RIPK3 signaling and its role in the pathogenesis of cancers.
RIPK3 signaling and its role in the pathogenesis of cancers.
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DOI：
10.1007/s00018-021-03947-y
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Liu S;Joshi K;Denning MF;Zhang J
RIPK 3（Receptor-interacting protein kinase 3，受体相互作用蛋白激酶3）是一种丝氨酸/苏氨酸蛋白激酶。作为坏死体的关键组分，RIPK 3是炎症因子（如TNFα-肿瘤坏死因子α）和感染诱导的坏死性凋亡（一种程序性坏死）的重要介质。此外，RIPK 3信号传导还通过与相应信号传导途径的关键调节剂相互作用和/或磷酸化而参与细胞凋亡、细胞因子/趋化因子产生、线粒体代谢、自噬和细胞增殖的调节。与细胞凋亡类似，RIPK 3信号转导介导的坏死性凋亡在大多数类型的癌症中失活，这表明RIPK 3可能在癌症的发病机制中起关键的抑制作用。然而，在某些炎性类型的癌症中，如胰腺癌和结直肠癌，RIPK 3信号可能通过刺激肿瘤细胞中的增殖信号并诱导肿瘤环境中的免疫抑制反应来促进癌症发展。本文综述了近年来RIPK 3信号通路调控因子的研究进展，并讨论了该通路在混合谱系激酶结构域样（MLKL）介导的坏死性凋亡和MLKL非依赖性细胞行为调控中的作用。此外，我们讨论了RIPK 3信号通路在不同类型癌症发病机制中的潜在作用，并讨论了在癌症治疗中靶向该通路的潜在策略。
RIPK3 (Receptor-interacting protein kinase 3) is a serine/threonine-protein kinase. As a key component of necrosomes, RIPK3 is an essential mediator of inflammatory factors (such as TNFα-tumor necrosis factor α) and infection-induced necroptosis, a programmed necrosis. In addition, RIPK3 signaling is also involved in regulation of apoptosis, cytokine/chemokine production, mitochondrial metabolism, autophagy, and cell proliferation by interacting with and/or phosphorylating the critical regulators of the corresponding signaling pathways. Similar to apoptosis, RIPK3-signaling mediated necroptosis is inactivated in most types of cancers, suggesting RIPK3 might play a critical suppressive role in the pathogenesis of cancers. However, in some inflammatory types of cancers, such as pancreatic cancers and colorectal cancers, RIPK3 signaling might promote cancer development by stimulating proliferation signaling in tumor cells and inducing an immunosuppressive response in the tumor environment. In this review, we summarize recent research progress in the regulators of RIPK3 signaling, and discuss the function of this pathway in the regulation of mixed lineage kinase domain-like (MLKL)-mediated necroptosis and MLKL-independent cellular behaviors. In addition, we deliberate the potential roles of RIPK3 signaling in the pathogenesis of different types of cancers and discuss the potential strategies for targeting this pathway in cancer therapy.
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