Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Int J Mol Sci. 2024 May 11;25(10):5254. doi: 10.3390/ijms25105254.
The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer's disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer's disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes.
Src 同源结构域 2 内含肌醇 5-磷酸酶 SHIP1 和 SHIP2 是两种参与细胞内信号通路的蛋白质，与多种疾病的发病机制有关。这两种蛋白同源物都因参与各种癌症的形成而广为人知。SHIP1 在造血细胞中表达为主，已被认为是白血病发生中的肿瘤抑制因子，特别是在髓样白血病中，而广泛表达的 SHIP2 已被认为是多种癌症类型中的癌基因，并被认为参与癌细胞转移过程。然而，还有许多其他疾病，如炎症性疾病以及过敏反应、阿尔茨海默病和中风，SHIP1 可以在其中发挥作用。此外，SHIP2 的过表达与 opsismodysplasia 和阿尔茨海默病以及代谢疾病有关。SHIP1 抑制剂 3-α-氨基胆甾烷（3AC）、SHIP1 激活剂，如 AQX-435 和 AQX-1125，以及 SHIP2 抑制剂，如 K161 和 AS1949490，已被开发并在临床试验中进行了部分测试，这表明 SHIP 同源物作为这些疾病治疗的可能靶点的重要性。本文的目的是提供对 SHIP 蛋白在癌症和其他人类疾病发病机制中作用的最新认识，并使人们认识到 SHIP1 和 SHIP2 不仅仅是肿瘤抑制因子和癌基因。
