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Title: p-21-Activated kinase 1 mediates gastrin-stimulated proliferation in the colorectal mucosa via multiple signaling pathways.
Austin Authors: Huynh, Nhi;Yim, Mildred;Chernoff, Jonathan;Shulkes, Arthur;Baldwin, Graham S;He, Hong 
Affiliation: Department of Surgery, University of Melbourne, Austin Health, Victoria, Australia
Issue Date: 10-Jan-2013
Publication information: American Journal of Physiology. Gastrointestinal and Liver Physiology 2013; 304(6): G561-7
Abstract: Gastrins, including amidated (Gamide) and glycine-extended (Ggly) forms, function as growth factors for the gastrointestinal mucosa. The p-21-activated kinase 1 (PAK1) plays important roles in growth factor signaling networks that control cell motility, proliferation, differentiation, and transformation. PAK1, activated by both Gamide and Ggly, mediates gastrin-stimulated proliferation and migration, and activation of β-catenin, in gastric epithelial cells. The aim of this study was to investigate the role of PAK1 in the regulation by gastrin of proliferation in the normal colorectal mucosa in vivo. Mucosal proliferation was measured in PAK1 knockout (PAK1 KO) mice by immunohistochemistry. The expression of phosphorylated and unphosphorylated forms of the signaling molecules PAK1, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT), and the expression of β-catenin and its downstream targets c-Myc and cyclin D1, were measured in gastrin knockout (Gas KO) and PAK1 KO mice by Western blotting. The expression and activation of PAK1 are decreased in Gas KO mice, and these decreases are associated with reduced activation of ERK, AKT, and β-catenin. Proliferation in the colorectal mucosa of PAK1 KO mice is reduced, and the reduction is associated with reduced activation of ERK, AKT, and β-catenin. In compensation, antral gastrin mRNA and serum gastrin concentrations are increased in PAK1 KO mice. These results indicate that PAK1 mediates the stimulation of colorectal proliferation by gastrins via multiple signaling pathways involving activation of ERK, AKT, and β-catenin.
Gov't Doc #: 23306081
DOI: 10.1152/ajpgi.00218.2012
Type: Journal Article
Subjects: Animals
Cell Differentiation.physiology
Cell Movement.physiology
Cell Proliferation
Cell Survival.physiology
Cyclin D1.metabolism
Extracellular Signal-Regulated MAP Kinases.metabolism
Intestinal Mucosa.metabolism.pathology
Mice, Inbred C57BL
Mice, Knockout
Proto-Oncogene Proteins c-akt.metabolism
Signal Transduction.physiology
beta Catenin.metabolism
p21-Activated Kinases.metabolism
Appears in Collections:Journal articles

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