PCSK9 regulates the NODAL signaling pathway and cellular proliferation in hiPSCs.
Adaptor Proteins, Signal Transducing
/ metabolism
Cell Differentiation
Cell Line
Cell Membrane
/ metabolism
Cell Proliferation
Gene Expression Regulation
Humans
Induced Pluripotent Stem Cells
/ cytology
Loss of Function Mutation
Nodal Protein
/ genetics
Phosphorylation
Proprotein Convertase 9
/ chemistry
Protein Binding
Protein Domains
Receptors, Transforming Growth Factor beta
/ metabolism
Signal Transduction
Smad2 Protein
/ metabolism
Up-Regulation
DACT2
NODAL
PCSK9
SMAD2
TGFβR1
hiPSC
proliferation
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
14 12 2021
14 12 2021
Historique:
received:
15
10
2020
revised:
06
10
2021
accepted:
07
10
2021
pubmed:
6
11
2021
medline:
4
3
2022
entrez:
5
11
2021
Statut:
ppublish
Résumé
Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) cholesterol metabolism and the target of lipid-lowering drugs. PCSK9 is mainly expressed in hepatocytes. Here, we show that PCSK9 is highly expressed in undifferentiated human induced pluripotent stem cells (hiPSCs). PCSK9 inhibition in hiPSCs with the use of short hairpin RNA (shRNA), CRISPR/cas9-mediated knockout, or endogenous PCSK9 loss-of-function mutation R104C/V114A unveiled its new role as a potential cell cycle regulator through the NODAL signaling pathway. In fact, PCSK9 inhibition leads to a decrease of SMAD2 phosphorylation and hiPSCs proliferation. Conversely, PCSK9 overexpression stimulates hiPSCs proliferation. PCSK9 can interfere with the NODAL pathway by regulating the expression of its endogenous inhibitor DACT2, which is involved in transforming growth factor (TGF) β-R1 lysosomal degradation. Using different PCSK9 constructs, we show that PCSK9 interacts with DACT2 through its Cys-His-rich domain (CHRD) domain. Altogether these data highlight a new role of PCSK9 in cellular proliferation and development.
Identifiants
pubmed: 34739847
pii: S2213-6711(21)00539-7
doi: 10.1016/j.stemcr.2021.10.004
pmc: PMC8693623
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
DACT2 protein, human
0
Nodal Protein
0
Receptors, Transforming Growth Factor beta
0
Smad2 Protein
0
Proprotein Convertase 9
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2958-2972Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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