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途径，重点是乳腺癌和卵巢癌。人类上皮性恶性肿瘤经常表现出非调控的酪氨酸激酶活性。了解这些激酶调节信号的机制应该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，这是一种调节酪氨酸激酶活性的蛋白质家族。CBL蛋白属于泛素蛋白连接酶(E3s)的无名指类，其功能是激活酪氨酸激酶的E3s。我的团队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蛋白都介导了激活的表皮生长因子受体(EGFR)以及信号复合体的其他成分的泛素化和降解。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，并阐明它们在特异性和/或功能上的差异。我们一直关注CBLC的功能，CBLC是最近发现的、知之甚少的家庭成员。这种蛋白只在上皮细胞中表达，我的团队对乳腺癌等上皮性恶性肿瘤特别感兴趣。此前，为了了解CBLC蛋白的功能，我们与奥地利维也纳IMBA的Josef Penninger合作敲除了CBLC。不幸的是，CBLC基因缺失的小鼠没有检测到异常。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，我们正在研究这些蛋白质的功能以及它们与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.