IQGAP1 in tumorigenesis

IQGAP1在肿瘤发生中的作用

• 批准号: 8565384
• 负责人: David Sacks
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8565384
• 关键词: A kinase anchoring protein; Adherens Junction; Antioxidants; Binding; Brain; Brain Edema; Breast; Breast Carcinoma; Calcium; Calcium-Binding Proteins; Calmodulin; Cancerous; Cell Adhesion; Cells; Comprehension; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; Data; Dimerization; ERBB2 gene; Elements; Endothelial Cells; Enzymes; Epidermal Growth Factor Receptor; Erythroid; Escherichia coli; Estrogen Receptors; Estrogens; Goals; Hormones; Human; Invaded; Laboratories; Malignant - descriptor; Mediating; Meningitis; Mitogen-Activated Protein Kinases; Molecular; Multiprotein Complexes; NMR Spectroscopy; Neonatal; Neoplasm Metastasis; Neoplastic Cell Transformation; Neurites; Normal Cell; Nuclear; Oxidative Stress; Pathogenesis; Pathway interactions; Process; Regulation; Research; Role; Salmonella; Salmonella enterica; Scaffolding Protein; Second Messenger Systems; Serotyping; Signal Pathway; Signal Transduction; Staging; Tight Junctions; Transactivation; Transcriptional Activation; cancer cell; cell motility; insight; microbial; overexpression; second messenger; therapeutic target; tumor; tumorigenesis

During the fiscal year we accomplished the following: 1. Documented that Salmonella enterica serotype Typhimurium usurps the scaffold protein IQGAP1 to manipulate Rac1 and MAPK (mitogen-activated protein kinase) signaling. These observations promote our understanding of how Salmonella re-arranges the host-cell cytoskeleton to invade cells and suggest that IQGAP1 may be a potential therapeutic target for Salmonella pathogenesis. 2. Discovered that the protein kinase A anchoring protein AKAP220 interacts with the cytoskeletal scaffolding protein IQGAP1. AKAP220/IQGAP1 networks receive and integrate calcium and cAMP second messenger signals, thus organizing signaling elements that impact cell migration. The findings provide insight into cytoskeletal polarization during invasion and metastasis of cancer cells. 3. Demonstrated that the calcium-binding protein calmodulin binds the human estrogen receptor (ER). Detailed structural analysis by nuclear magnetic resonance spectroscopy yielded the surprising finding that a single calmodulin binds two molecules of ER. Thus, calmodulin facilitates dimerization of ER in the absence of the hormone estrogen. These data enhance our comprehension of the mechanism by which calmodulin regulates ER-mediated transcriptional activation and may have implications in the treatment of breast carcinoma. 4. Showed that IQGAP1 mediates the disruption of adherens junctions to promote Escherichia coli K1 invasion of brain endothelial cells. These findings provide insight into the molecular mechanism by which E. coli disrupts tight junctions, thereby leading to brain edema in neonatal meningitis. 5. Identified nuclear factor-erythroid-related factor 2 (Nrf2) as a binding partner of IQGAP1. Nrf2 is a critical transcriptional factor in regulating cellular defense against oxidative stress. Functional analysis of the interaction revealed a critical role for IQGAP1 in the stability and transactivation of Nrf2. Collectively, these data suggest that IQGAP1 may contribute to regulation of antioxidant enzymes by Nrf2.

在本财年中，我们完成了以下工作： 1. 记录表明，鼠伤寒沙门氏菌血清型侵占支架蛋白 IQGAP1 来操纵 Rac1 和 MAPK（丝裂原激活蛋白激酶）信号传导。这些观察结果促进了我们对沙门氏菌如何重新排列宿主细胞细胞骨架以侵入细胞的理解，并表明 IQGAP1 可能是沙门氏菌发病机制的潜在治疗靶点。 2.发现蛋白激酶A锚定蛋白AKAP220与细胞骨架支架蛋白IQGAP1相互作用。 AKAP220/IQGAP1 网络接收并整合钙和 cAMP 第二信使信号，从而组织影响细胞迁移的信号元件。这些发现提供了对癌细胞侵袭和转移过程中细胞骨架极化的深入了解。 3. 证明钙结合蛋白钙调蛋白与人类雌激素受体（ER）结合。通过核磁共振波谱进行的详细结构分析得出了令人惊讶的发现：单个钙调蛋白结合两个 ER 分子。因此，在缺乏雌激素的情况下，钙调蛋白促进 ER 二聚化。这些数据增强了我们对钙调蛋白调节 ER 介导的转录激活机制的理解，并可能对乳腺癌的治疗产生影响。 4.表明IQGAP1介导粘附连接的破坏促进大肠杆菌K1对脑内皮细胞的侵袭。这些发现提供了对大肠杆菌破坏紧密连接从而导致新生儿脑膜炎脑水肿的分子机制的深入了解。 5. 确定核因子-红细胞相关因子 2 (Nrf2) 为 IQGAP1 的结合伴侣。 Nrf2 是调节细胞防御氧化应激的关键转录因子。相互作用的功能分析揭示了 IQGAP1 在 Nrf2 的稳定性和反式激活中的关键作用。总的来说，这些数据表明 IQGAP1 可能有助于 Nrf2 对抗氧化酶的调节。