ArticleAmerican journal of physiology. Gastrointestinal and liver physiology2016
PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells.
Article in American journal of physiology. Gastrointestinal and liver physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- Pharmacologic Modulation of the PAR-2-ERK Axis by Statins Converts Inflammatory Survival Signalling into Apoptosis in Colorectal Cancer Cells.International journal of molecular sciences · 2026Article
- Mast Cells Inhibit Stem Cell-driven Epithelial Repair in Inflammatory Bowel Disease via Suppressing Wnt/lrp6/β-Catenin Signaling Pathway.Cellular and molecular gastroenterology and hepatology · 2026Article
- Proteases in intestinal health and disease.Nature reviews. Gastroenterology & hepatology · 2026Review
- Dynamic remodelling of epithelial plasticity in colorectal cancer from single-cell and spatially resolved perspectives.Journal of translational medicine · 2025Article
- Targeting PAR-2-driven inflammatory pathways in colorectal cancer: mechanistic insights from atorvastatin and rosuvastatin treatment in cell line models.Translational cancer research · 2025Article
- Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target.Theranostics · 2025Review
- Shear Stress Drives the Cleavage Activation of Protease-Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Prenatal stress induces changes in PAR2- and M3-dependent regulation of colon primitive cells.American journal of physiology. Gastrointestinal and liver physiology · 2022Article
- Predictive value of protease-activated receptor-2 (PARJournal of cellular and molecular medicine · 2021Article
- Review
- Sexual dimorphism in PARBiology of sex differences · 2019Article
- Article
- Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer.Frontiers in endocrinology · 2019Review
- Protease-activated receptor 2 signaling modulates susceptibility of colonic epithelium to injury through stabilization of YAP in vivo.Cell death & disease · 2018Article
- Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a protease-activated receptor 1- and protease-activated receptor 4-dependent mechanism.British journal of pharmacology · 2018Article
- Anti-inflammatory and anticancer effects of flavonol glycosides from Diplotaxis harra through GSK3β regulation in intestinal cells.Pharmaceutical biology · 2017Article
- MiR-92a promotes stem cell-like properties by activating Wnt/β-catenin signaling in colorectal cancer.Oncotarget · 2017Article
- G Protein-Coupled Receptor Signaling Through β-Arrestin-Dependent Mechanisms.Journal of cardiovascular pharmacology · 2017Review
- Article
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protease-activated receptors PAR1 and PAR2 play an important role in the control of epithelial cell proliferation and migration. However, the survival of normal and tumor intestinal stem/progenitor cells promoted by proinflammatory mediators may be critical in oncogenesis. The glycogen synthase kinase-3β (GSK3β) pathway is overactivated in colon cancer cells and promotes their survival and drug resistance. We thus aimed to determine PAR1 and PAR2 effects on normal and tumor intestinal stem/progenitor cells and whether they involved GSK3β. First, PAR1 and PAR2 were identified in colon stem/progenitor cells by immunofluorescence. In three-dimensional cultures of murine crypt units or single tumor Caco-2 cells, PAR2 activation decreased numbers and size of normal or cancerous spheroids, and PAR2-deficient spheroids showed increased proliferation, indicating that PAR2 represses proliferation. PAR2-stimulated normal cells were more resistant to stress (serum starvation or spheroid passaging), suggesting prosurvival effects of PAR2 Accordingly, active caspase-3 was strongly increased in PAR2-deficient normal spheroids. PAR2 but not PAR1 triggered GSK3β activation through serine-9 dephosphorylation in normal and tumor cells. The PAR2-triggered GSK3β activation implicates an arrestin/PP2A/GSK3β complex that is dependent on the Rho kinase activity. Loss of PAR2 was associated with high levels of GSK3β nonactive form, strengthening the role of PAR2 in GSK3β activation. GSK3 pharmacological inhibition impaired the survival of PAR2-stimulated spheroids and serum-starved cells. Altogether our data identify PAR2/GSK3β as a novel pathway that plays a critical role in the regulation of stem/progenitor cell survival and proliferation in normal colon crypts and colon cancer.
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Registered trials
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 OpenQuestion graph.