p-21-Activated kinase 1 mediates gastrin-stimulated proliferation in the colorectal mucosa via multiple signaling pathways

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.

Tracing PAKs from GI inflammation to cancer

“…Inversely, PAK1 knockout (KO) mice (which have no distinct phenotype) display reduced expression of RAS key effectors including ERK and AKT within the colon 63 64. PAK4 KO mice are embryonically lethal 65.…”

“…The Rac1 effector, PAK1, directly interacts with β-catenin and regulates its transcriptional activity through phosphorylation at Ser-663 and Ser-67513 74 (figure 3). PAK1 KO mice in an adenomatous polyposis coli (APC) wildtype background displayed a marked reduction in nuclear β-catenin expression 63. PAK4 phosphorylates β-catenin at ser-675, and colocalises with β-catenin in the nucleus thereby increasing TCF/LEF transcriptional activation 59.…”

“…Gastrin is post-translationally modified into amidated gastrin (Gamide) and glycine extended gastrin (Gly-gastrin). Gastrin KO mice display marked reduction in expression of total and phosphorylated PAK1 within the colorectal mucosa,63 and both Gamide and Gly-gastrin increased Rho GTPase activity and increased the phosphorylation status of PAK1 within a transgenic mouse gastric mucosal cell line 128 130 131…”

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

“…Similar to pancreatic acini, endothelin did not activate Group-I-PAKs in myocytes[87]. Also, in various tissues, gastrin, which interacts with the high affinity CCK2 receptor, which is also coupled to PLC, stimulated Group-I-PAKs[31,88,89]. Our results are consistent with observations that CCK, in pancreatic acini, stimulates, in a PLC-dependent manner[72], Rac1, which is a PAK activator in other tissues[1,13].…”

The Neural Mechanism by Which the Dorsal Vagal Complex Mediates the Regulation of the Gastric Motility by Weishu (RN12) and Zhongwan (BL21) Stimulation

“…Gastrin is a vital gastrointestinal hormone distributed in the central nervous system and gastrointestinal tract. It acts as a neuromodulator in the central nervous system and as a hormone in gastrointestinal tract, participating in the regulation of gastric motility [28]. It belongs to the family of brain-gut peptides and it promotes gastrointestinal motility.…”