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BRAF/MAPK and GSK3 signaling converges to control MITF nuclear export

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dc.contributor Háskóli Íslands (HÍ)
dc.contributor University of Iceland (UI)
dc.contributor.author Ngeow, Kao Chin
dc.contributor.author Friedrichsen, Hans J.
dc.contributor.author Li, Linxin
dc.contributor.author Zeng, Zhiqiang
dc.contributor.author Andrews, Sarah
dc.contributor.author Volpon, Laurent
dc.contributor.author Brunsdon, Hannah
dc.contributor.author Berridge, Georgina
dc.contributor.author Picaud, Sarah
dc.contributor.author Fischer, Roman
dc.contributor.author Lisle, Richard
dc.contributor.author Knapp, Stefan
dc.contributor.author Filippakopoulos, Panagis
dc.contributor.author Knowles, Helen
dc.contributor.author Steingrimsson, Eirikur
dc.contributor.author Borden, Katherine L. B.
dc.contributor.author Patton, E. Elizabeth
dc.contributor.author Goding, Colin R.
dc.date.accessioned 2020-01-13T14:45:29Z
dc.date.available 2020-01-13T14:45:29Z
dc.date.issued 2018-08-27
dc.identifier.citation Ngeow et al., 2018. BRAF/MAPK and GSK3 signaling converges to control MITF nuclear export. Proceedings of the National Academy of Sciences of the United States of America, 115(37), pp.E8668–E8677.
dc.identifier.issn 0027-8424
dc.identifier.issn 1091-6490 (eISSN)
dc.identifier.uri https://hdl.handle.net/20.500.11815/1453
dc.description Publisher's version (útgefin grein).
dc.description.abstract The close integration of the MAPK, PI3K, and WNT signaling pathways underpins much of development and is deregulated in cancer. In principle, combinatorial posttranslational modification of key lineage-specific transcription factors would be an effective means to integrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia-associated transcription factor MITF plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts, and mast cells and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell-cycle progression, cell migration, metabolism, and lysosome biogenesis. However, how the activity of this key transcription factor is controlled remains poorly understood. Here, we show that GSK3, downstream from both the PI3K and Wnt pathways, and BRAF/MAPK signaling converges to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activating a previously unrecognized hydrophobic export signal. Nonmelanocyte MITF isoforms exhibit poor regulation by MAPK signaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import–export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal.
dc.description.sponsorship Funding text #1 aLudwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Headington, OX3 7DQ Oxford, United Kingdom; bMedical Research Council Human Genetics Unit & Edinburgh Cancer Research Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XR Edinburgh, United Kingdom; cInstitute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada; dDepartment of Pathology and Cell Biology, Université de Montréal, Montréal, QC H3T 1J4, Canada; eDiscovery Proteomics Facility, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, OX3 7FZ Oxford, United Kingdom; fStructural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, OX3 7DQ Oxford, United Kingdom; gBotnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Headington, OX3 7HE Oxford, United Kingdom; and hDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. Funding text #2 ACKNOWLEDGMENTS. We thank Katherine Dowsett for assistance with the zebrafish experiments. Mass spectrometry analysis was performed in the Target Discovery Institute MS Laboratory led by Benedikt M. Kessler. This research was supported by the Agency for Science, Technology and Research Singapore (K.C.N.); Cancer Research UK (CRUK) Grant C38302/A12981, through a CRUK Oxford Centre Prize DPhil Studentship (to H.J.F.); The China Scholarship Council (L.L.); Wellcome Trust Career Development Fellowship 095751/Z/11/Z (to P.F. and S.P.); the Structural Genomics Consortium (S.K.); Arthritis Research UK Grant MP/19200 and Rosetrees Trust Grant M456 (to H.K.); The Research Fund of Iceland (E.S.); the Ludwig Institute for Cancer Research (C.R.G., S.A., and G.B.); the Kennedy Trust Fund (R.F.); The Medical Research Council Human Genetics Unit Programme MC_PC_U127585840 (to E.E.P. and Z.Z.); The European Research Council Grant ZF-MEL-CHEMBIO-g48489 (to E.E.P. and H.B.); and L’Oreal-Melanoma Research Alliance Grant 401181 (to E.E.P.). K.L.B.B. is supported by NIH Grants NIH 98571 and NIH 80728 and holds a Canada Research Chair (Tier 1).
dc.format.extent E8668-E8677
dc.language.iso en
dc.publisher Proceedings of the National Academy of Sciences
dc.relation.ispartofseries Proceedings of the National Academy of Sciences;115(37)
dc.rights info:eu-repo/semantics/openAccess
dc.subject GSK3
dc.subject MAPK
dc.subject Melanoma
dc.subject MITF
dc.subject Nuclear export
dc.subject Krabbameinsrannsóknir
dc.subject Húðkrabbamein
dc.title BRAF/MAPK and GSK3 signaling converges to control MITF nuclear export
dc.type info:eu-repo/semantics/article
dcterms.license This article is a PNAS Direct Submission.
dc.description.version Peer Reviewed
dc.identifier.journal Proceedings of the National Academy of Sciences
dc.identifier.doi 10.1073/pnas.1810498115
dc.contributor.department Faculty of Medicine (UI)
dc.contributor.department Læknadeild (HÍ)
dc.contributor.school Heilbrigðisvísindasvið (HÍ)
dc.contributor.school School of Health Sciences (UI)

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