results indicate that a strategy targeting c-Met signalling may be important for resolving treatment-resistant RA.References:[1]Nakamura T, Nishizawa T, Hagiya M, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989 Nov 23;342(6248):440-3.[2]Hosonuma M, Sakai N, Furuya H, et al. Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis. Rheumatology (Oxford). 2021 Jan 5;60(1):408-419.Disclosure of Interests:None declared

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Liu, Yuning, Zhen Yang, Dongbo Kong, Youzhi Zhang, Wei Yu, and Wenliang Zha. "Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway." Oxidative Medicine and Cellular Longevity 2019 (November 28, 2019): 1–14. http://dx.doi.org/10.1155/2019/5681701.

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Approximately 90% of male diabetes mellitus patients have varying degrees of testicular dysfunction. The molecular mechanism underlying diabetes-induced testicular damage has not been thoroughly elucidated. In this research, we sought to determine the influence of metformin (Met) on diabetes-induced testicular injury and the mechanism involved with a focus on testicular dysfunction, apoptosis, autophagy, and prokineticin 2 (PK2) signalling. In our study, C57BL/6J mice were randomly divided into the normal control group, the diabetes group, and the Met-treated group. Streptozotocin (50 mg·kg-1·d-1) was injected intraperitoneally into the mice for 5 days in a row to induce type 1 diabetes, which was diagnosed by a blood glucose level≥16.7 mmol/L after 7 days. The experimental animals were orally administered Met (250 mg·kg-1·d-1) for 16 weeks. Properties of testicular function, including sperm motility and the total concentration of epididymal sperm, were assessed. Changes in testicular structure, such as the blood-testis barrier, histological pathology, and organelles, were observed. The levels of apoptosis and expression of related proteins, such as Bax and Bcl-2, were measured. Moreover, autophagy-related proteins, including Beclin-1, p62, and LC3B, as well as the PK2/PKR pathway, which consists of PK2, PKR1, PKR2, AKT, and GSK3β, were analysed. Upon the induction of diabetes, reproductive capacity was significantly impaired and a disordered arrangement of testicular seminiferous tubules and destroyed organelles in spermatogenic cells was observed. Met administration preserved testicular function and structure. In addition, in mice with diabetes, the levels of PK2, PKR2, p-Akt, and p-GSK3β were significantly decreased at different times, while that of PKR1 was markedly increased, and these changes were normalized by Met. Furthermore, diabetic mice showed increased apoptosis and decreased autophagy in the testes, the effects of which were nullified by Met. These results suggest that Met rescues diabetes-induced testicular damage by attenuating apoptosis and inducing autophagy. This effect is likely mediated by the PK2/PKR/AKT/GSK3β signalling pathway.

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Hosonuma, Masahiro, Nobuhiro Sakai, Hidekazu Furuya, Yutaro Kurotaki, Yurie Sato, Kazuaki Handa, Yusuke Dodo, et al. "Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis." Rheumatology 60, no. 1 (August 8, 2020): 408–19. http://dx.doi.org/10.1093/rheumatology/keaa310.

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Abstract Objectives To determine the expression of hepatocyte growth factor (HGF) in RA biological fluids, the role of HGF in monocyte migration and the therapeutic effect of the c-Met inhibitor savolitinib in an arthritis model mice. Methods HGF/c-Met expression in serum, SF and synovial tissues (STs) obtained from RA patients and controls, as well as RA fibroblast-like synoviocytes (FLSs), was evaluated by ELISA and immunostaining. To determine the function of HGF in RA SF, we preincubated RA SF with a neutralizing anti-HGF antibody and measured the chemotactic ability of a human acute monocytic leukaemia cell line (THP-1). Additionally, examinations were conducted of SKG mice treated with savolitinib for 4 weeks. Results HGF levels in serum from RA patients were significantly higher than those in the controls and were decreased by drug treatment for 24 weeks. Additionally, the HGF level in SF from RA patients was higher than that in SF from OA patients. HGF and c-Met expression was also noted in RA STs. Stimulation of RA FLSs with TNF-α increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition suppressed production of fractalkine/CX3CL1 and macrophage inflammatory protein-1α/CCL3. When HGF was removed by immunoprecipitation, migration of THP-1 in RA SF was suppressed. In SKG mice, savolitinib significantly suppressed ankle bone destruction on µCT, with an associated reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. Conclusion HGF produced by inflammation in synovium of RA patients activates monocyte migration to synovium and promotes bone destruction via a chemotactic effect and enhanced chemokine production.

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Cristóbal, Ion, Jaime Rubio, Andrea Santos, Melani Luque, Marta Sanz‐Alvarez, Federico Rojo, and Jesús García‐Foncillas. "Therapeutic implications of the PP2A/MET signalling axis in doxorubicin‐induced cardiotoxicity and antitumour properties." British Journal of Pharmacology 177, no. 16 (June 14, 2020): 3850–51. http://dx.doi.org/10.1111/bph.15130.

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Zhou, Qiang, Tongzhou Hu, and Yuan Xu. "Anticancer potential of TUG1 knockdown in cisplatin-resistant osteosarcoma through inhibition of MET/Akt signalling." Journal of Drug Targeting 28, no. 2 (July 24, 2019): 204–11. http://dx.doi.org/10.1080/1061186x.2019.1644651.

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Journal articles on the topic 'MET signalling'

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