Molecular mechanisms of CIB1 signaling

CIB1信号传导的分子机制

• 批准号: 9761659
• 负责人: XIAN CHEN
• 金额: $ 30.86万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761659
• 关键词: Address; Adhesions; Affect; Binding; Biochemical; Biological Process; Biology; Blood Vessels; Breast Cancer cell line; Calmodulin; Cardiomegaly; Cell Survival; Cell physiology; Cells; Complement; Cytoplasmic Tail; Data; Disease; EF Hand Motifs; Endothelial Cells; Event; Focal Adhesions; Growth; Heart Hypertrophy; Integrin alpha Chains; Integrin alphaV; Integrins; Knowledge; MEKs; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Membrane; Molecular; Normal Cell; Oncogenic; PAK-1 kinase; PDPK1 gene; PI3K/AKT; Pathologic; Pathologic Processes; Pathway Analysis; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Play; Process; Protein-Serine-Threonine Kinases; Proteins; Regulatory Pathway; Retinal Diseases; Role; Signal Pathway; Signal Transduction; Site; Stress; Structure; System; Testing; Therapeutic; Validation; angiogenesis; base; cancer cell; cell growth; cell transformation; cell type; data integration; fascinate; feeding; inhibitor/antagonist; innovation; migration; myristoylation; novel; phosphoproteomics; protein function; protein protein interaction; response; response to injury; scaffold; therapeutic target; tool; triple-negative invasive breast carcinoma; tumor

ABSTRACT CIB1 is an intracellular protein that regulates cell growth, survival and proliferation, most notably under pathologic conditions. It functions by binding directly to effector kinases, integrins and other targets and modulates their activity, thereby serving as a signaling node for key regulatory pathways. Inhibition of CIB1 binding to select partners has excellent therapeutic potential in multiple diseases such as cancer, retinopathies and cardiac hypertrophy. It is therefore critical to understand CIB1 signaling in different cell types. In many breast cancer cell lines but not in normal cells tested to date, CIB1 is required for survival and proliferation via the PI3K/AKT and MEK/ERK pathways. In endothelial cells, CIB1 supports efficient angiogenesis in response to injury via the MEK/ERK pathway. However, how and why CIB1 selectively regulates these pathways under stressed or transformed conditions is poorly understood. We found that CIB1 interacts directly with PAK1 and PDK1, which can feed into these pathways. Moreover, while some data suggest that CIB1 regulates integrin signaling, which can activate the PI3K/AKT and MEK/ERK pathways, it is completely unknown whether or how CIB1 connects integrin signaling to these pathways. Our overall hypothesis is that under select stress or oncogenic conditions in a variety of cell types, CIB1 binds to specific partners to regulate the PI3K/AKT, MEK/ERK and potentially other pathways, to promote cell viability, growth and proliferation. To address this hypothesis, we will use a combination of targeted and unbiased approaches to determine how the CIB1 interaction with PAK1, PDK1 and the αV integrin support the PI3K/AKT and MEK/ERK pathways. We will complement targeted approaches with unbiased phosphoproteomics and interactomics to delineate on a global scale, how CIB1 signaling affects not only MEK/ERK and PI3K/AKT but other phospho-signaling pathways that may help explain CIB1 biology.

摘要 CIB 1是一种调节细胞生长、存活和增殖的细胞内蛋白， 特别是在病理条件下。它通过直接结合效应激酶发挥作用， 整合素和其他目标，并调节其活性，从而作为一个信号转导， 关键调控途径的节点。抑制CIB 1与选择的配偶体结合， 在多种疾病如癌症、视网膜病变和 心脏肥大因此，了解不同细胞中CIB 1信号传导是至关重要的。 类型在许多乳腺癌细胞系中，但在迄今为止测试的正常细胞中没有，CIB 1是 通过PI 3 K/AKT和MEK/ERK途径存活和增殖所需。在 CIB 1支持有效的血管生成，以响应损伤，通过 MEK/ERK通路。然而，CIB 1如何以及为什么选择性地调节这些通路， 在应激或转化条件下的作用机制知之甚少。我们发现CIB 1 与PAK 1和PDK 1直接相互作用，可以进入这些途径。此外，委员会认为， 虽然一些数据表明CIB 1调节整合素信号传导，其可以激活 PI 3 K/AKT和MEK/ERK通路，CIB 1是否或如何 将整合素信号传导与这些通路连接起来。我们的总体假设是， 在多种细胞类型中选择应激或致癌条件，CIB 1结合特异性 合作伙伴调节PI 3 K/AKT、MEK/ERK和潜在的其他途径， 促进细胞活力、生长和增殖。为了解决这个假设，我们将使用一个 结合有针对性和公正的方法，以确定CIB如何1 与PAK 1、PDK 1和αV整合素的相互作用支持PI 3 K/AKT和MEK/ERK 途径。我们将补充有针对性的方法与公正磷酸蛋白质组学 和interactomics来描绘在全球范围内，CIB 1信号如何不仅影响 MEK/ERK和PI 3 K/AKT以及其他可能有助于解释的磷酸化信号通路 CIB 1生物学