Role of RGS proteins in Ras- and B-Raf--mediated transformation

RGS 蛋白在 Ras 和 B-Raf 介导的转化中的作用

• 批准号: 7405399
• 负责人: CHANNING J. DER
• 金额: $ 22.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-11 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405399
• 关键词: Behavior; Binding; Biology; Cell Line; Cell Proliferation; Cell physiology; Cellular biology; Complex; Development; Endosomes; Epithelial Cells; Evaluation; Fibroblasts; Fluorescence; GTP-Binding Protein Regulators; Growth; HRAS gene; Heterotrimeric GTP-Binding Proteins; Large Intestine Carcinoma; Light; MAP Kinase Gene; MEKs; Malignant - descriptor; Malignant Epithelial Cell; Mediating; Mitogen-Activated Protein Kinases; Monomeric GTP-Binding Proteins; Mutation; Nature; Normal Cell; Oncogenes; Oncogenic; Output; Pathway interactions; Personal Satisfaction; Phosphotransferases; RGS Proteins; RNA; Raf Kinase Inhibitor; Ras/Raf; Regulation; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Molecule; Structure; Techniques; base; cancer cell; cancer therapy; interest; melanoma; mutant; neoplastic; neoplastic cell; novel strategies; research clinical testing; scaffold; small molecule; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): The importance of the Ras small GTPases in normal cell physiology and the aberrant behavior of cancer cells is well-established. Ras functions' as a signaling node that regulates normal cell proliferation, differentiation and survival. The diverse cellular roles of Ras are mediated through Ras regulation of multiple, functionally distinct, downstream signaling networks, with the Raf-MEK-ERK mitogen-activated protein kinase (MARK) cascade the best understood. The mutational activation of Ras results in persistent, deregulated signaling that promotes the aberrant growth and behavior of malignant cancer cells. Consequently, there is considerable interest and effort in targeting Ras signaling for the development of novel approaches for cancer treatment. In particular, current evaluation is focused on clinical evaluation of small molecule kinase inhibitors of the Raf-MEK-ERK pathway. However, these efforts have been complicated by the fact that Ras can also utilize multiple Raf-independent effector pathways to promote oncogenesis. Furthermore, the Raf-MEK-ERK cascade is not a simple linear signaling pathway, but instead, represents the core of a complex signaling network that is regulated by an ever-expanding roster of functionally diverse signaling molecules. In particular, several scaffold proteins dictate the input signals that activate this kinase cascade and serve to diversify the spatial and temporal nature of the signaling output. Our recent preliminary observations determined that (a) the subfamily-D regulators of G protein signaling (RGS) proteins (RGS12 and RGS14) are putative effectors of Ras and that (b) RGS12 may function as a scaffold protein that regulates the Raf-MEK-ERK cascade. In light of the important role of the ERK MARK pathway in neoplastic cell biology, we hypothesize that RGS12 and RGS14 will be found to be important effectors of Ras-mediated oncogenesis and that RGS12 will be a critical regulator of Raf-MEK-ERK signaling and function. Four specific aims are proposed to critically evaluate the role of subfamily D RGS proteins in aberrant Ras and Raf signaling and oncogenesis to: (1) determine the roles of RGS12 and RGS14 as effectors of Ras-mediated oncogenes, (2) determine if RGS12 is critical for mutant B-Raf-mediated oncogenesis, (3) determine if RGS12 is an endosome-specific effector of Ras function, and (4) determine the structures of RGS12 (and/or RGS14) with Ras-MAPK binding partners.

描述（由申请人提供）：RAS小GTPases在正常细胞生理学和癌细胞异常行为中的重要性是完善的。 RAS的功能是调节正常细胞增殖，分化和存活的信号传导节点。 RAS的各种细胞作用是通过RAS调节的多个功能上不同的下游信号网络介导的，其中Raf-Mek-Mek-ERK促分裂原激活的蛋白激酶（MARK）级联对级联的理解是最好的理解。 RAS的突变激活导致持续，放松管制的信号传导，促进了恶性癌细胞的异常生长和行为。因此，在靶向RAS信号传导以开发癌症治疗方法的开发方面存在很大的兴趣和精力。特别是，当前的评估集中于Raf-Mek-ERK途径的小分子激酶抑制剂的临床评估。但是，这些努力使RAS还可以利用多个无RAF依赖性效应子途径来促进肿瘤发生的事实使这些努力变得复杂。此外，RAF-Mek-ERK Cascade不是一个简单的线性信号通路，而是代表一个复杂信号网络的核心，该核心由功能多样的信号分子的不断扩展的花名册调节。特别是，几种脚手架蛋白决定激活该激酶级联的输入信号，并使信号输出的空间和时间性质多样化。我们最近的初步观察结果确定（a）G蛋白信号传导（RGS）蛋白（RGS12和RGS14）的亚家族-D调节剂是RAS的推定效应子，并且（b）RGS12可以用作调节RAF-MEK-ERK-ERK CasCade的支架蛋白。鉴于ERK标记途径在肿瘤细胞生物学中的重要作用，我们假设RGS12和RGS14将被认为是RAS介导的肿瘤发生的重要效应子，RGS12将是RAF-MEK-MEK-ERK信号传导和功能的关键调节剂。 Four specific aims are proposed to critically evaluate the role of subfamily D RGS proteins in aberrant Ras and Raf signaling and oncogenesis to: (1) determine the roles of RGS12 and RGS14 as effectors of Ras-mediated oncogenes, (2) determine if RGS12 is critical for mutant B-Raf-mediated oncogenesis, (3) determine if RGS12 is an RAS功能的内体特异性效应子，（4）用RAS-MAPK结合伙伴确定RGS12（和/或RGS14）的结构。