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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

基本信息

批准号：
10702443
负责人：
Stanley Lipkowitz
金额：
$ 64.79万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10702443
关键词：
Biochemical Breast Cancer Model CBL Protein CBLB gene Carcinoma Cells Collaborations Complex Down-Regulation ERBB2 gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Human In Vitro Laboratories Malignant Neoplasms Mammalian Cell Mediating Molecular Target Mus Mutation Natural Killer Cells Outcome PIK3CA gene Pathogenesis Pathway interactions Protein Family Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Regulation Research Personnel Ring Finger Domain Role Signal Pathway Signal Transduction Solid Neoplasm Structure T-Lymphocyte Tumor Immunity Ubiquitin-Conjugating Enzymes Ubiquitination Work cancer cell cell killing in vivo inhibitor malignant breast neoplasm member mutant overexpression patient subsets programs trafficking tumor ubiquitin-protein ligase

项目摘要

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 proteins. 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 proteins found in murine and human solid tumors. 4) a screen to identify Cblb E3 inhibitors In a translational project we have found that EGFR is amplified in 2% of breast cancer tumors and that this protends a poor outcome. Further, we have found that the EGFR amplified tumors frequently have activating mutations in the PI3K pathway (40-70%). Ongoing work is 1) characterizing the ability of EGFR inhibitors +/- PIK3CA inhibitors to kill cells with mutations in these pathways in vitro and in vivo; and 2) evaluating the effects of these inhibitors on tumor initiating cells.

RTK，例如 EGFR、HER2、MET 和 RET，在多种上皮恶性肿瘤中通常不适当地活跃（由于突变或过度表达）。我的实验室克隆了哺乳动物 Cbl 蛋白家族三个成员中的两个，并证明它们是哺乳动物细胞中 EGFR 的负调节因子。我们已经证明Cbl蛋白是环指E3并且所有哺乳动物Cbl蛋白介导激活的EGFR的泛素化，导致激活的EGFR信号复合物的降解。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，我的实验室还对 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 Cblc（最难表征的 Cbl 蛋白）相互作用并改变其功能的蛋白质，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 蛋白一起发挥作用的泛素结合酶 (E2) 谱。 2) 通过质谱分析鉴定活性复合物中的蛋白质，研究与 Cbl 蛋白质协作介导 RTK 下调的蛋白质。 3) 研究小鼠和人类实体瘤中发现的 Cbl 蛋白突变。 4) 筛选 Cblb E3 抑制剂在一个转化项目中，我们发现 EGFR 在 2% 的乳腺癌肿瘤中扩增，这预示着不良结果。此外，我们发现 EGFR 扩增的肿瘤经常在 PI3K 通路中存在激活突变 (40-70%)。正在进行的工作是 1) 表征 EGFR 抑制剂 +/- PIK3CA 抑制剂在体外和体内杀死这些途径中存在突变的细胞的能力； 2) 评估这些抑制剂对肿瘤起始细胞的影响。