抑制剂和激活剂：SHIP 在免疫和癌症中的双重功能。
Inhibitor and activator: dual functions for SHIP in immunity and cancer.
机构信息
SUNY Upstate Medical University, Syracuse, New York, USA.
出版信息
Ann N Y Acad Sci. 2011 Jan;1217:1-17. doi: 10.1111/j.1749-6632.2010.05869.x. Epub 2010 Dec 13.
Abstract
SHIP1 is at the nexus of intracellular signaling pathways in immune cells that mediate bone marrow (BM) graft rejection, production of inflammatory and immunosuppressive cytokines, immunoregulatory cell formation, the BM niche that supports development of the immune system, and immune cancers. This review summarizes how SHIP participates in normal immune physiology or the pathologies that result when SHIP is mutated. This review also proposes that SHIP can have either inhibitory or activating roles in cell signaling that are determined by whether signaling pathways distal to PI3K are promoted by SHIP's substrate (PI(3,4,5)P(3) ) or its product (PI(3,4)P(2) ). This review also proposes the "two PIP hypothesis" that postulates that both SHIP's product and its substrate are necessary for a cancer cell to achieve and sustain a malignant state. Finally, due to the recent discovery of small molecule antagonists and agonists for SHIP, this review discusses potential therapeutic settings where chemical modulation of SHIP might be of benefit.
摘要
SHIP1 位于介导骨髓 (BM) 移植物排斥、炎症和免疫抑制细胞因子产生、免疫调节细胞形成、支持免疫系统发育的 BM 生态位以及免疫癌症的免疫细胞内信号通路的交汇点。这篇综述总结了 SHIP 如何参与正常免疫生理或当 SHIP 发生突变时导致的病理。这篇综述还提出，SHIP 在细胞信号传导中既可以发挥抑制作用，也可以发挥激活作用，这取决于 SHIP 的底物（PI(3,4,5)P(3)）或其产物（PI(3,4)P(2)）是否促进了 PI3K 下游的信号通路。这篇综述还提出了“两个 PIP 假说”，即假设SHIP 的产物及其底物对于癌细胞实现和维持恶性状态都是必需的。最后，由于最近发现了SHIP 的小分子拮抗剂和激动剂，这篇综述讨论了化学调节 SHIP 可能有益的潜在治疗环境。
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