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：
7316004
负责人：
RICHARD A. CERIONE
金额：
$ 32.32万
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/7316004
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 Goals Growth Growth Factor Receptors Guanine Nucleotide Exchange Factors Guanosine Diphosphate 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 Range Rattus Receptor Down-Regulation Receptor Signaling Regulation Research Personnel Role Role playing therapy 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 Gdi2 protein 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）：与RAS相关的GTPase CDC42在广泛的细胞过程中起着重要作用，包括建立细胞极性以及控制细胞生长和迁移。 Cdc42-偶联信号传导活性的适当调控对于其细胞功能至关重要，这是通过致癌鸟嘌呤核苷酸交换因子（GEFS）对Cdc42的过度激活所证明的，或者突变引起GDP的加速GDP的GDP交换，导致细胞转化和Tumor Trumor的形成，并导致了Tumor的形成。在过去的资金期间，我们确定了CDC42及其调节蛋白cool-1（用于克隆的文库）如何作为CDC42的GEF和靶标/效应子来调节细胞的生长，从而通过维持适当的EGF受体（EGFR）稳态来调节细胞的生长。我们还发现，Cool-1的磷酸化 - 二磷酸化周期会影响细胞迁移，这增加了CDC42及其信号伴侣可能与细胞运动的调节相协调细胞生长控制的有趣可能性。此外，我们对不同细胞和遗传模型系统的研究突出了CDC42在细胞分化和细胞命运测定中的作用。在即将到来的资金期间，我们将继续将生化和结构生物学的研究与遗传方法结合起来，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根本重要的细胞过程，即细胞生长，迁移和差异。这些研究将构成3条特定的调查线。 1）确定CDC42及其信号合作伙伴如何一起工作以保持适当的EGFR稳态。在这些研究中，我们将特别有兴趣确定为CDC42介导的信号设定时机的调节线索，这些信号在EGFR偶联的有丝分裂信号与受体下调和降解之间建立了适当的平衡。 2.）检查Cool-1及其结合伴侣如何调节细胞迁移。在这里，我们将跟进最近的线索，表明Cool-1的磷酸化刺激其与CAT的解离（用于冷却相关的酪氨酸激酶底物），并有助于触发焦点复合物的拆卸。我们还想看看Cool-1的CDC42-GEF活性是否由其磷酸化引起，赋予了对细胞迁移的重要调节作用。 3.）检查CDC42及其信号伴侣在细胞分化中的作用。我们将探讨CDC42可能参与，以确保神经元分化所需的信号活动的适当寿命。此外，我们将基于我们最近在小鼠胚胎（P19）细胞（P19）细胞中进行的研究，该研究表明CDC42和我们最近发现的双功能CDC42- GEF/靶向效应器在神经发生中起重要作用。我们预计，这些研究将对CDC42如何介导正常生物学结果所必需的各种细胞反应产生新的见解，并在脱离调节时会引起各种疾病状态，包括癌症和神经退行性疾病。