TY - JOUR
T1 - Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration
AU - Zhang, Xiao
AU - Bandyopadhyay, Sheila
AU - Araujo, Leandro Pires
AU - Tong, Kevin
AU - Flores, Juan
AU - Laubitz, Daniel
AU - Zhao, Yanlin
AU - Yap, George
AU - Wang, Jingren
AU - Zou, Qingze
AU - Ferraris, Ronaldo
AU - Zhang, Lanjing
AU - Hu, Wenwei
AU - Bonder, Edward M.
AU - Kiela, Pawel R.
AU - Coffey, Robert
AU - Verzi, Michael P.
AU - Ivanov, Ivaylo I.
AU - Gao, Nan
N1 - Funding Information:
We thank the facility of Genome Editing of Rutgers Cancer Institute of New Jersey (P30CA072720) for developing Cdc42 V2Tg mice. This work was supported by NIH (R01DK098378, R01AI144808 R21CA178599, R01DK102934, R01AT010243, R01DK119198), American Cancer Society Scholar Award (RSG-15-060-01-TBE), National Science Foundation/Instrument Development for Biological Research (1353890, 1952823), and a Rutgers Initiative for Multidisciplinary Research Teams award to NG; NIH/ National Cancer Institute R01CA190558 to MPV; NSF Grant (IOS-1456673, IOS-1754783) to RPF; NIH F31 DK121428-01 to SB; and New Jersey Commission on Cancer Research fellowships (DHFS16PPC036, DHFS17PPC036, DCHS19PPC038) to KT, SB, and JF, respectively.
Funding Information:
We thank the facility of Genome Editing of Rutgers Cancer Institute of New Jersey (P30CA072720) for developing Cdc42 V2Tg mice. This work was supported by NIH (R01DK098378, R01AI144808 R21CA178599, R01DK102934, R01AT010243, R01DK119198), American Cancer Society Scholar Award (RSG-15-060-01-TBE), National Science Foundation/Instrument Development for Biological Research (1353890, 1952823), and a Rutgers Initiative for Multidisciplinary Research Teams award to NG; NIH/National Cancer Institute R01CA190558 to MPV; NSF Grant (IOS-1456673, IOS-1754783) to RPF; NIH F31 DK121428-01 to SB; and New Jersey Commission on Cancer Research fellowships (DHFS16PPC036, DHFS17PPC036, DCHS19PPC038) to KT, SB, and JF, respectively.
Publisher Copyright:
© 2020 American Society for Clinical Investigation. All rights reserved.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - 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.
AB - 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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U2 - 10.1172/jci.insight.135923
DO - 10.1172/jci.insight.135923
M3 - Article
C2 - 32686657
AN - SCOPUS:85089768554
VL - 5
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 16
M1 - e135923
ER -