Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

胃肠肽/生长因子作用的细胞基础

基本信息

批准号：
10932755
负责人：
Robert Jensen
金额：
$ 93.06万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10932755
关键词：
Acinar Cell Acinus organ component Actins Address Area Bombesin Bombesin Receptor Cell physiology Cells Central Nervous System Cholecystokinin Consensus Development ERBB2 gene ERBB3 gene Endothelin Endothelin Receptor Enzymes Epidermal Growth Factor Receptor Family Family member G-Protein-Coupled Receptors Gastrointestinal Hormones Gastrointestinal tract structure Growth Growth Factor Growth Factor Receptors Hormones Human MAP Kinase Gene MAPK8 gene Malignant Neoplasms Malignant neoplasm of central nervous system Mediating Mediator Neuropeptides Neurotensin Neurotransmitters Pancreas Pancreatitis Paper Pathologic Processes Peptides Physiological Play Positioning Attribute Process Proliferating Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Receptor Protein-Tyrosine Kinases Reporting Role Serine Serine/Threonine Phosphorylation Signal Transduction Stimulation of Cancer Cell Growth Stimulation of Cell Proliferation Therapeutic Tissues Transactivation Transfection Tyrosine Tyrosine Phosphorylation Vasoactive Intestinal Peptide Receptors Writing cell growth cell motility cofilin dimer examination questions experimental study gastrointestinal genetic regulatory protein human disease insulin secretion islet lung cancer cell member migration neoplastic novel novel therapeutic intervention pancreatic cancer cells pituitary adenylate cyclase activating polypeptide pituitary adenylate cyclase-activating peptide receptor receptor response tumor growth tyrosine receptor

项目摘要

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.

肌动蛋白调节蛋白丝切蛋白在许多细胞中对于多种细胞反应（包括增殖、发育、运动、迁移、分泌和生长）发挥着关键的信号传导作用。在胰腺中，它对于胰岛胰岛素分泌、胰腺癌细胞的生长和胰腺炎很重要。然而，尚无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，我们研究了缩胆囊素 (CCK) 在胰腺腺泡细胞、AR42J 细胞和 CCK1-R 转染的 Panc-1 细胞中激活丝切蛋白的能力、所涉及的信号级联及其对酶分泌和 MAPK 激活的影响，这是关键胰腺生长的介质。我们的结果支持这样的结论：肌动蛋白丝切蛋白激活对于胰腺腺泡中 CCK 介导的生长/酶分泌中的各种细胞信号级联 PKC/PKD、Src、PAK4、JNK、ROCK 起着关键的汇聚作用。最近的研究表明，在正常和肿瘤组织中，胃肠激素（GI）和胃肠道生长因子（GF）可能通过刺激多个细胞内酪氨酸/丝氨酸/苏氨酸磷酸化（TyrP）信号级联以及生长因子的反式激活来引起细胞生长受体。然而，目前对许多胃肠激素/生长因子激活这些级联的能力知之甚少。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，同时主要通过包括 EGFR、HER2 在内的许多 EGFR 家族成员的反式激活来发出信号，然而，尚不清楚神经降压素是否也反式激活其他 EGFR/Neu HER3等成员，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 HER3 来刺激增殖，具体表现为刺激 EGFR/HER3 和 HER2/HER3 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机制涉及许多不同的机制，并且对 PACAP-VIP、Bombesin、内皮素和神经降压素进行了详细回顾在今年的邀请评审中。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，特别是正常组织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，我们最近还撰写了许多受邀评论和批判性分析，这些评论和分析部分基于我们对我们正在研究的各种胃肠肽（铃蟾肽受体家族、VIP-PACAP）作用的细胞基础的研究肽家族、内皮素受体家族、神经降压素）。其中包括报告通过 EGF 受体家族的反式激活激活许多此类受体对癌症生长的影响的论文，以及对 PACAP/VIP 和铃蟾肽受体家族在各种人类疾病和中枢神经系统癌症中可能的治疗作用的评论，分别。

项目成果

期刊论文数量（32）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies.

DOI：
10.1097/med.0b013e328342568a
发表时间：
2011-02
期刊：
Current opinion in endocrinology, diabetes, and obesity
影响因子：
0
作者：
Moody TW;Ito T;Osefo N;Jensen RT
通讯作者：
Jensen RT

Cofilin activation in pancreatic acinar cells plays a pivotal convergent role for mediating CCK-stimulated enzyme secretion and growth.

DOI：
10.3389/fphys.2023.1147572
发表时间：
2023
期刊：
Frontiers in physiology
影响因子：
4
作者：
通讯作者：

Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells.

DOI：
10.1016/j.peptides.2017.01.012
发表时间：
2017-04
期刊：
Peptides
影响因子：
3
作者：
Moody TW;Ramos-Alvarez I;Moreno P;Mantey SA;Ridnour L;Wink D;Jensen RT
通讯作者：
Jensen RT

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.

DOI：
10.1016/j.bbadis.2016.02.008
发表时间：
2016-06
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Nuche-Berenguer B;Ramos-Álvarez I;Jensen RT
通讯作者：
Jensen RT

Bombesin marine toxin conjugates inhibit the growth of lung cancer cells.

DOI：
10.1016/j.lfs.2008.01.019
发表时间：
2008-04
期刊：
Life sciences
影响因子：
6.1
作者：
T. Moody;T. Pradhan;S. Mantey;R. Jensen;M. Dyba;Deborah L. Moody;N. Tarasova;C. Michejda
通讯作者：
T. Moody;T. Pradhan;S. Mantey;R. Jensen;M. Dyba;Deborah L. Moody;N. Tarasova;C. Michejda