{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:30:22Z","timestamp":1788877822948,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pntd.0010027","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000}}],"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["107475\/Z\/15\/Z (FUGI)"],"award-info":[{"award-number":["107475\/Z\/15\/Z (FUGI)"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002745","name":"Bayerische Forschungsstiftung","doi-asserted-by":"publisher","award":["AZ-1341-18"],"award-info":[{"award-number":["AZ-1341-18"]}],"id":[{"id":"10.13039\/501100002745","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Faculty, University of W\u00fcrzburg","award":["GSLS\/KS\/270194"],"award-info":[{"award-number":["GSLS\/KS\/270194"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The metacestode larval stage of the fox-tapeworm <jats:italic>Echinococcus multilocularis<\/jats:italic> causes alveolar echinococcosis by tumour-like growth within the liver of the intermediate host. Metacestode growth and development is stimulated by host-derived cytokines such as insulin, fibroblast growth factor, and epidermal growth factor via activation of cognate receptor tyrosine kinases expressed by the parasite. Little is known, however, concerning signal transmission to the parasite nucleus and cross-reaction with other parasite signalling systems.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/Principal findings<\/jats:title>\n<jats:p>Using bioinformatic approaches, cloning, and yeast two-hybrid analyses we identified a novel mitogen-activated kinase (MAPK) cascade module that consists of <jats:italic>E<\/jats:italic>. <jats:italic>multilocularis<\/jats:italic> orthologs of the tyrosine kinase receptor interactor <jats:italic>Growth factor receptor-bound 2<\/jats:italic>, EmGrb2, the MAPK kinase kinase EmMEKK1, a novel MAPK kinase, EmMKK3, and a close homolog to c-Jun N-terminal kinase (JNK), EmMPK3. Whole mount <jats:italic>in situ<\/jats:italic> hybridization analyses indicated that EmMEKK1 and EmMPK3 are both expressed in <jats:italic>E<\/jats:italic>. <jats:italic>multilocularis<\/jats:italic> germinative (stem) cells but also in differentiated or differentiating cells. Treatment with the known JNK inhibitor SP600125 led to a significantly reduced formation of metacestode vesicles from stem cells and to a specific reduction of proliferating stem cells in mature metacestode vesicles.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions\/Significance<\/jats:title>\n<jats:p>We provide evidence for the expression of a MEKK1-JNK MAPK cascade module which, in mammals, is crucially involved in stress responses, cytoskeletal rearrangements, and apoptosis, in <jats:italic>E<\/jats:italic>. <jats:italic>multilocularis<\/jats:italic> stem cells. Inhibitor studies indicate an important role of JNK signalling in <jats:italic>E<\/jats:italic>. <jats:italic>multilocularis<\/jats:italic> stem cell survival and\/or maintenance. Our data are relevant for molecular and cellular studies into crosstalk signalling mechanisms that govern <jats:italic>Echinococcus<\/jats:italic> stem cell function and introduce the JNK signalling cascade as a possible target of chemotherapeutics against echinococcosis.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0010027","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T18:44:54Z","timestamp":1638989094000},"page":"e0010027","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["A MEKK1 \u2013 JNK mitogen activated kinase (MAPK) cascade module is active in Echinococcus multilocularis stem cells"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0595-2698","authenticated-orcid":true,"given":"Kristin","family":"Stoll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Bergmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Spiliotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-824X","authenticated-orcid":true,"given":"Klaus","family":"Brehm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"key":"pntd.0010027.ref001","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/bs.apar.2016.11.002","article-title":"Ecology and life cycle patterns of Echinococcus species","volume":"95","author":"T Romig","year":"2017","journal-title":"Adv Parasitol"},{"key":"pntd.0010027.ref002","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/2041-9139-5-10","article-title":"The unique stem cell system of the immortal larva of the human parasite Echinococcus multilocularis","volume":"5","author":"U Koziol","year":"2014","journal-title":"Evodevo"},{"key":"pntd.0010027.ref003","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/bs.apar.2016.09.001","article-title":"Echinococcus-Host interactions at cellular and molecular levels.","volume":"95","author":"K Brehm","year":"2017","journal-title":"Adv Parasitol"},{"key":"pntd.0010027.ref004","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/bs.apar.2016.07.001","article-title":"Biology and systematics of Echinococcus","volume":"95","author":"RCA Thompson","year":"2017","journal-title":"Adv Parasitol"},{"key":"pntd.0010027.ref005","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12915-016-0233-x","article-title":"Comparative analysis of Wnt expression identifies a highly conserved developmental transition in flatworms.","volume":"14","author":"U Koziol","year":"2016","journal-title":"BMC Biol"},{"key":"pntd.0010027.ref006","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.apar.2016.09.005","article-title":"Immunology of Alveolar and Cystic Echinococcosis (AE and CE).","volume":"96","author":"B Gottstein","year":"2017","journal-title":"Adv Parasitol"},{"key":"pntd.0010027.ref007","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/bs.apar.2016.09.006","article-title":"The Echinococcoses: Diagnosis, clinical management and burden of disease.","volume":"96","author":"P Kern","year":"2017","journal-title":"Adv Parasitol"},{"key":"pntd.0010027.ref008","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1741-7007-12-5","article-title":"Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development","volume":"12","author":"S Hemer","year":"2014","journal-title":"BMC Biol"},{"key":"pntd.0010027.ref009","doi-asserted-by":"crossref","first-page":"e0006959","DOI":"10.1371\/journal.pntd.0006959","article-title":"The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction","volume":"13","author":"S F\u00f6rster","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0010027.ref010","doi-asserted-by":"crossref","first-page":"e0005418","DOI":"10.1371\/journal.pntd.0005418","article-title":"u. a. 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