Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

肌动蛋白调节蛋白，cofilin在许多细胞中对许多细胞应答起关键的信号传导作用，包括增殖、发育、运动、迁移、分泌和生长。在胰腺中，它在胰岛胰岛素分泌、胰腺癌细胞生长和胰腺炎中很重要。然而，还没有关于其在胰腺腺泡细胞中的作用或激活的研究。为了解决这个问题，我们研究了胆囊收缩素（CCK）激活胰腺腺泡细胞，AR 42 J细胞和CCK 1-R转染的Panc-1细胞中cofilin的能力，涉及的信号级联及其对酶分泌和MAPK激活的影响，MAPK是胰腺生长的关键介质。我们的研究结果支持这样的结论，即cofilin激活在CCK介导的胰腺腺泡生长/酶分泌中对各种细胞信号级联PKC/PKD、Src、PAK 4、JNK、ROCK起关键的会聚作用。 最近的研究表明，在正常和肿瘤组织中，胃肠激素（GI）和GI生长因子（GF）可通过刺激多个细胞内酪氨酸/丝氨酸/苏氨酸磷酸化（TyrP）信号级联以及通过生长因子受体的反式激活来引起细胞生长。然而，目前人们对许多胃肠道激素/生长因子激活这些级联反应的能力知之甚少。在过去，我们报道了肺癌细胞中的神经肽，神经降压素刺激这些肿瘤的生长，同时主要通过一些EGFR家族成员（包括EGFR、HER 2）的反式激活来进行信号传导，然而，尚不清楚神经降压素是否也反式激活其他EGFR/Neu成员（如HER 3），因此我们在肺癌细胞中研究了这个问题。我们发现这些细胞中的神经降压素通过激活HER 3刺激增殖，其表现为刺激EGFR/HER 3和HER 2/HER 3二聚体的形成。最近的研究，包括我们的研究表明，在不同的细胞中，这些肽刺激酪氨酸磷酸化和受体酪氨酸激酶的能力的机制涉及许多不同的机制，这是详细审查PACAP-VIP，蛙皮素，内皮素和神经降压素在今年的邀请审查。这些GPCR激活这些酪氨酸激酶级联的新能力证明了这些受体在许多生理/病理过程中的重要性，特别是正常和癌症组织的生长级联，开辟了新的治疗方法。 除了我们的实验研究之外，我们最近还撰写了一些特邀评论和批判性分析，这些评论和分析部分基于我们正在研究的各种胃肠道肽（蛙皮素受体家族，VIP-PACAP肽家族，内皮素受体家族，神经降压素）的细胞作用基础。其中包括报告了通过EGF受体家族的反式激活这些受体中的一些对癌症生长的影响的论文，以及PACAP/VIP和蛙皮素受体家族分别在各种人类疾病和CNS癌症中的可能治疗作用的综述。

The actin regulatory protein, cofilin plays a key signaling role in many cells for numerous cellular responses including in proliferation, development, motility, migration, secretion, and growth. In the pancreas it is important in islet insulin secretion, growth of pancreatic cancer cells and in pancreatitis. However, there are no studies on its role or activation in pancreatic acinar cells. To address this question, we studied the ability of Cholecystokinin (CCK) to activate cofilin in pancreatic acinar cells, AR42J cells and CCK1-R transfected Panc-1 cells, the signaling cascades involved and its effect on enzyme secretion and MAPK activation, a key mediator of pancreatic growth. Our results support the conclusion that cofilin activation plays a pivotal convergent role for various cell signaling cascades PKC/PKD, Src, PAK4, JNK, ROCK in CCK-mediated growth/enzyme secretion in pancreatic acini. 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/serine/threonine phosphorylation (TyrP) signaling cascades as well as by transactivation of growth factor receptors. However, at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. In the past, we reported that the neuropeptide, neurotensin in lung cancer cells stimulates growth of these tumors while signaling principally by transactivation of a number of EGFR family members including EGFR, HER2, however, it is unclear whether neurotensin also transactivates other EGFR/Neu members such as HER3, hence we examined this question in lung cancer cells. We found that neurotensin in these cells stimulates proliferation by activating HER3 manifested by stimulating the formation of EGFR/HER3 and HER2/HER3 dimers. Recent studies, including ours have demonstrated that in different cells the mechanisms of the ability of these peptides to stimulate tyrosine phosphorylation and receptor tyrosine kinases involves a number of different mechanisms, and this was reviewed in detail for PACAP-VIP, Bombesin, endothelin and neurotensin in an invited review this year. The novel abilities of these GPCRs to activate these tyrosine kinase cascades are demonstrating the importance of these receptors in numerous physiological/pathological processes, particular growth cascades of both normal and cancer tissues, opening new therapeutic approaches. In addition to our experimental studies, we have recently we have written a number of invited reviews and critical analyses which are partially based on our studies of the cellular basis of action of various gastrointestinal peptides that we are studying (bombesin receptor family, VIP-PACAP peptide family, endothelin receptor family, neurotensin). These include papers reporting the effects of activation of a number of these receptors on cancer growth through the transactivation of the EGF receptor family as well as reviews of the possible therapeutic roles of PACAP/VIP and bombesin receptor families in various human diseases and CNS cancers, respectively.