Tyrosine phosphorylation of transcriptional coactivator WW-domain binding protein 2 regulates estrogen receptor α function in breast cancer via the Wnt pathway
Tyrosine phosphorylation of transcriptional coactivator WW-domain binding protein 2 regulates estrogen receptor α function in breast cancer via the Wnt pathway
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DOI：
10.1096/fj.10-169136
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发表时间：
2011-09-01
期刊：
影响因子：
4.8
通讯作者：
Lim, Yoon Pin
中科院分区：
文献类型：
--
作者：
Lim, Shen Kiat;Orhant-Prioux, Magali;Lim, Yoon Pin
ww结合蛋白2 （WBP2）在不同的研究中被证明是酪氨酸激酶底物，激活雌激素受体α (ER α)/孕激素受体（PR）转录，并在乳腺癌中发挥作用。然而，WBP2酪氨酸磷酸化在调节内质网α功能和乳腺癌生物学中的作用尚不清楚。在这里，我们通过EGFR串扰确定WBP2是雌激素信号的酪氨酸磷酸化靶点。通过显性阴性、组成型活性突变体、RNAi和药理学研究，我们证明了WBP2 Tyr192和Tyr231位点的磷酸化可以被c-Src和c-Yes激酶调节。我们进一步发现，取消WBP2磷酸化可以通过阻断WBP2的核进入及其与ER α的相互作用，使bbb60 %的ER α报告蛋白活性受损。与载体对照相比，在MCF7细胞中过表达WBP2及其磷酸化模拟突变体导致小鼠肿瘤变大，诱导细胞-细胞粘附丧失，并以雌激素依赖性和非依赖性方式增强细胞增殖、非锚定生长、迁移和侵袭，磷酸化缺陷突变体可通过过表达基本消除这些事件。表达WBP2磷酸化模拟突变体的细胞的激素独立性与ER α和Wnt报告活性升高有关。Wnt/ β -连环蛋白抑制剂FH535比他莫昔芬和氟维司汀更明显地阻断磷酸化- wbp2介导的癌细胞生长，部分原因是通过降低ER α的表达。Wnt通路可能是wbp2介导的乳腺癌生物学的关键组成部分。-Lim, s K K, Orhant-Prioux， M., Toy， W., Tan， K. Y., Lim， Y. P.酪氨酸磷酸化的Wnt通路调控乳腺癌雌激素受体α功能。中国生物医学工程学报，2011,32(2):444 - 444。www.fasebj.org
WW-binding protein 2 (WBP2) has been demonstrated in different studies to be a tyrosine kinase substrate, to activate estrogen receptor alpha (ER alpha)/progesterone receptor (PR) transcription, and to play a role in breast cancer. However, the role of WBP2 tyrosine phosphorylation in regulating ER alpha function and breast cancer biology is unknown. Here, we established WBP2 as a tyrosine phosphorylation target of estrogen signaling via EGFR crosstalk. Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases. We further showed that abrogating WBP2 phosphorylation impaired >60% of ER alpha reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ER alpha. Compared to vector control, overexpression of WBP2 and its phospho-mimic mutant in MCF7 cells resulted in larger tumors in mice, induced loss of cell-cell adhesion, and enhanced cell proliferation, anchorage-independent growth, migration, and invasion in both estrogen-dependent and -independent manners, events of which could be substantially abolished by overexpression of the phosphorylation-defective mutant. Hormone independence of cells expressing WBP2 phospho-mimic mutant was associated with heightened ER alpha and Wnt reporter activities. Wnt/beta-catenin inhibitor FH535 blocked phospho-WBP2-mediated cancer cell growth more pronouncedly than tamoxifen and fulvestrant, in part by reducing the expression of ER alpha. Wnt pathway is likely to be a critical component in WBP2-mediated breast cancer biology.-Lim, S. K., Orhant-Prioux, M., Toy, W., Tan, K. Y., Lim, Y. P. Tyrosine phosphorylation of transcriptional coactivator WW-domain binding protein 2 regulates estrogen receptor alpha function in breast cancer via the Wnt pathway. FASEB J. 25, 3004-3018 (2011). www.fasebj.org