Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells.
Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells.
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DOI：
10.1016/j.cellsig.2010.09.004
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发表时间：
2011-01
影响因子：
4.8
通讯作者：
Pasquale EB
中科院分区：
文献类型：
--
作者：
Yang NY;Fernandez C;Richter M;Xiao Z;Valencia F;Tice DA;Pasquale EB
Eph家族的受体酪氨酸激酶在组织稳态的生理调节和包括癌症在内的各种疾病的发病机制中发挥多种作用。EphA 2受体在大多数癌细胞类型中高度表达，其中它具有不同的活性，这些活性尚不清楚。据报道，EphA 2与致癌信号传导途径的相互作用独立于肝配蛋白配体结合和受体激酶活性促进癌细胞恶性化。相反，用肝配蛋白-A配体刺激EphA 2信号传导可以通过抑制Ras-MAP激酶途径、整合素介导的粘附和上皮向间充质转化来抑制恶性肿瘤。在这里，我们表明，ephrin-A1配体依赖性激活EphA 2减少了PC 3前列腺癌细胞的生长，并深刻地抑制Akt-mTORC 1途径，这是过度激活，由于损失的PTEN肿瘤抑制因子。我们的研究结果并没有暗示Akt上游调节因子（如Ras家族GTP酶、PI 3激酶、整合素或Ship 2脂质磷酸酶）的活性变化与观察到的EphA 2下游Akt T308和S473磷酸化的丧失有关。事实上，EphA 2不仅可以抑制PTEN的致癌突变诱导的Akt磷酸化，还可以抑制PI 3激酶的致癌突变诱导的Akt磷酸化。此外，它可以减少Akt的组成性膜靶向诱导的过度磷酸化。我们的数据表明，EphA 2通过丝氨酸/苏氨酸磷酸酶介导的Akt去磷酸化使Akt-mTORC 1致癌通路失活的一种新的信号传导机制。Ephrin-A1诱导的Akt去磷酸化不仅在PC 3前列腺癌细胞中观察到，而且在其他癌细胞类型中也观察到。因此，EphA 2信号传导的激活代表了抗癌疗法的一种可能的新途径，该疗法利用该受体抵消多种致癌信号传导途径的显著能力。
Receptor tyrosine kinases of the Eph family play multiple roles in the physiological regulation of tissue homeostasis and in the pathogenesis of various diseases, including cancer. The EphA2 receptor is highly expressed in most cancer cell types, where it has disparate activities that are not well understood. It has been reported that interplay of EphA2 with oncogenic signaling pathways promotes cancer cell malignancy independently of ephrin ligand binding and receptor kinase activity. In contrast, stimulation of EphA2 signaling with ephrin-A ligands can suppress malignancy by inhibiting the Ras-MAP kinase pathway, integrin-mediated adhesion, and epithelial to mesenchymal transition. Here we show that ephrin-A1 ligand-dependent activation of EphA2 decreases the growth of PC3 prostate cancer cells and profoundly inhibits the Akt-mTORC1 pathway, which is hyperactivated due to loss of the PTEN tumor suppressor. Our results do not implicate changes in the activity of Akt upstream regulators (such as Ras family GTPases, PI3 kinase, integrins, or the Ship2 lipid phosphatase) in the observed loss of Akt T308 and S473 phosphorylation downstream of EphA2. Indeed, EphA2 can inhibit Akt phosphorylation induced by oncogenic mutations of not only PTEN but also PI3 kinase. Furthermore, it can decrease the hyperphosphorylation induced by constitutive membrane-targeting of Akt. Our data suggest a novel signaling mechanism whereby EphA2 inactivates the Akt-mTORC1 oncogenic pathway through Akt dephosphorylation mediated by a serine/threonine phosphatase. Ephrin-A1-induced Akt dephosphorylation was observed not only in PC3 prostate cancer cells but also in other cancer cell types. Thus, activation of EphA2 signaling represents a possible new avenue for anti-cancer therapies that exploit the remarkable ability of this receptor to counteract multiple oncogenic signaling pathways.
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