Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10817065 | Cellular Signalling | 2005 | 11 Pages |
Abstract
Although expression of the gastrin/cholecystokinin-2 receptor (CCK2R) is widely reported in human colorectal cancer, little is known on its role in mediating mature amidated gastrin (gastrin-17 amide, G-17) induced intracellular signal transduction in colon cancer cells. The purpose of this study was to explore the intracellular events of colorectal cancer cells after gastrin binding to CCK2R. Meanwhile, the influence of a natural point mutation 286VâF in the third intracellular loop of CCK2R on gastrin-envoked intracellular signal transduction was also investigated. Firstly, Colo320 cells were stably transfected with wild type (Colo320 WT) and mutant CCK2R (Colo320 M), respectively. The intracellular signal transduction events in response to gastrin were investigated in both Colo320 WT and Colo320 M cells. In Colo320 WT cells, G-17 induced formation of intracellular cyclic AMP and inositol 1,4,5-trisphosphate, and stimulated intracellular calcium mobilization. G-17 also stimulated tyrosine phosphorylation of ERKl/2, p38, FAK, and paxillin, and up-regulated the mRNA expression of early response gene c-Jun and c-Fos. However, G-17 inhibited proliferation and induced apoptosis in Colo320 WT cells. Mutation 286VâF in the third intracellular loop of CCK2R blocked G-17 induced biological without affecting binding affinity of CCK2R to G-17. Our results suggest that activation of CCK2R by gastrin stimulates heterotrimeric G-protein Gq and G12/13 mediated intracellular signal transduction pathway in colon cancer cells. The valine-287 residue in third intracellular loop of CCK2R plays a pivotal role in CCK2R mediated intracellular signal transduction.
Keywords
G-17P-TyrFAKERKG12/13IP3CCK2RGPCRPLCcyclic AMPcAMPinositol 1,4,5-trisphosphateMAPKmutationthird intracellular loopphosphotyrosinephospholipase Cmitogen-activated protein kinasecholecystokinin 2 receptorextracellular signal-regulated kinasefocal adhesion kinasegastrinCCK2 receptorG protein-coupled receptor
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Authors
Hong-Gang Yu, Heiner Schäfer, Stefan Mergler, Susanne Müerköster, Torsten Cramer, Michael Höcker, Karl-Heinz Herzig, Wolfgang E. Schmidt, Frank Schmitz,