Cbl Proteins as Regulators of Tyrosine Kinase Signaling

Cbl 蛋白作为酪氨酸激酶信号传导的调节剂

• 批准号: 8937913
• 负责人: Stanley Lipkowitz
• 金额: $ 100.13万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8937913
• 关键词: Biochemical; Collaborations; Complex; Down-Regulation; ERBB2 gene; Epidermal Growth Factor Receptor; Epithelial; Fingers; Human; Laboratories; Malignant Neoplasms; Mammalian Cell; Mediating; Mus; Mutation; Pathogenesis; Protein Family; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Research Personnel; Signal Pathway; Signal Transduction; Solid Neoplasm; Structure; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligase Complexes; Ubiquitination; Work; human RBX1 protein; inhibitor/antagonist; meetings; member; mutant; overexpression; trafficking; tumor; ubiquitin-protein ligase

RTKs, such as EGFR, HER2, MET and RET, are often inappropriately active (due to mutation or overexpression) in a wide array of epithelial malignancies. My laboratory cloned two of the three members of the mammalian Cbl protein family and demonstrated that they are negative regulators of the EGFR in mammalian cells. We have shown that Cbl proteins are RING finger E3s and that all mammalian Cbl proteins mediate ubiquitination of the activated EGFR, resulting in the degradation of the activated EGFR signaling complex. Work in my lab, in collaborations with other laboratories, and by other investigators has shown the Cbl proteins regulate many RTKs and signaling pathways. In addition, my lab has contributed to the structure function analysis of the Cbl proteins. More recently my laboratory has identified and characterized proteins which interact with and modify the function of Cblc, the least well characterized Cbl protein, identified and are characterizing E2 proteins that interact with the Cbl proteins, and identified mutant forms of Cbl proteins in human and mouse epithelial tumors. Ongoing work: 1) investigates the spectrum of ubiquitin conjugating enzymes (E2s) that function with Cbl protiens. 2) investigates the proteins that collaborate with Cbl proteins to mediate RTK downregulation by identifying proteins in the active complex by mass spec analysis. 3) studies mutations of Cbl protiens found in murine and human solid tumors. 4) developes a screen to identify Cbl E3 inhibitors

RTK，如EGFR，HER2，MET和RET，通常在广泛的上皮恶性肿瘤中具有不适当的活性（由于突变或过表达）。我的实验室克隆了哺乳动物Cbl蛋白家族的三个成员中的两个，并证明它们是哺乳动物细胞中EGFR的负调节因子。我们已经表明，Cbl蛋白是环指E3，所有哺乳动物Cbl蛋白介导活化EGFR的泛素化，导致活化EGFR信号复合物的降解。在我的实验室，与其他实验室合作，以及其他研究人员的工作表明，Cbl蛋白调节许多RTK和信号通路。此外，我的实验室还为Cbl蛋白的结构功能分析做出了贡献。最近，我的实验室已经鉴定并表征了与Cbl c相互作用并改变Cbl c功能的蛋白质，Cbl c是表征最少的Cbl蛋白，鉴定并表征了与Cbl蛋白相互作用的E2蛋白，并鉴定了人和小鼠上皮肿瘤中Cbl蛋白的突变形式。正在进行的工作：1）研究与Cbl蛋白一起起作用的泛素缀合酶（E2）的谱。2)通过质谱分析鉴定活性复合物中的蛋白质，研究了与Cbl蛋白协作介导RTK下调的蛋白质。3)研究在鼠和人实体瘤中发现的Cbl蛋白的突变。4)开发了一种筛选方法来鉴定Cbl E3抑制剂