Signaling Pathways in Neuronal Cells

神经元细胞中的信号通路

基本信息

批准号：
7227485
负责人：
MARSHA R ROSNER
金额：
$ 37.83万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-05-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7227485
关键词：
Bacteria Binding Binding Sites Cell Cycle Stage Cell Proliferation Cells Complex Condition DNA biosynthesis DNA chemical synthesis Development Differentiation and Growth Epidermal Growth Factor Epidermal Growth Factor Receptor Epithelial Event Family Fibroblast Growth Factor Generations Genes Goals Grant Growth Growth Factor Growth and Development function Laboratories Lead Ligand Binding Ligands MAPK1 gene MAPK3 gene MUK protein kinase Mediating Mediator of activation protein Mitogen-Activated Protein Kinases Mitogens Mitotic Mus Neuronal Differentiation Neurons Physiological Proline Protein Kinase Protein Kinase C Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-raf RNA Interference Ras/Raf Reagent Receptor Protein-Tyrosine Kinases Regulation Role S-Phase Fraction Signal Pathway Signal Transduction Site Stimulation of Cell Proliferation Testing Therapeutic Agents Tumor-Derived X-Ray Crystallography cell growth citrate carrier inhibitor/antagonist man member mutant neural growth neuronal growth prevent prostatic binding protein raf Kinases relating to nervous system tumor

项目摘要

DESCRIPTION (provided by applicant): Activation of growth signaling cascades by epidermal growth factor (EGF) and other mitogens is a key step in cell growth and development as well as the generation of neural and other epithelial-derived tumors. Among the main mediators of signals transmitted by tyrosine kinase receptors such as the EGF receptor are the mitogenactivated protein kinases (MAPKs), a superfamily of highly homologous proline-directed serine/threonine kinases that participate in the transduction of growth and differentiation-promoting signals. The Ras/Raf kinase cascade that leads to activation of ERK1 and ERK2, two members of the ERK subfamily of MAPKs, is required for cell growth and thus is an important target of therapeutic agents for tumor treatment. Recent studies from our laboratory have revealed a new mechanism for the regulation of Raf-1 by growth factors. Under nonstimulatory conditions, Raf-1 can form a complex with a Raf Kinase Inhibitory Protein (RKIP/PEBP). An evolutionarily conserved protein that is present from bacteria to man, RKIP prevents Raf- 1 from downstream signaling. We have shown that different growth factors activate specific members of the protein kinase C (PKC) family that, in turn, cause release of RKIP, enabling activation of Raf and the MAPK signaling cascade. More recent results have implicated RKIP in mitotic progression. We therefore hypothesize that RKIP is a key regulator of mitogenesis. The goal of this proposal is to characterize further the physiological functions of RKIP, elucidate the mechanisms by which RKIP functions, and define the structural interactions that underlie these mechanisms. Specifically, we plan to (1) Determine the role(s) of RKIP at different stages of the cell cycle in regulating cell growth; (2) Determine the mechanism(s) by which RKIP regulates MAP kinase signaling and mitotic progression; and (3) Identify the key functional domains in RKIP. The studies proposed here will increase our understanding of the regulation of these key events in cell proliferation, and should lead to the development of new reagents that can inhibit growth of neural and other epithelial-derived tumors.

描述（由申请人提供）：表皮生长因子（EGF）和其他有丝分裂原激活生长信号级联是细胞生长和发育以及神经和其他上皮源性肿瘤生成的关键步骤。丝裂原激活蛋白激酶 (MAPK) 是酪氨酸激酶受体（例如 EGF 受体）传递信号的主要介质之一，它是高度同源的脯氨酸定向丝氨酸/苏氨酸激酶超家族，参与生长和分化促进信号的转导。 Ras/Raf 激酶级联导致细胞生长所需的 ERK1 和 ERK2（MAPK 的 ERK 亚家族的两个成员）激活，因此是肿瘤治疗药物的重要靶点。我们实验室最近的研究揭示了生长因子调节 Raf-1 的新机制。在非刺激条件下，Raf-1 可以与 Raf 激酶抑制蛋白 (RKIP/PEBP) 形成复合物。 RKIP 是一种从细菌到人类都存在的进化保守蛋白，可阻止 Raf-1 下游信号传导。我们已经证明，不同的生长因子会激活蛋白激酶 C (PKC) 家族的特定成员，进而导致 RKIP 释放，从而激活 Raf 和 MAPK 信号级联。最近的结果表明 RKIP 参与有丝分裂进展。因此，我们假设 RKIP 是有丝分裂的关键调节因子。该提案的目标是进一步表征 RKIP 的生理功能，阐明 RKIP 发挥作用的机制，并定义这些机制背后的结构相互作用。具体来说，我们计划（1）确定RKIP在细胞周期不同阶段调节细胞生长的作用； (2) 确定 RKIP 调节 MAP 激酶信号传导和有丝分裂进程的机制； (3) 确定 RKIP 的关键功能域。这里提出的研究将增加我们对细胞增殖中这些关键事件的调节的理解，并应导致开发出可以抑制神经和其他上皮源性肿瘤生长的新试剂。