EphA2通过调节细胞连接蛋白磷酸化调节血管通透性和前列腺癌转移。

IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Carolin Offenhäuser, Keyur A Dave, Kirrilee J Beckett, Fiona M Smith, Buddhika A Jayakody, Leanne T Cooper, Helen Agyei-Yeboah, Jennifer K McCarron, Yuchen Li, Kate Bastick, Fares Al-Ejeh, Jason K Cullen, Mark G Coulthard, Jeffrey J Gorman, Andrew W Boyd, Bryan W Day
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引用次数: 0

摘要

前列腺癌的发病率和死亡率表明,需要更有效的靶向疗法。EphA2是一个潜在的靶点,但矛盾的是,促癌和抗癌作用都是由EphA2介导的。我们证明,独特的激活和阻断 EphA2 靶向单克隆抗体在体内显示出截然相反的肿瘤抑制和致癌特性。为了进一步探索这种复杂性,我们在配体诱导 EphA2 激活后进行了详细的磷酸化蛋白质组分析。我们的分析确定了与 PI3K/AKT/mTOR 和 ERK/MAPK 通路相关的 73 种下游蛋白的磷酸化改变,其中大多数与细胞连接和细胞骨架组织、细胞运动和肿瘤转移有关。我们证明,适配蛋白 SHB 是 EphA2 受体活化时介导 ERK/MAPK 通路抑制的重要成分。此外,我们还发现粘附连接蛋白 afadin 是一种受 EphA2 调节的磷蛋白,它参与了前列腺癌的迁移和侵袭。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
EphA2 regulates vascular permeability and prostate cancer metastasis via modulation of cell junction protein phosphorylation.

Prostate cancer morbidity and mortality demonstrate a need for more effective targeted therapies. One potential target is EphA2, although paradoxically, pro- and anti-oncogenic effects have been shown to be mediated by EphA2. We demonstrate that unique activating and blocking EphA2-targeting monoclonal antibodies display opposing tumor-suppressive and oncogenic properties in vivo. To further explore this complexity, we performed detailed phosphoproteomic analysis following ligand-induced EphA2 activation. Our analysis identified altered phosphorylation of 73 downstream proteins related to the PI3K/AKT/mTOR and ERK/MAPK pathways, with the majority implicated in cell junction and cytoskeletal organization, cell motility, and tumor metastasis. We demonstrate that the adapter protein SHB is an essential component in mediating the inhibition of the ERK/MAPK pathway in response to EphA2 receptor activation. Furthermore, we identify the adherence junction protein afadin as an EphA2-regulated phosphoprotein which is involved in prostate cancer migration and invasion.

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来源期刊
Oncogene
Oncogene 医学-生化与分子生物学
CiteScore
15.30
自引率
1.20%
发文量
404
审稿时长
1 months
期刊介绍: Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.
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