Yap1-Scribble polarization is required for hematopoietic stem cell division and fate.

TitleYap1-Scribble polarization is required for hematopoietic stem cell division and fate.
Publication TypeJournal Article
Year of Publication2020
AuthorsAlthoff MJ, Nayak RC, Hegde S, Wellendorf AM, Bohan B, Filippi M-D, Xin M, Q Lu R, Geiger H, Zheng Y, Diaz-Meco MT, Moscat J, Cancelas JA
JournalBlood
Volume136
Issue16
Pagination1824-1836
Date Published2020 10 15
ISSN1528-0020
KeywordsAdaptor Proteins, Signal Transducing, Biomarkers, cdc42 GTP-Binding Protein, Cell Differentiation, Cell Proliferation, Cell Self Renewal, Cells, Cultured, Hematopoietic Stem Cells, Humans, Membrane Proteins, Signal Transduction, Transcription Factors, Tumor Suppressor Proteins
Abstract

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.

DOI10.1182/blood.2019004113
Alternate JournalBlood
PubMed ID32483624
PubMed Central IDPMC7568035
Grant ListR01 DK108743 / DK / NIDDK NIH HHS / United States
R01 CA211794 / CA / NCI NIH HHS / United States
P30 CA030199 / CA / NCI NIH HHS / United States
F31 HL132468 / HL / NHLBI NIH HHS / United States
R01 CA193350 / CA / NCI NIH HHS / United States
R01 CA192642 / CA / NCI NIH HHS / United States
R01 CA218254 / CA / NCI NIH HHS / United States
R01 HL147536 / HL / NHLBI NIH HHS / United States
R01 DK104814 / DK / NIDDK NIH HHS / United States
Related Faculty: 
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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