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dc.contributor.authorAmmoun, Sylwia
dc.contributor.authorProvenzano, L
dc.contributor.authorZhou, L
dc.contributor.authorBarczyk, M
dc.contributor.authorEvans, K
dc.contributor.authorHilton, DA
dc.contributor.authorHafizi, S
dc.contributor.authorHanemann, Clemens Oliver
dc.date.accessioned2018-10-25T10:31:34Z
dc.date.available2018-10-25T10:31:34Z
dc.date.issued2014-01-16
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.urihttp://hdl.handle.net/10026.1/12641
dc.description.abstract

TAM family receptor tyrosine kinases comprising Tyro3 (Sky), Axl, and Mer are overexpressed in some cancers, correlate with multidrug resistance and contribute to tumourigenesis by regulating invasion, angiogenesis, cell survival and tumour growth. Mutations in the gene coding for a tumour suppressor merlin cause development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas occurring spontaneously or as part of a hereditary disease neurofibromatosis type 2. The benign character of merlin-deficient tumours makes them less responsive to chemotherapy. We previously showed that, amongst other growth factor receptors, TAM family receptors (Tyro3, Axl and Mer) are significantly overexpressed in schwannoma tissues. As Axl is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1, previously shown to be a key regulator in schwannoma growth we hypothesized that Axl is a good target to study in merlin-deficient tumours. Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma. Here, we demonstrated strong overexpression and activation of Axl receptor as well as its ligand Gas6 in human schwannoma primary cells compared to normal Schwann cells. We show that Gas6 is mitogenic and increases schwannoma cell-matrix adhesion and survival acting via Axl in schwannoma cells. Stimulation of the Gas6/Axl signalling pathway recruits Src, focal adhesion kinase (FAK) and NFκB. We showed that NFκB mediates Gas6/Axl-mediated overexpression of survivin, cyclin D1 and FAK, leading to enhanced survival, cell-matrix adhesion and proliferation of schwannoma. We conclude that Axl/FAK/Src/NFκB pathway is relevant in merlin-deficient tumours and is a potential therapeutic target for schwannoma and other merlin-deficient tumours.

dc.format.extent336-346
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.subjectGas6/Axl
dc.subjectNF kappa B
dc.subjectmerlin
dc.subjectproliferation/adhesion/survival
dc.subjectschwannoma
dc.titleAxl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival
dc.typejournal-article
dc.typeJournal Article
dc.typeResearch Support, Non-U.S. Gov't
plymouth.author-urlhttps://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000330214000008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008
plymouth.issue3
plymouth.volume33
plymouth.publication-statusPublished
plymouth.journalOncogene
dc.identifier.doi10.1038/onc.2012.587
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Research Groups
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
plymouth.organisational-group/Plymouth/Users by role/Researchers in ResearchFish submission
dc.publisher.placeEngland
dcterms.dateAccepted2012-10-29
dc.identifier.eissn1476-5594
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1038/onc.2012.587
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2014-01-16
rioxxterms.typeJournal Article/Review


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