The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3β and β-catenin
The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3β and β-catenin
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DOI：
10.1074/jbc.c000754200
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发表时间：
2001-03-02
影响因子：
4.8
通讯作者：
Kufe, D
中科院分区：
文献类型：
--
作者：
Li, YQ;Kuwahara, H;Kufe, D
DF3/MUC1粘蛋白样糖蛋白在大多数人类癌中异常过表达。MUC1的细胞质结构域与糖原合成酶激酶3 β (GSK3 β)相互作用，从而降低MUC1与β -catenin的结合。目前的研究表明MUC1与c-Src酪氨酸激酶相关。c-Src磷酸化位于与GSK3 β和β -catenin相互作用位点之间的YEKV基序MUC1细胞质结构域。结果表明，c-Src SH2结构域直接结合pYEKV并抑制MUC1和GSK3 β之间的相互作用。此外，与GSK3 β相反，体外和体内研究表明，c- src介导的MUC1磷酸化增加了MUC1与β -catenin的结合。这些发现支持c-Src在调节MUC1与GSK3 β和β -catenin相互作用中的新作用。
The DF3/MUC1 mucin-like glycoprotein is aberrantly overexpressed in most human carcinomas. The cytoplasmic domain of MUC1 interacts with glycogen synthase kinase 3 beta (GSK3 beta) and thereby decreases binding of MUC1 and beta -catenin. The present studies demonstrate that MUC1 associates with the c-Src tyrosine kinase. c-Src phosphorylates the MUC1 cytoplasmic domain at a YEKV motif located between sites involved in interactions with GSK3 beta and beta -catenin. The results demonstrate that the c-Src SH2 domain binds directly to pYEKV and inhibits the interaction between MUC1 and GSK3 beta. Moreover and in contrast to GSK3 beta, in vitro and in vivo studies demonstrate that c-Src-mediated phosphorylation of MUC1 increases binding of MUC1 and beta -catenin. The findings support a novel role for c-Src in regulating interactions of MUC1 with GSK3 beta and beta -catenin.