ArticleCellular and molecular gastroenterology and hepatology2021
A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation.
Article in Cellular and molecular gastroenterology and hepatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 30 citations in OpenAlex.
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- Regulation of Vascular Injury and Repair by P21-Activated Kinase 1 and P21-Activated Kinase 2: Therapeutic Potential and Challenges.Biomolecules · 2024Review
- Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses.BMC microbiology · 2024Article
- Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice.Nature communications · 2024Article
- Glutamine boosts intestinal stem cell-mediated small intestinal epithelial development during early weaning: Involvement of WNT signaling.Stem cell reports · 2023Article
- The Protective Effects of Iron Free Lactoferrin on Lipopolysaccharide-Induced Intestinal Inflammatory Injury via Modulating the NF-κB/PPAR Signaling Pathway.Foods (Basel, Switzerland) · 2022Article
- MUW researcher of the month.Wiener klinische Wochenschrift · 2022Article
- Gliquidone improves retinal injury to relieve diabetic retinopathy via regulation of SIRT1/Notch1 pathway.BMC ophthalmology · 2021Article
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- Atypical enteropathogenicGut microbesArticle
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsp21-activated kinase-1 (PAK1) belongs to a family of serine-threonine kinases and contributes to cellular pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Wingless-related integration site(Wnt)/β-catenin, all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to inflammatory bowel disease as well as colitis-associated cancer (CAC), and similarly was observed in interleukin (IL)10 knockout (KO) mice, a model of colitis and CAC. Here, we tested the effects of PAK1 deletion on intestinal inflammation and carcinogenesis in IL10 KO mice.
methodsIL10/PAK1 double-knockout (DKO) mice were generated and development of colitis and CAC was analyzed. Large intestines were measured and prepared for histology or RNA isolation. Swiss rolls were stained with H&E and periodic acid-Schiff. Co-immunoprecipitation and immunofluorescence were performed using intestinal organoids, SW480, and normal human colon epithelial cells 1CT.
resultsWhen compared with IL10 KO mice, DKOs showed longer colons and prolonged crypts, despite having higher inflammation and numbers of dysplasia. Crypt hyperproliferation was associated with Notch1 activation and diminished crypt differentiation, indicated by a reduction of goblet cells. Gene expression analysis indicated up-regulation of the Notch1 target hairy and enhancer of split-1 and the stem cell receptor leucin-rich repeat-containing G-protein-coupled receptor 5 in DKO mice. Interestingly, the stem cell marker olfactomedin-4 was present in colonic tissue. Increased β-catenin messenger RNA and cytoplasmic accumulation indicated aberrant Wnt signaling. Co-localization and direct interaction of Notch1 and PAK1 was found in colon epithelial cells. Notch1 activation abrogated this effect whereas silencing of PAK1 led to Notch1 activation.
conclusionsPAK1 contributes to the regulation of crypt homeostasis under inflammatory conditions by controlling Notch1. This identifies a novel PAK1-Notch1 axis in intestinal pathophysiology of inflammatory bowel disease and CAC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.