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: 7733382
• 负责人: Stanley Lipkowitz
• 金额: $ 61.9万
• 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/7733382
• 关键词: Apoptosis; Austria; Biochemical; Breast; Cancer Cell Growth; Class; Complex; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Family member; Fingers; Genes; Growth; Human; Knock-out; Knockout Mice; Laboratory Study; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Phosphotransferases; Physiological; Protein Family; Protein Tyrosine Kinase; Proteins; Signal Transduction; Signal Transduction Pathway; Specificity; Ubiquitin-Protein Ligase Complexes; Ubiquitination; Work; Yeasts; cancer cell; insight; interest; malignant breast neoplasm; novel; protein function; ubiquitin-protein ligase; yeast two hybrid system

My laboratory studies signal transduction pathways that regulate growth and programmed cell death in epithelial cancer cells, with a focus on breast and ovarian cancer. Human epithelial malignancies frequently display deregulated tyrosine kinase activity. Understanding the mechanisms that regulate signaling by these kinases should uncover new ways to inhibit cancer cell growth. We are investigating the function of Cbl proteins, a family of proteins that regulate tyrosine kinase activity. Cbl proteins belong to the RING finger class of ubiquitin protein ligases (E3s) and function as E3s for activated tyrosine kinases. My group cloned two of the three mammalian Cbl genes (Cblb and Cblc) and demonstrated that all mammalian Cbl proteins mediate ubiquitination and degradation of the activated epidermal growth factor receptor (EGFR) as well as other components of the signaling complex. Ongoing work is focused on understanding the biochemical and physiologic functions of the three mammalian Cbl proteins in epithelial cells and elucidating the differences in their specificity and/or function. We have been focused on the function of Cblc, the most recently identified family member about which the least is known. This protein is expressed only in epithelial cells and my group is particularly interested in epithelial malignancies such as breast cancer. Previously, to understand the function of the Cblc protein, we collaborated with Josef Penninger (IMBA, Vienna, Austria) to knock out Cblc. Unfortunately, the Cblc null mice have no detectable abnormalities. To gain insight into the fucntion of Cblc, we have used yeast two-hybrid screens to detect novel proteins that interact with Cblc. Currently, we are characterizing the function of these proteins and the consequences of their interactions with Cblc.

我的实验室研究调节生长和编程的信号传导途径 上皮癌细胞的细胞死亡，重点是乳腺癌和卵巢癌。人类 上皮恶性肿瘤经常表现出酪氨酸激酶活性失调。理解 通过这些激酶调节信号的机制应该会发现新的方法来抑制 癌细胞生长我们正在研究Cbl蛋白的功能， 调节酪氨酸激酶活性。Cbl蛋白属于环指类， 泛素蛋白连接酶（E3）和作为激活的酪氨酸激酶的E3起作用。我的小组 克隆了三种哺乳动物Cbl基因中的两种（Cblb和Cblc），并证明所有 哺乳动物Cbl蛋白介导活化表皮细胞的泛素化和降解 生长因子受体（EGFR）以及信号传导复合物的其它组分。正在进行 工作的重点是了解这三个生物化学和生理功能， 哺乳动物上皮细胞中的Cbl蛋白，并阐明它们在上皮细胞中的差异。 特异性和/或功能。我们一直关注Cblc的功能，最近 最不为人知的家庭成员。这种蛋白质只在 上皮细胞，我的团队对上皮恶性肿瘤特别感兴趣， 乳腺癌以前，为了了解Cblc蛋白的功能，我们合作了 与约瑟夫彭宁格（IMBA，维也纳，奥地利）淘汰Cblc。不幸的是，Cblc null 小鼠没有可检测到的异常。为了深入了解Cblc的功能，我们使用了 酵母双杂交筛选来检测与Cblc相互作用的新蛋白质。目前我们是 表征这些蛋白质的功能以及它们与 Cblc