Freeman Alyson K, Ritt Daniel A, Morrison Deborah K
Laboratory of Cell and Developmental Signaling; Center for Cancer Research; National Cancer Institute-Frederick; Frederick, MD USA.
Small GTPases. 2013 Jul-Sep;4(3):180-5. doi: 10.4161/sgtp.26117. Epub 2013 Aug 28.
The Raf family of protein kinases are key signaling intermediates, acting as a central link between the membrane-bound Ras GTPases and the downstream kinases MEK and ERK. Raf kinase regulation is well-known for its complexity but only recently has it been realized that many of the mechanisms involved in Raf regulation also modulate Raf dimerization, now acknowledged to be a required step for Raf signaling in multiple cellular contexts. Recent studies have shown that Raf dimerization is necessary for normal Ras-dependent Raf kinase activation and contributes to the pathogenic function of disease-associated mutant Raf proteins with all but high intrinsic kinase activity. Raf dimerization has also been found to alter therapeutic responses and disease progression in patients treated with ATP-competitive Raf inhibitors as well as certain other kinase-targeted drugs. This demonstration of clinical significance has stimulated the recent development of biosensor assays that can monitor inhibitor-induced Raf dimerization as well as studies demonstrating the therapeutic potential of blocking Raf dimerization.
蛋白质激酶Raf家族是关键的信号转导中间体，作为膜结合型Ras GTP酶与下游激酶MEK和ERK之间的核心纽带。Raf激酶的调节因其复杂性而闻名，但直到最近才意识到，许多参与Raf调节的机制也会调节Raf二聚化，而现在人们认为Raf二聚化是Raf在多种细胞环境中信号转导的必要步骤。最近的研究表明，Raf二聚化对于正常的Ras依赖性Raf激酶激活是必要的，并且除了具有高内在激酶活性外，还促成了与疾病相关的突变Raf蛋白的致病功能。还发现Raf二聚化会改变接受ATP竞争性Raf抑制剂以及某些其他激酶靶向药物治疗的患者的治疗反应和疾病进展。这种临床意义的证明刺激了最近生物传感器测定法的发展，该测定法可以监测抑制剂诱导的Raf二聚化，以及证明阻断Raf二聚化治疗潜力的研究。
