Cellular Basis Of Action Of Gastrointestinal Peptides/Gr

最近的研究表明，胃肠激素/生长因子可以通过刺激多个细胞内酪氨酸磷酸化（TyrP）信号级联来刺激细胞生长。然而，目前对许多胃肠激素/生长因子在GI组织中激活这些级联的能力知之甚少。在这一年中，我们已经报道了Src激酶林恩、衔接蛋白Gab 1、蛋白激酶c δ和衔接蛋白CRK 11的激活在介导胰腺腺泡对激素、生长因子和由活性氧引起的应激的应答中的重要性。我们证明了衔接蛋白GAB 1的激活对于生长因子肝细胞生长因子（HGF）改变胰腺腺泡细胞的能力是重要的。然而，它没有发挥作用的细胞信号转导的不同G-蛋白偶联受体存在于腺泡细胞，包括受体CCK，胆碱能药物，VIP，分泌素或蛙皮素。肝细胞生长因子在胰腺癌的发生发展中起着重要的作用，在胰腺癌的发生发展中起着重要的作用。我们的研究表明，HGF在GAB 1的Y307和Y 627 Tyr位点上快速有效地刺激GAB 1 TyrP。这不仅导致GAB 1重新分布到膜上，还刺激GAB 1与许多下游效应物的结合，包括SHP 2、PI 3 K、Shc和Crk同种型，但不包括PLC γ。这种刺激并不依赖于HGF刺激细胞钙离子变化或激活PKC的能力。这些结果表明，GAB 1在HGF而不是不同的G蛋白偶联受体改变胰腺腺泡细胞功能的能力中起核心作用。我们证明了激活腺苷酸环化酶的激素以及磷脂酶C和已知的胰腺生长因子，都引起Src激酶林恩的快速激活。这种激活导致随后大量细胞内级联的激活，证明Src激酶的激活在腺泡细胞信号传导中起着中心作用。

Recent studies show that gastrointestinal hormones/growth factors may stimulate cell growth by stimulating multiple intracellular tyrosine phosphorylation (TyrP) signaling cascades. However at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades in GI tissues. During this year we have reported the importance of activation of the Src kinase Lyn, the adaptor protein Gab1, protein kinase c delta and the adaptor protein CRK11 in mediating response of pancreatic acini to hormones, growth factors and stress caused by reactive oxygen species. We demonstrated that activation of the adaptor protein, GAB1 is important for the ability of the growth factor, hepatocyte growth factor (HGF) to alter pancreatic acinar cells. However it played no role in the cellular signaling by different G-protein-coupled receptors present on acinar cells including receptors for CCK, cholinergic agents, VIP, secretin or bombesin. HGF has been reported to play an important role in growth as well as the recovery from injury of acinar cells as well as function as an important growth factor in pancreatic cancer. Our studies show HGF stimulates GAB1 TyrP rapidly and potently at both the Y307 and Y627 Tyr loci of GAB1. This not only caused a redistribution of GAB1 to the membrane it also stimulated the association of GAB1 with numerous downstream effectors including SHP2, PI3K, Shc and Crk isoforms, but not PLC gamma. This stimulation did not depend on the ability of HGF to stimulate changes in cellular calcium or activate PKC. These results show GAB1 plays a central role in the ability of HGF but not different G protein coupled receptors to alter pancreatic acinar cell function. We demonstrated both hormones activating adenylate cyclase as well as phospholipase C and known pancreatic growth factors, all caused rapid activation of the Src kinase, lyn. This activation resulted in subsequent\ activation of a large number of intracellular cascades demonstrating the central role activation of the Src kinase plays in acinar cell signaling.