Journal
JCI INSIGHT
Volume 5, Issue 16, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.135923
Keywords
-
Categories
Funding
- NIH [R01DK098378, R01AI144808 R21CA178599, R01DK102934, R01AT010243, R01DK119198, F31 DK121428-01]
- American Cancer Society Scholar Award [RSG-15-060-01-TBE]
- National Science Foundation/Instrument Development for Biological Research [1353890, 1952823]
- Rutgers Initiative for Multidisciplinary Research Teams award
- NIH/National Cancer Institute [R01CA190558]
- NSF [IOS-1456673, IOS-1754783]
- New Jersey Commission on Cancer Research fellowships [DHFS16PPC036, DHFS17PPC036, DCHS19PPC038]
- Direct For Biological Sciences
- Div Of Biological Infrastructure [1353890, 1952823] Funding Source: National Science Foundation
Ask authors/readers for more resources
The regulatory mechanisms enabling the intestinal epithelium to maintain a high degree of regenerative capacity during mucosal injury remain unclear. Ex vivo survival and clonogenicity of intestinal stem cells (ISCs) strictly required growth response mediated by cell division control 42 (Cdc42) and Cdc42-deficient enteroids to undergo rapid apoptosis. Mechanistically, Cdc42 engaging with EGFR was required for EGF-stimulated, receptor-mediated endocytosis and sufficient to promote MAPK signaling. Proteomics and kinase analysis revealed that a physiologically, but nonconventionally, spliced Cdc42 variant 2 (V2) exhibited stronger MAPK-activating capability. Human CDC42-V2 is transcriptionally elevated in some colon tumor tissues. Accordingly, mice engineered to overexpress Cdc42-V2 in intestinal epithelium showed elevated MAPK signaling, enhanced regeneration, and reduced mucosal damage in response to irradiation. Overproducing Cdc42-V2 specifically in mouse ISCs enhanced intestinal regeneration following injury. Thus, the intrinsic Cdc42-MAPK program is required for intestinal epithelial regeneration, and elevating this signaling cascade is capable of initiating protection from genotoxic injury.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available