Protein tyrosine phosphatase receptor type R (PTPRR) antagonizes the Wnt signaling pathway in ovarian cancer by dephosphorylating and inactivating ?-catenin
Protein tyrosine phosphatase receptor type R (PTPRR) antagonizes the Wnt signaling pathway in ovarian cancer by dephosphorylating and inactivating ?-catenin
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R 型蛋白酪氨酸磷酸酶受体 (PTPRR) 通过去磷酸化和灭活 β-连环蛋白来拮抗卵巢癌中的 Wnt 信号通路。
DOI：
10.1074/jbc.ra119.010348
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发表时间：
2019-11-29
影响因子：
4.8
通讯作者：
Fan, Gaofeng
中科院分区：
文献类型：
--
作者：
Wang, Yuetong;Cao, Jian;Fan, Gaofeng
尽管缺乏突变，但越来越多的证据支持 Wnt/β-catenin 通路在卵巢肿瘤发生中的重要作用。然而，导致卵巢癌中Wnt信号级联异常激活的分子机制尚未完全阐明。在这里，我们发现 R 型蛋白酪氨酸磷酸酶受体 (PTPRR) 抑制卵巢癌中 Wnt/β-catenin 通路的激活。我们进行了基于 shRNA 的生化筛选，确定 PTPRR 负责 Tyr-142（控制 β-连环蛋白转录活性的关键位点）上 β-连环蛋白的酪氨酸去磷酸化。值得注意的是，PTPRR 在卵巢癌中下调，异位 PTPRR 重新表达在体外和体内均延迟了卵巢癌细胞的生长。使用基于邻近性的标记系统和RNA-Seq分析，我们确定了卵巢癌中的信号转导关系，包括PTPRR、β-连环蛋白、β-连环蛋白、E-钙粘蛋白和富含AT的相互作用结构域3C (ARID3C)。人类样本的免疫组织化学染色进一步表明 PTPRR 表达与疾病预后呈负相关。总的来说，我们的研究结果表明，PTPRR 通过去磷酸化和失活 β-连环蛋白而在卵巢癌中发挥肿瘤抑制因子的作用。这些结果表明 PTPRR 表达可能可用作预测总生存期的预后标记。
Despite a lack of mutations, accumulating evidence supports an important role for the Wnt/?-catenin pathway in ovarian tumorigenesis. However, the molecular mechanism that contributes to the aberrant activation of the Wnt signaling cascade in ovarian cancer has not been fully elucidated. Here, we found that protein tyrosine phosphatase receptor type R (PTPRR) suppressed the activation of the Wnt/?-catenin pathway in ovarian cancer. We performed an shRNA-based biochemical screen, which identified PTPRR as being responsible for tyrosine dephosphorylation of ?-catenin on Tyr-142, a key site controlling the transcriptional activity of ?-catenin. Of note, PTPRR was down-regulated in ovarian cancers, and ectopic PTPRR re-expression delayed ovarian cancer cell growth both in vitro and in vivo. Using a proximity-based tagging system and RNA-Seq analysis, we identified a signaling nexus that includes PTPRR, ?-catenin, ?-catenin, E-cadherin, and AT-rich interaction domain 3C (ARID3C) in ovarian cancer. Immunohistochemistry staining of human samples further suggested that PTPRR expression is inversely correlated with disease prognosis. Collectively, our findings indicate that PTPRR functions as a tumor suppressor in ovarian cancer by dephosphorylating and inactivating ?-catenin. These results suggest that PTPRR expression might have utility as a prognostic marker for predicting overall survival.