Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions?
Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions?
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DOI：
10.1242/jcs.022038
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发表时间：
2008-04-01
影响因子：
4
通讯作者：
Turley, Eva
中科院分区：
文献类型：
--
作者：
Alan Maxwell, Christopher;McCarthy, James;Turley, Eva
肿瘤细胞使用多种翻译后机制来修饰其转录组的功能库。一个新兴的，但仍然研究不足的机制涉及出口的细胞质蛋白，然后与细胞表面受体和修改的表面展示动力学和这些受体的信号传导特性的合作伙伴。最近的研究表明，在肿瘤发生和炎症过程中，表吗啡肽、FGF 1、FGF 2、PLK 1和Ku 80等蛋白质发挥了兼职作用。在这里，我们回顾了非常规的细胞质蛋白出口的分子机制，通过集中在有丝分裂纺锤体/透明质酸结合蛋白RHAMM，这是在许多人类肿瘤的高表达。细胞内RHAMM与BRCA 1和BARD 1相关;这种相关性减弱了RHAMM的有丝分裂纺锤体促进活性，这可能通过促进基因组不稳定性而促进肿瘤进展。细胞外RHAMM-CD 44结合维持CD 44表面展示并通过ERK 1和ERK 2（ERK 1/2）增强CD 44介导的信号传导;它还可能通过增强和/或激活CD 44的潜在促肿瘤特性而促进肿瘤进展。RHAMM等蛋白质的非常规输出是一种新的过程，它改变了肿瘤抑制因子和启动子（如BRCA 1和CD 44）的作用，并可能为治疗干预提供新的靶点。
Tumor cells use a wide variety of post-translational mechanisms to modify the functional repertoire of their transcriptome. One emerging but still understudied mechanism involves the export of cytoplasmic proteins that then partner with cell-surface receptors and modify both the surface-display kinetics and signaling properties of these receptors. Recent investigations demonstrate moonlighting roles for the proteins epimorphin, FGF1, FGF2, PLK1 and Ku80, to name a few, during oncogenesis and inflammation. Here, we review the molecular mechanisms of unconventional cytoplasmic-protein export by focusing on the mitotic-spindle/hyaluronan-binding protein RHAMM, which is hyper-expressed in many human tumors. Intracellular RHAMM associates with BRCA1 and BARD1; this association attenuates the mitotic-spindle-promoting activity of RHAMM that might contribute to tumor progression by promoting genomic instability. Extracellular RHAMM-CD44 partnering sustains CD44 surface display and enhances CD44-mediated signaling through ERK1 and ERK2 (ERK1/2); it might also contribute to tumor progression by enhancing and/or activating the latent tumor-promoting properties of CD44. The unconventional export of proteins such as RHAMM is a novel process that modifies the roles of tumor suppressors and promoters, such as BRCA1 and CD44, and might provide new targets for therapeutic intervention.