GI PEPTIDE SIGNALING THROUGH TYROSINE PHOSPHORYLATION

通过酪氨酸磷酸化的 GI 肽信号传导

基本信息

批准号：
7828185
负责人：
JUAN ENRIQUE ROZENGURT
金额：
$ 26.85万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7828185
关键词：
Adaptor Signaling Protein Adenylate Cyclase Agonist Applications Grants Biological Cell Cycle Progression Cells Cyclic AMP DNA biosynthesis Epidermal Growth Factor Receptor Epithelial Cells Event Fibroblasts Focal Adhesion Kinase 1 Focal Adhesions Funding G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Grant Growth Factor Receptors Infection Inflammatory Bowel Diseases Injury Intestines Ion Channel Ischemia Ligands Lipid Binding Lipids Maintenance Mediating Modeling Mucous Membrane Neurotransmitters Pathway interactions Peptide Signal Sequences Peptides Phospholipase C Phosphorylation Phosphorylation Site Play Process Protein Tyrosine Kinase Proteins RBL2 gene Radiation Receptor Activation Receptor Protein-Tyrosine Kinases Regulation Research Personnel Role Second Messenger Systems Serine Signal Transduction Signal Transduction Pathway Stimulation of Cell Proliferation Testing Transactivation Tyrosine Tyrosine Phosphorylation Ulcer base cell motility cytokine experience gastrointestinal interest migration novel paxillin programs receptor repaired response rho second messenger src-Family Kinases

项目摘要

DESCRIPTION (provided by applicant): Many gastrointestinal (Gl) peptides, neurotransmitters and bioactive lipids bind to G protein-coupled receptors (GPCRs) and induce cell migration and proliferation in their target cells. These processes play an essential role in the repair of many forms of injury to the mucosa of the Gl tract, including erosions, ulcers, inflammatory bowel disease, enteropathic infections, ischemia and radiation. The broad, long-term objective of this proposal is to elucidate the signal transduction pathways that mediate GPCR-induced migration and proliferation in intestinal epithelial cells. In addition to signaling via classic second messengers (e.g., Ca2+, DAG, cAMP), an emerging theme is that GPCR agonists also induce tyrosine phosphorylation of multiple proteins, including the non-receptor tyrosine kinase p125 focal adhesion kinase (FAK) and the adaptor proteins p130 Crk-associated substrate (CAS) and paxillin, which are implicated in cell migration and proliferation. GPCR stimulation also induces rapid epidermal growth factor receptor (EGFR) transactivation. During the past funding period, our studies established that GPCR agonists, including regulatory peptides and bioactive lipids induce tyrosine phosphorylation cascades involving FAK, Src, Pyk2 and EGFR in a variety of cells, including intestinal epithelial cells. These studies form the basis for further exploration of the mechanisms by which tyrosine phosphorylation events contribute to cell migration and proliferation in GPCR-stimulated cells described in the current grant proposal. Based on our previous findings, our central hypothesis is that tyrosine phosphorylation cascades play a critical role in GPCR-induced cellular migration and mitogenesis in intestinal epithelial cells. This proposal will pursue the following specific hypotheses and aims: Hypothesis I. GPCR agonists induce tyrosine and serine phosphorylation of focal adhesion tyrosine kinases implicated in the regulation of cell migration and cell cycle progression. Aims emanating from hypothesis I: 1) Characterize the regulation of novel phosphorylation sites of FAK in response to GPCR agonists and EGFR ligands in IEC-18 and T84 intestinal epithelial cells. 2) Define the role of FAK in mediating migration, DNA synthesis, proliferation and signal transduction in intestinal epithelial cells. Hypothesis II: EGFR transactivation contributes to transduce mitogenic signaling by GPCR agonists in intestinal epithelial cells Aims emanating from hypothesis II: 3) Characterize the signal transduction pathways that mediate GPCR-induced EGFR transactivation in intestinal epithelial cells and determine the role of this process in GPCR-induced mitogenesis in these cells 4) Define the signaling mechanism(s) by which EGFR transactivation contributes to GPCR-mediated mitogenesis in intestinal epithelial cells.

描述（由申请人提供）：许多胃肠道（GL）肽，神经递质和生物活性脂质与G蛋白偶联受体（GPCR）结合，并在其靶细胞中诱导细胞迁移和增殖。这些过程在修复多种形式的GL区损伤中起着至关重要的作用，包括侵蚀，溃疡，炎症性肠病，肠病感染，缺血和放射线。该提案的广泛长期目标是阐明介导GPCR诱导的肠上皮细胞迁移和增殖的信号转导途径。 In addition to signaling via classic second messengers (e.g., Ca2+, DAG, cAMP), an emerging theme is that GPCR agonists also induce tyrosine phosphorylation of multiple proteins, including the non-receptor tyrosine kinase p125 focal adhesion kinase (FAK) and the adaptor proteins p130 Crk-associated substrate (CAS) and paxillin, which are implicated在细胞迁移和增殖中。 GPCR刺激还诱导表皮生长因子受体（EGFR）的快速反式激活。在过去的资金期间，我们的研究确定，包括调节肽和生物活性脂质在内的GPCR激动剂诱导涉及FAK，SRC，PYK2和EGFR的酪氨酸磷酸化级联反应，包括各种细胞，包括肠上皮细胞。这些研究构成了进一步探索酪氨酸磷酸化事件的机制的基础。根据我们以前的发现，我们的中心假设是酪氨酸磷酸化级联反应在肠上皮细胞中GPCR诱导的细胞迁移和有丝分裂发生中起关键作用。该提案将追求以下特定的假设和目的：假设I. GPCR激动剂诱导酪氨酸和与细胞迁移和细胞周期进展有关的局部粘附酪氨酸激酶的酪氨酸和丝氨酸磷酸化。源自假设i的目的：1）表征了IEC-18和T84肠上皮细胞中GPCR激动剂和EGFR配体的FAK新型磷酸化位点的调节。 2）定义FAK在肠上皮细胞中介导迁移，DNA合成，增殖和信号转导的作用。假说II：EGFR反式激活有助于GPCR激动剂在肠上皮细胞中的促丝分裂信号传导，旨在从假说中引起的旨在提出假设II：3）表征了介导GPCR介导GPCR诱导EGFR诱导的EGFR在肠道上的细胞中的EGFR诱导的肠道上皮细胞中EGFR的作用的信号转导途径的作用，并确定了GPCR在GPCR中的作用。 EGFR反式激活有助于GPCR介导的肠上皮细胞中GPCR介导的有丝分裂发生的机制。