Muc1 affects c-Src signaling in PyV MT-induced mammary tumorigenesis
Muc1 affects c-Src signaling in PyV MT-induced mammary tumorigenesis
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DOI：
10.1038/sj.onc.1208738
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发表时间：
2005-09-01
期刊：
影响因子：
8
通讯作者：
Gendler, SJ
中科院分区：
文献类型：
--
作者：
Al Masri, A;Gendler, SJ
MUC 1是一种完整的膜粘蛋白糖蛋白，通常表达于大多数简单分泌上皮细胞和造血细胞的顶端表面。异常糖基化MUC 1的过表达是许多癌症的标志，包括90%的乳腺癌。MUC 1已显示在体外结合c-Src酪氨酸激酶，由此c-Src在YEKV基序处磷酸化MUC 1胞质结构域。c-Src是一种广泛研究的非受体酪氨酸激酶，与乳腺肿瘤发生有关。以前，小鼠乳腺肿瘤病毒驱动的多瘤中间T抗原（MMTV-PyV MT）转基因小鼠杂交到Muc 1空背景表现出显着延迟肿瘤进展。已显示c-Src与PyV MT相互作用，并在MMTV-PyV MT诱导的乳腺肿瘤发生中发挥不可或缺的作用。在这里，我们确定了Muc 1表达对c-Src激活和信号传导的影响。在野生型或Muc 1无效背景下对MMTV-PyV MT腺体的检查表明，Muc 1表达通过影响其与已知底物如磷脂酰肌醇3-激酶和β-连环蛋白的p85亚基的结合来促进c-Src信号传导。这些发现可能提供了一种机制，在肿瘤进展的延迟，观察到在Muc 1的情况下。
MUC1 is an integral membrane mucin glycoprotein that is normally expressed on the apical surface of most simple, secretory epithelia and hematopoietic cells. Overexpression of aberrantly glycosylated MUC1 is a hallmark of many carcinomas including 90% of breast carcinomas. MUC1 has been shown to bind to c-Src tyrosine kinase in vitro, whereby c-Src phosphorylates the MUC1 cytoplasmic domain at a YEKV motif. c-Src is an extensively studied nonreceptor tyrosine kinase implicated in mammary tumorigenesis. Previously, mouse mammary tumor virus-driven polyoma middle T-antigen (MMTV-PyV MT) transgenic mice crossed onto a Muc1 null background exhibited a significant delay in tumor progression. c-Src has been shown to interact with PyV MT, and to play an integral and indispensable role in MMTV-PyV MT-induced mammary tumorigenesis. Here, we determine the effect of Muc1 expression on c-Src activation and signaling. Examination of MMTV-PyV MT glands on a wild-type or Muc1 null background demonstrates that Muc1 expression promotes c-Src signaling by influencing its association with known substrates such as the p85 subunit of phosphatidylinositol 3-kinase and beta-catenin. These findings may provide a mechanism for the delay in tumor progression that is observed in the absence of Muc1.