Tyrosine Phosphorylation of Insulin Receptor Substrate-1 and Activation of the PI-3-Kinase Pathway by Glycine-Extended Gastrin Precursors (original) (raw)

1997, Biochemical and Biophysical Research Communications

cause of the non selectivity of the compounds used in Glycine-extended gastrin precursors (G-Gly) were these studies, the notion of autocrine loop for gastrin considered as processing intermediates devoid of bioremains controversial. logical activity. However, we have recently identified Like many other regulatory peptides, gastrin is charselective receptors for G-Gly which mediate the prolifacterized by the presence of a carboxyl-terminal amide erative effects of this precursor. Little is known about group. Post-translational processing of progastrin, that the signaling pathways activated by G-Gly. In the presleads to amidated gastrin, involves the formation of ent study, we demonstrate that PI-3-kinase is rapidly glycine-extended processing intermediates (G-Gly) and transiently activated by G-Gly. We also observed which serve as substrates for alpha amidation. Until a rapid increase in the tyrosine phosphorylation of recently, the alpha-amide group was presumed to be IRS-1 and an activation of the PI-3-kinase in anti-IRSessential for full biological activity. 1 immunoprecipitates, suggesting that PI-3-kinase In peptide-producing tumors, post-translational promay be activated by association with tyrosine phosphorylated IRS-1. We also demonstrated that gastrin cessing is often incomplete. Thus non-amidated progasprecursors activate the serine/threonine kinase, p70 trin-derived peptides have been shown to be present in kDa S6 kinase (p70 S6K), through a wortmannin sensilung, pancreas and colon tumors at concentrations tive pathway. ᭧ 1997 Academic Press higher than in normal tissues (10-12). In addition, levels of processing intermediates of gastrin are elevated in the circulation of patients with colorectal carcinomas (13). We have recently reported that glycine-extended pro-Gastrin, a peptide hormone produced from G cells in gastrin processing intermediates exert trophic effects the gastric antrum was first characterized as a regulathrough selective membrane receptors distinct from tor of gastric acid secretion (1). Gastrin also functions the G protein-coupled gastrin receptor (G/CCK B) that as a growth-promoting factor for normal gut mucosal mediates the effects of amidated gastrin (14). Similar cells (2). This peptide has also been reported to have results were obtained by another laboratory on colon trophic effects on a number of gastrointestinal cancers. cancer cells, normal fetal intestinal cells as well as fi-Many studies have demonstrated the stimulatory efbroblasts (15, 16). fects of exogenous gastrin on the growth in vitro of cell Little is known about the mitogenic signal transduclines established from pancreatic, gastric and colonic tion pathways activated by the binding of G-Gly to its carcinomas (3, 4). In addition, gastrin enhances the specific membrane receptors. Recent studies indicate growth in vivo of tumor cells transplanted in animals that activation of c-jun amino-terminal kinase (JNK) (5, 6). A potential autocrine effect of gastrin on colon may contribute to the intracellular events that are recancers has been proposed by different laboratories sponsible for the growth promoting effects of G-Gly based on the inhibitory effects of gastrin receptor an-(17). This enzyme has been shown to increase the phostagonists and gastrin antibodies (7-9). However, bephorylation and the transcriptional activity of the cjun proteins which control the transcription of early 1 Address correspondence to Catherine Seva, INSERM U.151, response genes including c-jun itself. Groupe de Recherche de Biologie et Pathologie digestive Institut PI-3-kinase is a lipid kinase that phosphorylates Louis Bugnard,