A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal InflammationSummary
Background & Aims: p21-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 in...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-01-01
|
| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20301806 |
| _version_ | 1818924881618665472 |
|---|---|
| author | Adrian Frick Vineeta Khare Kristine Jimenez Kyle Dammann Michaela Lang Anita Krnjic Christina Gmainer Maximilian Baumgartner Ildiko Mesteri Christoph Gasche |
| author_facet | Adrian Frick Vineeta Khare Kristine Jimenez Kyle Dammann Michaela Lang Anita Krnjic Christina Gmainer Maximilian Baumgartner Ildiko Mesteri Christoph Gasche |
| author_sort | Adrian Frick |
| collection | DOAJ |
| description | Background & Aims: p21-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. Methods: IL10/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. Results: When 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. Conclusions: PAK1 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. |
| first_indexed | 2024-12-20T02:32:23Z |
| format | Article |
| id | doaj.art-709ac4fc74d24866bd6d4548848d2c7b |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-20T02:32:23Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-709ac4fc74d24866bd6d4548848d2c7b2022-12-21T19:56:32ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-01113892907.e1A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal InflammationSummaryAdrian Frick0Vineeta Khare1Kristine Jimenez2Kyle Dammann3Michaela Lang4Anita Krnjic5Christina Gmainer6Maximilian Baumgartner7Ildiko Mesteri8Christoph Gasche9Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaDepartment of Surgery, Saint Luke’s University Hospital Bethlehem, Bethlehem, PennsylvaniaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, AustriaInstitute of Pathology Überlingen, Überlingen, GermanyDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Correspondence Address correspondence to: Christoph Gasche, MD, Division of Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. fax: (43) 40400-47350.Background & Aims: p21-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. Methods: IL10/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. Results: When 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. Conclusions: PAK1 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.http://www.sciencedirect.com/science/article/pii/S2352345X20301806PAK1Notch1Stem CellInflammationColitis-Associated CancerInflammatory Bowel Disease |
| spellingShingle | Adrian Frick Vineeta Khare Kristine Jimenez Kyle Dammann Michaela Lang Anita Krnjic Christina Gmainer Maximilian Baumgartner Ildiko Mesteri Christoph Gasche A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal InflammationSummary Cellular and Molecular Gastroenterology and Hepatology PAK1 Notch1 Stem Cell Inflammation Colitis-Associated Cancer Inflammatory Bowel Disease |
| title | A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal InflammationSummary |
| title_full | A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal InflammationSummary |
| title_fullStr | A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal InflammationSummary |
| title_full_unstemmed | A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal InflammationSummary |
| title_short | A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal InflammationSummary |
| title_sort | novel pak1 notch1 axis regulates crypt homeostasis in intestinal inflammationsummary |
| topic | PAK1 Notch1 Stem Cell Inflammation Colitis-Associated Cancer Inflammatory Bowel Disease |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X20301806 |
| work_keys_str_mv | AT adrianfrick anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT vineetakhare anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT kristinejimenez anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT kyledammann anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT michaelalang anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT anitakrnjic anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT christinagmainer anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT maximilianbaumgartner anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT ildikomesteri anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT christophgasche anovelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT adrianfrick novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT vineetakhare novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT kristinejimenez novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT kyledammann novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT michaelalang novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT anitakrnjic novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT christinagmainer novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT maximilianbaumgartner novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT ildikomesteri novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary AT christophgasche novelpak1notch1axisregulatescrypthomeostasisinintestinalinflammationsummary |