β-Catenin is required for Ron receptor-induced mammary tumorigenesis.
β-Catenin is required for Ron receptor-induced mammary tumorigenesis.
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DOI：
10.1038/onc.2011.86
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发表时间：
2011-08-25
期刊：
影响因子：
8
通讯作者：
Waltz, S. E.
中科院分区：
文献类型：
--
作者：
Wagh, P. K.;Gray, J. K.;Zinser, G. M.;Vasiliauskas, J.;James, L.;Monga, S. P.;Waltz, S. E.
关键词：
我们之前的研究表明，小鼠乳腺上皮中 Ron 受体酪氨酸激酶的选择性过度表达会导致乳腺肿瘤的形成。乳腺肿瘤裂解物的生化分析表明，Ron 过度表达与 β-连环蛋白表达和酪氨酸磷酸化的增加有关。 β-连环蛋白还被证明可通过受体酪氨酸激酶 Met、Fer 和 Fyn 的酪氨酸磷酸化进行调节。然而，β-连环蛋白和 Ron 下游的 β-连环蛋白酪氨酸磷酸化的分子和生理作用尚不清楚。为了研究这种关联，我们发现 Ron 和 β-连环蛋白在人类乳腺癌中协同升高。我们的数据还表明，通过肝细胞生长因子样蛋白 (HGFL) 的配体结合激活 Ron，诱导 β-连环蛋白的酪氨酸磷酸化，主要是在酪氨酸残基 Tyr 654 和 Tyr 670 上。此外，HGFL 介导的 Ron 激活诱导 β-连环蛋白核定位和转录活性，其中 β-连环蛋白的 Tyr 654 和 Tyr 670 残基对于这些作用至关重要。流程。我们还证明，乳腺癌细胞系中 Ron 的敲低会导致 HGFL 诱导的 β-连环蛋白依赖性转录激活和细胞生长的丧失，而这可以通过激活典型的 Wnt/β-连环蛋白信号传导来挽救。此外，我们发现HGFL依赖性Ron激活介导β-连环蛋白靶基因细胞周期蛋白D1和c-myc的上调，并且在抑制Ron和/或β-连环蛋白后这些靶基因在乳腺癌细胞中的表达降低。最后，我们发现表达 Ron 的乳腺癌细胞中 β-连环蛋白的基因消除可降低体外细胞增殖，以及原位移植到乳腺脂肪垫后乳腺肿瘤的生长和转移。总之，我们的数据表明，β-连环蛋白是 Ron 受体激活的关键下游调节因子，也是乳腺肿瘤发生的重要介质。
Our previous studies demonstrated that selective overexpression of the Ron receptor tyrosine kinase in the murine mammary epithelium leads to mammary tumor formation. Biochemical analysis of mammary tumor lysates showed that Ron overexpression was associated with increases in β-catenin expression and tyrosine phosphorylation. β-catenin has also been shown to be regulated through tyrosine phosphorylation by the receptor tyrosine kinases Met, Fer, and Fyn. However, the molecular and physiological roles of β-catenin and β-catenin tyrosine phosphorylation downstream of Ron are not known. To investigate this association, we show that Ron and β-catenin are coordinately elevated in human breast cancers. Our data also demonstrate that activation of Ron, through ligand binding by hepatocyte growth factor-like protein (HGFL), induces the tyrosine phosphorylation of β-catenin, primarily on tyrosine residues Tyr 654 and Tyr 670. In addition, HGFL mediated Ron activation induces both β-catenin nuclear localization and transcriptional activity, with Tyr 654 and Tyr 670 residues of β-catenin being critical for these processes. We also demonstrate that a knockdown of Ron in breast cancer cell lines leads to a loss of HGFL-induced β-catenin-dependent transcriptional activation and cell growth which can rescued by activation of canonical Wnt/β-catenin signaling. Moreover, we show that HGFL-dependent Ron activation mediates upregulation of the β-catenin target genes cyclin D1 and c-myc, and that expression of these target genes in breast cancer cells is decreased following inhibition of Ron and/or β-catenin. Finally, we show that genetic ablation of β-catenin in Ron-expressing breast cancer cells decreases cellular proliferation in vitro, as well as mammary tumor growth and metastasis following orthotopic transplantation into the mammary fat pad. Together, our data suggest that β-catenin is a crucial downstream regulator of Ron receptor activation and is an important mediator of mammary tumorigenesis.
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影响因子：
11.2
作者：
Castellone MD;De Falco V;Rao DM;Bellelli R;Muthu M;Basolo F;Fusco A;Gutkind JS;Santoro M
通讯作者：
Santoro M
影响因子：
8
作者：
Maggiora, P;Marchio, S;Comoglio, PM
通讯作者：
Comoglio, PM
影响因子：
4.8
作者：
McClaine, Rebecca J.;Marshall, Aaron M.;Waltz, Susan E.
通讯作者：
Waltz, Susan E.
DOI：
10.1073/pnas.060025397
发表时间：
2000-04-11
影响因子：
11.1
作者：
Lin, SY;Xia, WY;Hung, MC
通讯作者：
Hung, MC
影响因子：
7.5
作者：
Nakopoulou, L;Mylona, E;Keramopoulos, A
通讯作者：
Keramopoulos, A