Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-beta signaling

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The Hippo pathway is involved in intestinal epithelial homeostasis with Wnt, BMP, Notch, and EGF signaling. We investigated the relationship between Hippo and other signaling pathways and the role of MOB kinase activator 1A/1B (MOB1A/B) in intestinal homeostasis. Mice with intestinal epithelial cell (IEC)-specific depletion of MOB1A/B showed hyperproliferation in IECs, defects in secretory lineage differentiation and loss of intestinal stem cells and eventually died at 10-12 days after tamoxifen treatment. In MOB1A/B-depleted IECs, expression of Wnt target genes were downregulated but Bmp2 and Tgfbr2 were transcriptionally activated with enhanced YAP activity. In in vivo and in vitro experiments with several signaling inhibitors, it has been shown that the BMP inhibitor LDN193189 or TGF-beta inhibitor SB431542 had effects on partial restoration of the intestinal degenerative phenotype. Treatment with these inhibitors restored differentiation of secretory lineage cells in MOB1A/B-deficient mice, but not ISC pools in the crypt region. These studies reveal that IEC-specific depletion of MOB1A/B induced overexpression of Bmp2 and Tgfbr2 and inhibited Wnt activity, finally leading to loss of ISCs and functional epithelia in the mouse intestine. These results suggest that MOB1A/B has an essential function for intestinal epithelial homeostasis by regulating YAP, Wnt activity, and BMP/TGF-beta signaling.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2018-10
Language
English
Article Type
Article
Citation

CELL DEATH & DISEASE, v.9

ISSN
2041-4889
DOI
10.1038/s41419-018-1138-0
URI
http://hdl.handle.net/10203/246529
Appears in Collection
BS-Journal Papers(저널논문)
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