PTPRO represses ERBB2-driven breast oncogenesis by dephosphorylation and endosomal internalization of ERBB2.
PTPRO represses ERBB2-driven breast oncogenesis by dephosphorylation and endosomal internalization of ERBB2.
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PTPRO 通过 ERBB2 的去磷酸化和内体内化来抑制 ERBB2 驱动的乳腺肿瘤发生
DOI：
10.1038/onc.2016.213
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发表时间：
2017-01-19
期刊：
影响因子：
8
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Dong H;Ma L;Gan J;Lin W;Chen C;Yao Z;Du L;Zheng L;Ke C;Huang X;Song H;Kumar R;Yeung SC;Zhang H
质膜相关酪氨酸磷酸酶PTPRO在癌症中经常被转录抑制，并预示着乳腺癌患者的不良预后。在这项研究中，在MMTV-ERBB2转基因小鼠中PtPro的缺失显著缩短了乳腺肿瘤的潜伏期，并加速了肿瘤的生长，这是由于PtPro在乳腺癌细胞内的丢失，而不是异种移植研究证实的在周围组织中的丢失。体外和体内数据均表明，ERBB2及其下游信号通路失活所需的磷酸酶活性。PTPRO调控ERBB2在Y1248的磷酸化状态。免疫共沉淀和邻近连接实验(Duolink)表明PTPRO与ERBB2在物理上直接相互作用。此外，PTPRO磷酸酶活性通过促进ERBB2的内吞降解缩短了ERBB2的半衰期。经5-氮杂胞苷去甲基化处理后，PTPRO的重新表达降低了ERBB2阳性乳腺癌细胞的增殖和集落形成能力。综上所述，PTPRO通过去磷酸化抑制ERBB2信号转导和ERBB2内化双重作用来抑制ERBB2诱导的乳腺癌，因此，PTPRO的重新表达可能成为治疗ERBB2过表达乳腺癌的一种潜在的治疗方法。
The plasma membrane-associated tyrosine phosphatase PTPRO is frequently transcriptionally repressed in cancers and signifies poor prognosis of breast cancer patients. In this study, deletion of Ptpro in MMTV-Erbb2 transgenic mice dramatically shortened the mammary tumor latency and accelerated tumor growth due to loss of Ptpro within the breast cancer cells but not in surrounding tissue as confirmed by hetero-transplantation studies. Both in vitro and in vivo data demonstrated that the phosphatase activity was required for the inactivation of ERBB2 and its downstream signaling. PTPRO regulated the phosphorylation status of ERBB2 at Y1248. Co-immunoprecipitation and proximity ligation assay (Duolink) indicated that PTPRO directly physically interacted with ERBB2. Moreover, PTPRO phosphatase activity shortened the half-life of ERBB2 by increasing endocytotic degradation. PTPRO reexpression by demethylation treatment using 5-azacytidine reduced the proliferation and colony formation potential in ERBB2-positive breast cancer cells. Taken together, PTPRO inhibited ERBB2-driven breast cancer through dephosphorylation leading to dual effects of ERBB2 signaling suppression and endosomal internalization of ERBB2, Therefore, reexpression of PTPRO may be a potential therapy for ERBB2-overexpressing breast cancer.