Oncogenic Signaling by DF3/MUC1 in Human Breast Cancer

DF3/MUC1跨膜蛋白在人乳腺癌细胞表面高水平异常表达。MUC1在乳腺癌中过度表达的功能意义尚不清楚。从发现MUC1的细胞质结构域与连环蛋白家族的成员--β-连环蛋白、蛋白球蛋白和p120ctn--的关系中，已经得出了某些见解。β-连环蛋白与E-钙粘蛋白在细胞膜上相互作用，在胞浆中与腺瘤性息肉病(APC)蛋白相互作用，在细胞核内作为转录共激活因子与Tcf/Lef-1相互作用。β-连环蛋白信号的失调与多种人类肿瘤的发生有关。MUC1抑制β-连环素与E-钙粘附素的结合，从而破坏与肿瘤进展相关的黏附连接。MUC1与表皮生长因子受体(EGFR)、ErbB2(HER2/neu)以及与之相关的ErbB3和ErbB4受体酪氨酸激酶相关。通过激活EGFR或c-Src酪氨酸激酶使MUC1胞浆结构域磷酸化，增加了MUC1与β-连环蛋白之间的相互作用。相反，作为Wnt信号通路的效应者，糖原合成酶激酶3β(GSK3β)对MUC1的磷酸化下调了MUC1与β-catenin之间的相互作用。我们的假设是，作为乳腺癌细胞过度表达的结果，UM导致1)通过EGFR和相关的ErbB2-4受体调节生长因子信号的失调，以及2)连环蛋白家族成员在细胞膜和细胞核内的功能障碍。这项拟议的研究将解决这一假设，以及MUC1是否也在乳腺肿瘤发展中作为细胞表面受体发挥作用。其具体目的是：1)确定MUC1与EGF受体相互作用的功能意义；2)确定MUC1是否与ErbB2和ErbB受体家族的其他成员相互作用；3)确定MUC1在ErbB受体介导的细胞膜和细胞核内连环蛋白信号转导中的作用；4)确定直接激活MUC1作为细胞表面受体的配体。

The DF3/MUC1 transmembrane protein is aberrantly expressed at high levels on the surface of human breast cancer cells. The functional significance of MUC1 overexpression in breast cancer is unknown. Certain insights have been derived from the finding the cytoplasmic domain of MUC1 associates with members of the catenin family of signaling proteins, beta- catenin, plakoglobin and p120ctn. Beta-catenin interacts with E- cadherin at the cell membrane, with the adenomatous polyposis coli (APC) Protein in the cytosol and with Tcf/LEF-1 as a transcriptional coactivator in the nucleus. Dysregulation of beta-catenin signaling has been associated with the development of diverse human tumors. MUC1 suppresses binding of beta-catenin to E-cadherin and thereby disrupts the adherens junction, an event associated with tumor progression. MUC1 associates with the epidermal growth factor receptor (EGFR), ErbB2 (HER2/neu) and the related ErbB3 and ErbB4 receptor tyrosine kinases. Phosphorylation of the MUC1 cytoplasmic domain by activation of EGFR or the c-Src tyrosine kinase increases the interaction between MUC1 and beta-catenin. By contrast, phosphorylation of MUC1 by glycogen synthase kinase 3beta (GSK3beta), an effector of the Wnt signaling pathway, downregulates the interaction between MUC1 and beta-catenin. Our hypothesis is that, as a consequence of overexpression in breast cancer cells, MUM contributes to i) dysregulation of growth factor signaling through EGFR and the related ErbB2-4 receptors and ii) dysfunction of catenin family members at the cell membrane and in the nucleus. The proposed studies will address this hypothesis and whether MUC1 also functions as a cell surface receptor in breast tumor development. The Specific Aims are: 1) To define the functional significance of the interaction between MUC1 and the EGF receptor, 2) To determine whether MUC1 interacts with ErbB2 and other members of the ErbB receptor family; 3) To define the effects of MUC1 on ErbB receptor-mediated signaling of catenins at the cell membrane and in the nucleus; and 4) To identify ligands that function in directly activating MUC1 as a cell surface receptor.