Recent studies show that gastrointestinal hormones/growth factors may stimulate cell growth by stimulating multiple intracellular tyrosine phosphorylation (TyrP) signaling cascades as well as by transactivating growth factor receptors. However at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. Our studies have been in two general areas, which include studies of intracellular signaling cascades primarily by tyrosine kinases and studies of tumoral growth attempting to develop novel agents for growth inhibition. Recent studies show that gastrointestinal hormones, similar to growth factors, may stimulate cell growth/cell signaling by stimulating multiple intracellular tyrosine phosphorylation (TyrP) cascades. Whereas these cascades have been extensively investigated with growth factors, little is known in this area with may gastrointestinal hormones. The goal of these studies is to clarify this area primarily concentrating on cholecystokinin receptor cascades and bombesin receptor activation using primarily pancreatic acini as a model natural cell system. Studies involving the ability of agonists to stimulate the Bn related orphan receptor, BRS-3 to stimulate growth of lung cancer cells or BRS-3 transfected cells were performed. These studies show that BRS-3 activation stimulates transactivation of the EGF receptor which is dependent on activation of matrix metalloproteinases and the generation of reactive oxygen species. Related studies demonstrated the PACAP receptor activation in various cells results in p125FAK and paxillin tyrosine phosphorylation, two important docking proteins regulating cell motility, adhesion and important in growth. In pancreatic acini, CCK and other PLC activating hormones was shown to activate the novel PKC, PKC theta for the first time and it to play an important role in activating other key signaling cascades. In collaboration with Prof Ito, Fukuoka, Japan, VIP was shown to partially ameliorate experimental pancreatitis by inhibiting oxidative stress through the inhibition of NADPH oxidase.

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Ramos-Alvarez, Irene; Jensen, R T (2018) P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades. Am J Physiol Gastrointest Liver Physiol 315:G302-G317
Moreno, Paola; Mantey, Samuel A; Lee, Suk H et al. (2018) A possible new target in lung-cancer cells: The orphan receptor, bombesin receptor subtype-3. Peptides 101:213-226
Moody, Terry W; Ramos-Alvarez, Irene; Jensen, Robert T (2018) Neuropeptide G Protein-Coupled Receptors as Oncotargets. Front Endocrinol (Lausanne) 9:345
Moreno-Villegas, Zaida; Martín-Duce, Antonio; Aparicio, César et al. (2018) Activation of bombesin receptor Subtype-3 by [D-Tyr6,?-Ala11,Phe13,Nle14]bombesin6-14 increased glucose uptake and lipogenesis in human and rat adipocytes. Mol Cell Endocrinol 474:10-19
Moody, Terry W; Ramos-Alvarez, Irene; Moreno, Paula et al. (2017) Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells. Peptides 90:90-99
Lee, Lingaku; Ito, Tetsuhide; Nakamura, Taichi et al. (2017) Antifibrotic Effect of Saturated Fatty Acids via Endoplasmic Reticulum Stress Response in Rat Pancreatic Stellate Cells. Pancreas 46:385-394
Ito, Tetsuhide; Jensen, Robert T (2017) Molecular imaging in neuroendocrine tumors: recent advances, controversies, unresolved issues, and roles in management. Curr Opin Endocrinol Diabetes Obes 24:15-24
Nuche-Berenguer, Bernardo; Ramos-Álvarez, Irene; Jensen, R T (2016) The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events. Biochim Biophys Acta 1862:1122-36
Ito, Tetsuhide; Lee, Lingaku; Jensen, Robert T (2016) Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies. Expert Opin Pharmacother 17:2191-2205
Ramos-Álvarez, Irene; Nakamura, Taichi; Mantey, Samuel A et al. (2016) Novel chiral-diazepines function as specific, selective receptor agonists with variable coupling and species variability in human, mouse and rat BRS-3 receptor cells. Peptides 75:8-17

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