Patient derived mutation W257G of PPP2R1A enhances cancer cell migration through SRC-JNK-c-Jun pathway
Patient derived mutation W257G of PPP2R1A enhances cancer cell migration through SRC-JNK-c-Jun pathway
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DOI：
10.1038/srep27391
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发表时间：
2016-06-07
影响因子：
4.6
通讯作者：
Yang, Young
中科院分区：
文献类型：
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作者：
Jeong, Ae Lee;Han, Sora;Yang, Young
PPP 2 R1 A基因突变在子宫内膜浆液性癌中发生频率高，而在卵巢透明细胞癌中发生频率低。然而，PPP 2 R1 A突变在卵巢癌和子宫内膜癌进展中的生物学作用仍不清楚。在这项研究中，我们发现PPP 2 R1 A的表达在卵巢乳头状浆液性肿瘤的高级别原发性肿瘤患者中升高。为了确定PPP 2 R1 A的水平增加或突变是否可能有助于癌症进展，使用卵巢癌和子宫内膜癌细胞系研究PPP 2 R1 A的过表达或突变对细胞增殖、迁移和PP 2A磷酸酶活性的影响。其中PPP 2 R1 A-W257 G突变通过激活SRC-JNK-c-Jun途径增强细胞的体外迁移。野生型（WT）PPP 2 R1 A的过表达增加了其与B56调节亚基的结合能力，而PPP 2 R1 A突变失去了与除B56 δ之外的大多数B56亚基结合的能力。总PP 2A活性和PPP 2 R1 A相关的PP 2Ac活性在过表达PPP 2 R1 A-WT的细胞中显著增加。此外，PPP 2 R1 A-WT的过表达增加了体外细胞增殖和体内肿瘤生长。
Mutation of PPP2R1A has been observed at high frequency in endometrial serous carcinomas but at low frequency in ovarian clear cell carcinoma. However, the biological role of mutation of PPP2R1A in ovarian and endometrial cancer progression remains unclear. In this study, we found that PPP2R1A expression is elevated in high-grade primary tumor patients with papillary serous tumors of the ovary. To determine whether increased levels or mutation of PPP2R1A might contribute to cancer progression, the effects of overexpression or mutation of PPP2R1A on cell proliferation, migration, and PP2A phosphatase activity were investigated using ovarian and endometrial cancer cell lines. Among the mutations, PPP2R1A-W257G enhanced cell migration in vitro through activating SRC-JNK-c-Jun pathway. Overexpression of wild type (WT) PPP2R1A increased its binding ability with B56 regulatory subunits, whereas PPP2R1A-mutations lost the ability to bind to most B56 subunits except B56 delta. Total PP2A activity and PPP2R1A-associated PP2Ac activity were significantly increased in cells overexpressing PPP2R1A-WT. In addition, overexpression of PPP2R1A-WT increased cell proliferation in vitro and tumor growth in vivo.