Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Recent studies show that in both normal and neoplastic tissues, gastrointestinal hormones/neurotransmitters (GI) and GI growth factors (GF) may cause cell growth by stimulating multiple intracellular tyrosine/serine/threonine phosphorylation (TyrP) signaling cascades as well as by transactivation of growth factor receptors. However, at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. Recent studies, including ours have demonstrated that in different cells the mechanisms of the ability of these peptides to stimulate tyrosine phosphorylation and receptor tyrosine kinases involves a number of different mechanisms. The novel abilities of these GPCRs to activate these tyrosine kinase cascades are demonstrating the importance of these receptors in numerous physiological/pathological processes, particular growth cascades of both normal and cancer tissues, opening new therapeutic approaches. One of the key signaling cascades that GPCRs use to stimulate growth is through the transactivation of receptor tyrosine kinases such as members of the EGFR/HER family. While it is well established that EGFR is transactivated in such a manner, less is known about the ability of EGFR to transactivate HER2 receptors. This year we studied the ability of Bombesin(BN)-related peptides to transactivage HER2 in lung cancer cells, because of the well established growth effects of BN pepite on these cancers. We found BRS-3 activation in NSCLC cell stimulated tumor cell growth through activation of HER2 in a ROS dependent manner. The cellular signaling molecules, serine/threonine phosphatases PPI and PP2a play key signaling roles in many cells for numerous cellular responses incuding in proliferation, development, motility, migration, secretion, and growth. In the pancreas it is important in islet insulin secretion, growth of pancreatic cancer cells and in pancreatitis. However, their roles in secretion in general is poorly studies, and their role in secretion or growth in pancreatic acinar cells is controversial. To address these questions, the role of PP1/PP2A in secretion from various tissues was reviewed in a publication by us this year and in addition, we studied the ability of Cholecystokinin (CCK), a physiological activator of pancreatic exocrine function, as well as various pancreatic secretagogues to activate PP1/PP2A in pancreatic acinar cells and the pancreatic acinar tumor cell line, AR42J cells, and its effect on enzyme secretion and MAPK activation, a key mediator of pancreatic growth. Our results support the conclusion that acinar cell stimuation by CCK and othe PLC activating agents stimulate activation of both PP1 And PP2A in acinar cells and AR42 J cells. Using specific PP1 ansd PP2 inhibitors and siRNA studies demonstrate, however, we fund that only activation of PP2A was arequired for CCK stimulated enzyme secretion or growth.