Cbl Proteins as Regulators of Tyrosine Kinase Signaling

RTK，如EGFR，HER 2，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是表征最不充分的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）i通过质谱分析鉴定活性复合物中的蛋白质来研究与Cbl蛋白协作以介导RTK下调的蛋白质。2)Cblb E3抑制剂的筛选; 3）TROP 2在TNBC中的功能及其下调机制的研究。在一个翻译项目中，我们发现EGFR在2%的乳腺癌肿瘤中扩增，这预示着预后不良。此外，我们发现EGFR扩增的肿瘤经常在PI 3 K途径中具有激活突变（40-70%）。正在进行的工作是1）表征EGFR抑制剂+/-PIK 3CA抑制剂在体外和体内杀死在这些途径中具有突变的细胞的能力;和2）评价这些抑制剂对肿瘤起始细胞的作用。

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) i investigates the proteins that collaborate with Cbl proteins to mediate RTK downregulation by identifying proteins in the active complex by mass spec analysis. 2) a screen to identify Cblb E3 inhibitors; 3) Investigations on the function of TROP2 in TNBC and the mechanisms of downregualtion of TROP2. 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.