Cellular Basis Of Action Of Gastrointestinal Peptides/Gr

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Recent studies show that gastrointestinal hormones/growth factors may stimulate cell growth by stimulating multiple intracellular tyrosine phosphorylation (TyrP) signaling cascades. However at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades in GI tissues. During this year we have reported the importance of activation of the Src kinase Lyn, the adaptor protein Gab1, protein kinase c delta and the adaptor protein CRK11 in mediating response of pancreatic acini to hormones, growth factors and stress caused by reactive oxygen species. We demonstrated that activation of the adaptor protein, GAB1 is important for the ability of the growth factor, hepatocyte growth factor (HGF) to alter pancreatic acinar cells. However it played no role in the cellular signaling by different G-protein-coupled receptors present on acinar cells including receptors for CCK, cholinergic agents, VIP, secretin or bombesin. HGF has been reported to play an important role in growth as well as the recovery from injury of acinar cells as well as function as an important growth factor in pancreatic cancer. Our studies show HGF stimulates GAB1 TyrP rapidly and potently at both the Y307 and Y627 Tyr loci of GAB1. This not only caused a redistribution of GAB1 to the membrane it also stimulated the association of GAB1 with numerous downstream effectors including SHP2, PI3K, Shc and Crk isoforms, but not PLC gamma. This stimulation did not depend on the ability of HGF to stimulate changes in cellular calcium or activate PKC. These results show GAB1 plays a central role in the ability of HGF but not different G protein coupled receptors to alter pancreatic acinar cell function. We demonstrated both hormones activating adenylate cyclase as well as phospholipase C and known pancreatic growth factors, all caused rapid activation of the Src kinase, lyn. This activation resulted in subsequent\ activation of a large number of intracellular cascades demonstrating the central role activation of the Src kinase plays in acinar cell signaling.