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 (GI) and GI growth factors (GF) 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 have performed two studies into the ability of various gastrointestinal hormones to stimulate tumoral growth cascades by transactivating the EGF family of receptors. In one study we demonstrated that the hormone pituitary adenylate cyclase activating peptide(PACAP) which interacts with three G protein coupled receptors (PAC-1/VPAC1,2) can stimulate growth of lung cancer cells and it does so by transactivating the EGF receptor. The EGFR transactivation requires activation of phospholipase C, mobilization of cellular Ca2+, and generation of reactive oxygen species. A second study demonstrated that in lung cancer cells the ability of the GI hormone, neurotensin (NT) to stimulate growth of these tumors was also dependent of the activation of reactive oxygen species and was dependent on transactivation of both EGFR and the related EGFR receptor, HER2. NT stimulated the formation of EGFR-HER2 heterodimers and its growth promoting affects were blocked by lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor. These results show novel cellular pathways that may prove useful in inhibitor the growth of these tumors. Recently we have demonstrated at that the p21-activated kinases (PAKs),which have been extensively studied for their roles in cancer growth are also important in mediating some of the cellular effects of GI hormones/neurotransmitters in normal tissues. In two studies over the last year we have extended our previous studies. In one study we demonstrate that the two GI hormones/neurotransmitters, vasoactive intestinal peptide and secretin, which each interact with specify G protein-coupled receptors to mediate their actions, which we found were dependent on activation of the p21-actiaved kinase, PAK4. Specifically , in dispersed pancreatic acinar cells both hormones stimulated activation of acinar Na2+,K2+ ATPase which mediates acinar electrolytes and water secretion, and that it was dependent on a PAK4 mechanism which in term required activation of adenylate cyclase with subsequent stimulation of cyclic AMP-dependent protein kinase as well as activation of the EPAC signaling cascade. In another study with pancreatic acinar cells, we explored the role of PAK4 activation in mediating the effects of the physiological activator of pancreatic acinar cells, CCK, to stimulate enzyme secretion or growth mediating cascades in these cells. We found that PAK4 in these cells was activated by numerous signaling cascades including PKC-, Src-, p44/42-, and p38-dependent cascades. Pak4 activation was required for both enzyme secretion and activation of MAP kinases, which mediate growth cascades in these cells. These observations coupled with recent studies showing the p21-activated kinases are also important in such pancreatic diseases as pancreatic cancer growth and pancreatitis, coupled with the present studies showing its importance in normal pancreatic processes, suggest they should be considered an important signaling molecule in pancreatic cells and included in future investigations.