Yap1-Scribble polarization is required for hematopoietic stem cell division and fate.
Adaptor Proteins, Signal Transducing
/ genetics
Biomarkers
Cell Differentiation
/ genetics
Cell Proliferation
Cell Self Renewal
Cells, Cultured
Hematopoietic Stem Cells
/ cytology
Humans
Membrane Proteins
/ genetics
Signal Transduction
Transcription Factors
/ genetics
Tumor Suppressor Proteins
/ genetics
YAP-Signaling Proteins
cdc42 GTP-Binding Protein
/ genetics
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
15 10 2020
15 10 2020
Historique:
received:
14
11
2019
accepted:
13
05
2020
pubmed:
3
6
2020
medline:
16
6
2021
entrez:
3
6
2020
Statut:
ppublish
Résumé
Yap1 and its paralogue Taz largely control epithelial tissue growth. We have identified that hematopoietic stem cell (HSC) fitness response to stress depends on Yap1 and Taz. Deletion of Yap1 and Taz induces a loss of HSC quiescence, symmetric self-renewal ability, and renders HSC more vulnerable to serial myeloablative 5-fluorouracil treatment. This effect depends on the predominant cytosolic polarization of Yap1 through a PDZ domain-mediated interaction with the scaffold Scribble. Scribble and Yap1 coordinate to control cytoplasmic Cdc42 activity and HSC fate determination in vivo. Deletion of Scribble disrupts Yap1 copolarization with Cdc42 and decreases Cdc42 activity, resulting in increased self-renewing HSC with competitive reconstitution advantages. These data suggest that Scribble/Yap1 copolarization is indispensable for Cdc42-dependent activity on HSC asymmetric division and fate. The combined loss of Scribble, Yap1, and Taz results in transcriptional upregulation of Rac-specific guanine nucleotide exchange factors, Rac activation, and HSC fitness restoration. Scribble links Cdc42 and the cytosolic functions of the Hippo signaling cascade in HSC fate determination.
Identifiants
pubmed: 32483624
pii: S0006-4971(20)61632-9
doi: 10.1182/blood.2019004113
pmc: PMC7568035
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Biomarkers
0
Membrane Proteins
0
SCRIB protein, human
0
Transcription Factors
0
Tumor Suppressor Proteins
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
CDC42 protein, human
EC 3.6.5.2
cdc42 GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1824-1836Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK108743
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY032029
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL132468
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193350
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA192642
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218254
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147536
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104814
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132211
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211794
Pays : United States
Informations de copyright
© 2020 by The American Society of Hematology.
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