Little is known of the role of activation of Src family kinases or of p21-activated kinases(PAKs) in mediating actions of GI hormones/neurotrasmitters. In two different studies we used pancreatic acinar cells which are highly responsive to number of gastrointestinal hormones/neurotransmitter to explore the role of Src family of kinases and PAK2 in mediating the signaling of these agents on cellular cascades known to mediate physiological and pathophysiological responses in these cells. Both inhibition and overactivation of SFK was used employing methods of chemical inhibition as well as dominate negative constructs. We found SFK played key roles in number of important signaling cascades known to mediate growth, secretion, cell conformation, plasticity, protein synthesis, as well a cellular changes seen in pancreatitis. Furthermore, we found that only PAK2 of the type I family of PAKs was present in pancreatic acini and that its activation required stimulation of small GTP binding proteins, phospholipase C, but not changes in cytosolic calcium, cAMP, PI3K and that its activation was essential for hormones to activate MAP kinases or stimulate enzyme secretion. These two studies demonstrate both of these signaling cascades are essential for GI hormone/GF effects on pancreatic acinar cells. Recent studies show that gastrointestinal hormones/growth factors may cause cell growth by stimulating multiple intracellular tyrosine phosphorylation (TyrP) signaling cascades as well as by transactivation growth factor receptors. However at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. During the year we published two general reviews of this subject. Also, in a study on lung cancer cells we investigated the ability of the G-protein coupled receptors for neurotensin to stimulate their growth. We found that the mechanism involved transactivation of the EGF receptor as well as stimulating activation of reactive oxygen species, matrix metalloproteinases and Src. SI RNA for NT receptors 1 reduced the ability the NTS1 anatagonist,SR48692, to inhibit the growth of the lung cancer cells. THe antagonist potentiated the inhibitory action of gefitinib. In collaboration with Dr N.Gonzalez(Madrid, Spain) we explored the cellular mechanisms by which the BnR receptor, BRS-3 regulates fat and insulin metabolism. BRS-3 signaling was investigated in dispersed myocytes form normal, obese, or diabetic subjects. BRS3 agonists increased activity of MAPK,p90RSK1, PKB, PI3K,and P70sgK. It also stimualted glycogen synthetase a activity and glycogen synthesis. Myocytes from obesity or diabetic patients were more sensitive. In a separate review the importance of the BRS-3 receptor as a possible target for treatment of diabetes or obesity was reviewed.
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