Roles of Cdc42 and its signaling partners in cell growth and differentiation

Cdc42 及其信号传导伴侣在细胞生长和分化中的作用

基本信息

批准号：
7817131
负责人：
RICHARD A. CERIONE
金额：
$ 32.02万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7817131
关键词：
Back Binding Biochemical Biochemical Genetics Biological Biological Models Brain Cell Differentiation process Cell Line Cell Lineage Cell Polarity Cell physiology Cells Coat Protein Complex I Complement Complex Coupled Cues Development Disease Dissociation EGF gene Embryo Endocytosis Ensure Epidermal Growth Factor Receptor Equilibrium Event Excision Felis catus Funding Genetic Genetic Models Goals Growth Growth Factor Receptors Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Homeostasis Integrins Investigation Laboratories Learning Libraries Link Malignant Neoplasms Mediating Molecular Morphogenesis Movement Mus Mutation Names Nerve Neurites Neurodegenerative Disorders Neuronal Differentiation Neurons Nude Mice Oncogenic Outcome PC12 Cells PTK2 gene Pheochromocytoma Phosphoric Monoester Hydrolases Phosphorylation Play Process Protein Dephosphorylation Protein Family Protein Tyrosine Kinase Proteins Rattus Receptor Down-Regulation Receptor Signaling Regulation Research Personnel Role Running Signal Pathway Signal Transduction Teratoma Testing Time Tyrosine Phosphorylation Ubiquitination Work Wound Healing X-Linked Mental Retardation base cdc42 GTP-Binding Protein cell growth cell motility feeding follow-up genetic regulatory protein insight interest member metaplastic cell transformation migration mouse development mutant neurogenesis novel olfactory lobe programs ras-Related G-Proteins receptor receptor coupling response rhoB p20 GDI structural biology trafficking tumor

项目摘要

DESCRIPTION (provided by applicant): The Ras-related GTPase Cdc42 plays important roles in a wide range of cellular processes including the establishment of cell polarity and the control of cell growth and migration. The proper regulation of Cdc42- coupled signaling activities is crucial for its cellular functions, as evidenced by the hyper-activation of Cdc42 by oncogenic guanine nucleotide exchange factors (GEFs), or mutations that give rise to an accelerated exchange of GDP for GTP, resulting in cellular transformation and tumor formation in nude mice. During the past funding period, we established how Cdc42 and its regulatory protein Cool-1 (for Cloned-out of library), which functions both as a GEF and a target/effector for Cdc42, regulate cell growth by helping to maintain proper EGF receptor (EGFR) homeostasis. We also discovered that the phosphorylation-dephosphorylation cycle of Cool-1 influences cell migration, raising the interesting possibility that Cdc42 and its signaling partners may coordinate cell growth control with the regulation of cell motility. Moreover, our studies with different cell and genetic model systems have highlighted a role for Cdc42 in cellular differentiation and cell fate determination. In the coming funding period, we will continue to combine biochemical and structural biology-based studies with genetic approaches to extend these findings and better establish how Cdc42 and its regulatory proteins impact three fundamentally important cellular processes, namely cell growth, migration, and differentiation. These studies will constitute 3 specific lines of investigation. 1) Determine how Cdc42 and its signaling partners work together to maintain proper EGFR homeostasis. In these studies, we will be particularly interested in determining the regulatory cues that set the timing for the Cdc42- mediated signals that establish the proper balance between EGFR-coupled mitogenic signaling versus receptor down-regulation and degradation. 2.) Examine how Cool-1 and its binding partners regulate cell migration. Here, we will follow-up recent clues suggesting that the phosphorylation of Cool-1 stimulates its dissociation from Cat (for Cool-associated tyrosine kinase substrate) and helps trigger the disassembly of focal complexes. We also will want to see whether the Cdc42-GEF activity of Cool-1, which is triggered by its phosphorylation, confers important regulatory effects on cell migration. 3.) Examine the roles of Cdc42 and its signaling partners in cellular differentiation. We will explore the possible involvement of Cdc42 in ensuring the proper lifetime for signaling activities necessary for neuronal differentiation. In addition, we will build on our recent studies in mouse embryonic (P19) cells that suggest Cdc42 and a dual function Cdc42- GEF/target-effector that we recently discovered, play important roles in neurogenesis. We expect that these studies will yield new insights into how Cdc42 is able to mediate a diversity of cellular responses that are necessary for normal biological outcomes and, when de-regulated, gives rise to a variety of disease states including cancer and neurodegenerative disorders.

描述（由申请人提供）：Ras 相关的 GTPase Cdc42 在广泛的细胞过程中发挥重要作用，包括细胞极性的建立以及细胞生长和迁移的控制。 Cdc42 偶联信号活动的正确调节对其细胞功能至关重要，致癌鸟嘌呤核苷酸交换因子 (GEF) 过度激活 Cdc42 或导致 GDP 加速交换为 GTP 的突变就证明了这一点。裸鼠的细胞转化和肿瘤形成。在过去的资助期间，我们确定了 Cdc42 及其调节蛋白 Cool-1（用于库克隆）如何通过帮助维持适当的 EGF 受体来调节细胞生长，Cool-1 既充当 GEF 又充当 Cdc42 的靶标/效应器（EGFR）体内平衡。我们还发现 Cool-1 的磷酸化-去磷酸化循环影响细胞迁移，这提出了 Cdc42 及其信号传导伙伴可能协调细胞生长控制与细胞运动调节的有趣可能性。此外，我们对不同细胞和遗传模型系统的研究强调了 Cdc42 在细胞分化和细胞命运决定中的作用。在接下来的资助期内，我们将继续将基于生化和结构生物学的研究与遗传方法相结合，以扩展这些发现，并更好地确定 Cdc42 及其调节蛋白如何影响三个基本重要的细胞过程，即细胞生长、迁移和分化。这些研究将构成 3 个具体的研究方向。 1) 确定 Cdc42 及其信号传导伙伴如何协同工作以维持适当的 EGFR 稳态。在这些研究中，我们将特别感兴趣的是确定调节线索，这些线索为 Cdc42 介导的信号设定时间，从而在 EGFR 偶联有丝分裂信号传导与受体下调和降解之间建立适当的平衡。 2.) 检查 Cool-1 及其结合伙伴如何调节细胞迁移。在这里，我们将跟踪最近的线索，这些线索表明 Cool-1 的磷酸化会刺激其与 Cat（Cool 相关酪氨酸激酶底物）的解离，并有助于触发焦点复合物的分解。我们还想了解 Cool-1 的磷酸化触发的 Cdc42-GEF 活性是否对细胞迁移具有重要的调节作用。 3.) 检查 Cdc42 及其信号传导伴侣在细胞分化中的作用。我们将探索 Cdc42 在确保神经元分化所需的信号活动的适当寿命方面的可能参与。此外，我们将基于我们最近对小鼠胚胎 (P19) 细胞的研究，这些研究表明 Cdc42 和我们最近发现的双重功能 Cdc42-GEF/靶效应器在神经发生中发挥重要作用。我们预计这些研究将产生关于 Cdc42 如何能够介导正常生物学结果所必需的多种细胞反应的新见解，并且当解除管制时，会引起包括癌症和神经退行性疾病在内的多种疾病状态。