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The infantile myofi...
The infantile myofibromatosis NOTCH3 L1519P mutation leads to hyperactivated ligand-independent Notch signaling and increased PDGFRB expression
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- Wu, Dan (författare)
- 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.
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- Wang, Sailan (författare)
- Karolinska Inst, Dept Neurobiol Care Sci & Soc, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden.
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- Oliveira, Daniel V. (författare)
- Karolinska Institutet
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- Del Gaudio, Francesca (författare)
- Karolinska Institutet
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- Vanlandewijck, Michael, 1982- (författare)
- Karolinska Institutet,Uppsala universitet,Vaskulärbiologi,Karolinska Inst, Dept Med, S-14186 Huddinge, Sweden.;Karolinska Inst, Integrated Cardio Metab Ctr ICMC, S-14186 Huddinge, Sweden.
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- Lebouvier, Thibaud (författare)
- Uppsala universitet,Vaskulärbiologi,Univ Lille, INSERM, CHU Lille, U1171,Memory Ctr, F-59000 Lille, France.
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- Betsholtz, Christer (författare)
- Uppsala universitet,Vaskulärbiologi,Karolinska Inst, Dept Med, S-14186 Huddinge, Sweden.;Karolinska Inst, Integrated Cardio Metab Ctr ICMC, S-14186 Huddinge, Sweden.
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- Zhao, Jian (författare)
- Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden.
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- Jin, ShaoBo (författare)
- Karolinska Institutet
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- Lendahl, Urban (författare)
- Karolinska Institutet
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- Karlström, Helena (författare)
- Karolinska Institutet
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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)
- COMPANY BIOLOGISTS LTD, 2021
- 2021
- Engelska.
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Ingår i: Disease Models and Mechanisms. - : COMPANY BIOLOGISTS LTD. - 1754-8403 .- 1754-8411. ; 14:2
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://journals.bio...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Infantile myofibromatosis
- Notch
- PDGF
- Fibroblast
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Wu, Dan
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Wang, Sailan
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Oliveira, Daniel ...
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Del Gaudio, Fran ...
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Vanlandewijck, M ...
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Lebouvier, Thiba ...
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visa fler...
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Betsholtz, Chris ...
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Zhao, Jian
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Jin, ShaoBo
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Lendahl, Urban
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Karlström, Helen ...
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visa färre...
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- MEDICIN OCH HÄLSOVETENSKAP
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Disease Models a ...
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Uppsala universitet
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Karolinska Institutet