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Search: onr:"swepub:oai:DiVA.org:uu-440473" > The infantile myofi...

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  • Wu, DanKarolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Womens Hosp, Dept Obstet & Gynecol, Nanjing 211166, Peoples R China. (author)

The infantile myofibromatosis NOTCH3 L1519P mutation leads to hyperactivated ligand-independent Notch signaling and increased PDGFRB expression

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • COMPANY BIOLOGISTS LTD,2021
  • electronicrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:uu-440473
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-440473URI
  • https://doi.org/10.1242/dmm.046300DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:146101975URI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

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  • De två första författarna delar förstaförfattarskapet.
  • Infantile myofibromatosis (IMF) is a benign tumor form characterized by the development of nonmetastatic tumors in skin, bone, muscle and sometimes viscera. Autosomal-dominant forms of IMF are caused by mutations in the PDGFRB gene, but a family carrying a L1519P mutation in the NOTCH3 gene has also recently been identified. In this study, we address the molecular consequences of the NOTCH3L1519P mutation and the relationship between Notch and PDGFRB signaling in IMF. The NOTCH3L1519P receptor generates enhanced downstream signaling in a ligand-independent manner. Despite the enhanced signaling, the NOTCH3L1519P receptor is absent from the cell surface and instead accumulates in the endoplasmic reticulum. Furthermore, the localization of the NOTCH3L1519P receptor in the bipartite, heterodimeric state is altered, combined with avid secretion of the mutated extracellular domain from the cell. Chloroquine treatment strongly reduces the amount of secreted NOTCH3L1519P extracellular domain and decreases signaling. Finally, NOTCH3L1519P upregulates PDGFRB expression in fibroblasts, supporting a functional link between Notch and PDGF dysregulation in IMF. Collectively, our data define a NOTCH3-PDGFRB axis in IMF, in which an IMF-mutated NOTCH3 receptor elevates PDGFRB expression. The functional characterization of a ligand-independent gain-of-function NOTCH3 mutation is important for Notch therapy considerations for IMF, including strategies aimed at altering lysosome function.

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  • Wang, SailanKarolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden. (author)
  • Oliveira, Daniel V.Karolinska Institutet (author)
  • Del Gaudio, FrancescaKarolinska Institutet (author)
  • Vanlandewijck, Michael,1982-Uppsala universitet,Vaskulärbiologi,Karolinska Inst, Dept Med, S-14186 Huddinge, Sweden.;Karolinska Inst, Integrated Cardio Metab Ctr ICMC, S-14186 Huddinge, Sweden.(Swepub:uu)micva660 (author)
  • Lebouvier, ThibaudUppsala universitet,Vaskulärbiologi,Univ Lille, INSERM, CHU Lille, U1171,Memory Ctr, F-59000 Lille, France. (author)
  • Betsholtz, ChristerUppsala universitet,Vaskulärbiologi,Karolinska Inst, Dept Med, S-14186 Huddinge, Sweden.;Karolinska Inst, Integrated Cardio Metab Ctr ICMC, S-14186 Huddinge, Sweden.(Swepub:uu)chbet517 (author)
  • Zhao, JianKarolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden. (author)
  • Jin, ShaoBoKarolinska Institutet (author)
  • Lendahl, UrbanKarolinska Institutet (author)
  • Karlström, HelenaKarolinska Institutet (author)
  • Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Womens Hosp, Dept Obstet & Gynecol, Nanjing 211166, Peoples R China.Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden. (creator_code:org_t)

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  • In:Disease Models and Mechanisms: COMPANY BIOLOGISTS LTD14:21754-84031754-8411

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