Cbl Proteins as Regulators of Tyrosine Kinase Signaling

我的实验室研究调节上皮癌细胞生长和程序性细胞死亡的信号转导通路，重点研究乳腺癌和卵巢癌。人类上皮恶性肿瘤经常表现出酪氨酸激酶活性失调。了解这些激酶调控信号传导的机制将会发现抑制癌细胞生长的新方法。我们正在研究Cbl蛋白的功能，这是一个调节酪氨酸激酶活性的蛋白家族。Cbl蛋白属于环指类泛素蛋白连接酶（E3s），作为激活酪氨酸激酶的E3s起作用。我的小组克隆了三个哺乳动物Cbl基因中的两个（Cblb和Cblc），并证明了所有哺乳动物Cbl蛋白介导泛素化和活化的表皮生长因子受体（EGFR）以及信号复合物的其他成分的降解。正在进行的工作集中在了解三种哺乳动物Cbl蛋白在上皮细胞中的生化和生理功能，并阐明它们的特异性和/或功能的差异。我们一直专注于Cblc的功能，这是最近发现的最不为人所知的家族成员。这种蛋白仅在上皮细胞中表达，我的小组对上皮恶性肿瘤如乳腺癌特别感兴趣。此前，为了了解Cblc蛋白的功能，我们与Josef Penninger （IMBA, Vienna, Austria）合作敲除了Cblc。不幸的是，Cblc缺失小鼠没有可检测到的异常。为了深入了解Cblc的功能，我们使用酵母双杂交筛选来检测与Cblc相互作用的新蛋白。目前，我们正在描述这些蛋白质的功能及其与Cblc相互作用的后果。

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.