Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration.

JCI Insight
Xiao ZhangNan Gao

Abstract

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.

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Citations

Mar 5, 2021·The Journal of Biological Chemistry·Ewa StypulkowskiNan Gao
Aug 20, 2021·Developmental Biology·Meng-Han WuChristopher M Cox

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Datasets Mentioned

BETA
GSE124848

Methods Mentioned

BETA
IECs
GTPase
Assay
PCR
RNA-Seq
IEC
GTPases
nucleotide exchange
transfection
immunoprecipitation

Software Mentioned

Excel
esyN
GSEA
ImageJ
Excel 3D Scatter Plot
Database for Annotation , Visualization and Integrated Discove...
Fiji
AIM
GraphPad Prism
Scaffold

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis