Cellular Basis Of Action Of Gastrointestinal Peptides/Gr

Diabetes, Digestive, Kidney Diseases

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Abstract

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 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 celluar signalling 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 pancratic acinar cell function.