Recent studies show that gastrointestinal hormones/growth factorsGI/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 published a study demonstarting that endothelin(ET) can interact with ETA receptors on lung cancer cells to stimulate growth and that this is mediated by transactivation of both epidermal growth factor receptor and ERB2/HER2/Neu activation. The transactivation requires activation of Src, matrix metalloproteinases and generation of oxygen free radicals. Little is known of the role of activation of p21-activated kinases (PAKs) or Src family kinases or in mediating actions of GI hormones/neurotransmitters. In a number of different studies we used pancreatic acinar cells, which are highly responsive to number of gastrointestinal hormones/neurotransmitter to explore the role of PAK2 and Src family of kinases and in mediating the signaling of these agents on cellular cascades known to mediate physiological and pathophysiological responses in these cells. We found that only PAK2 of the type I family of was present in pancreatic acinar cells and its activation was important in mediating the activation of a number of cell signaling cascades by pancreatic hormones/neurotransmitters in acinar cells and in the early onset of acute pancreatitis. In addition, we found both inhibition and over activation 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. In addition, we found that activation of Src kinases play a dual role in determining the severity of pancreatitis.
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