Show simple item record

dc.contributor.authorBok, Seoyeon
dc.contributor.authorShin, Dong Yeon
dc.contributor.authorYallowitz, Alisha R.
dc.contributor.authorEiseman, Mark
dc.contributor.authorCung, Michelle
dc.contributor.authorXu, Ren
dc.contributor.authorLi, Na
dc.contributor.authorSun, Jun
dc.contributor.authorWilliams, Alfred L.
dc.contributor.authorScott, John E.
dc.contributor.authorSu, Bing
dc.contributor.authorShim, Jae-Hyuck
dc.contributor.authorGreenblatt, Matthew B.
dc.date2022-08-11T08:09:58.000
dc.date.accessioned2022-08-23T16:50:34Z
dc.date.available2022-08-23T16:50:34Z
dc.date.issued2020-11-11
dc.date.submitted2021-01-15
dc.identifier.citation<p>Bok S, Shin DY, Yallowitz AR, Eiseman M, Cung M, Xu R, Li N, Sun J, Williams AL, Scott JE, Su B, Shim JH, Greenblatt MB. MEKK2 mediates aberrant ERK activation in neurofibromatosis type I. Nat Commun. 2020 Nov 11;11(1):5704. doi: 10.1038/s41467-020-19555-6. PMID: 33177525; PMCID: PMC7658220. <a href="https://doi.org/10.1038/s41467-020-19555-6">Link to article on publisher's site</a></p>
dc.identifier.issn2041-1723 (Linking)
dc.identifier.doi10.1038/s41467-020-19555-6
dc.identifier.pmid33177525
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41685
dc.description.abstractNeurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1(fl/fl);Dmp1-Cre) and Mekk2(-/-) each displaying skeletal defects, Nf1(fl/fl);Mekk2(-/-);Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=33177525&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCell signalling
dc.subjectBone
dc.subjectPeripheral nervous system
dc.subjectDiseases
dc.subjectCell Biology
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectMusculoskeletal Diseases
dc.subjectNervous System Diseases
dc.titleMEKK2 mediates aberrant ERK activation in neurofibromatosis type I
dc.typeJournal Article
dc.source.journaltitleNature communications
dc.source.volume11
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5505&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4475
dc.identifier.contextkey21101557
refterms.dateFOA2022-08-23T16:50:35Z
html.description.abstract<p>Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1(fl/fl);Dmp1-Cre) and Mekk2(-/-) each displaying skeletal defects, Nf1(fl/fl);Mekk2(-/-);Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1.</p>
dc.identifier.submissionpathoapubs/4475
dc.contributor.departmentDivision of Rheumatology, Department of Medicine
dc.source.pages5704


Files in this item

Thumbnail
Name:
s41467_020_19555_6.pdf
Size:
3.207Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

Copyright © The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as Copyright © The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.