Cellular Basis Of Action Of Gastrointestinal Peptides

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Recent studies show that gastrointestinal hormones, similar to many growth factors, may stimulate cell growth by stimulating intracellular tyrosine phosphorylation signaling cascades. However at present little is known about the ability of these G-protein-coupled receptors to activate these cascades. During the year we have investigated the ability of 4 GI hormones to activate these cascades. In lung cancer cells where PACAP, bombesin-related peptides and neurotensin are known growth factors, we demonstrate each can activate tyrosine kinase cascades with stimulation of tyrosine phosphorylation of p125 focal adhesion kinase, an important cellular mediator of motility and cell attachment. We also demonstrate activation of both the bombesin-related receptor BRS-3 and the PACAP receptor activates the MAP kinase cascade which is an important mediator of cell growth in many cell systems. Furthermore, activation of MAP kinase cascade increases VEGF expression in these cells. In pancreatic acinar cells we have demonstrated activation of the CCKA-R causes rapid tyrosine phosphorylation of p125FAK, paxillin, p130Cas, PYK2 and PKC delta. Our recent studies show PKC delta activation is independent of changes in [Ca2+]i or PI3K but is regulated by activation of PKC-alpha. These studies demonstrate each of these GI hormones/neuropeptides causes activation of tyrosine phosphorylation cascades, and it is likely activation of these cascades is important in mediating many of their growth effects in normal and neoplastic tissues.