Frodyma Danielle, Neilsen Beth, Costanzo-Garvey Diane, Fisher Kurt, Lewis Robert
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
F1000Res. 2017 Aug 31;6:1621. doi: 10.12688/f1000research.11895.1. eCollection 2017.
Many cancers, including those of the colon, lung, and pancreas, depend upon the signaling pathways induced by mutated and constitutively active Ras. The molecular scaffolds Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2) play potent roles in promoting Ras-mediated signaling through the Raf/MEK/ERK kinase cascade. Here we summarize the canonical role of KSR in cells, including its central role as a scaffold protein for the Raf/MEK/ERK kinase cascade, its regulation of various cellular pathways mediated through different binding partners, and the phenotypic consequences of KSR1 or KSR2 genetic inactivation. Mammalian KSR proteins have a demonstrated role in cellular and organismal energy balance with implications for cancer and obesity. Targeting KSR1 in cancer using small molecule inhibitors has potential for therapy with reduced toxicity to the patient. RNAi and small molecule screens using KSR1 as a reference standard have the potential to expose and target vulnerabilities in cancer. Interestingly, although KSR1 and KSR2 are similar in structure, KSR2 has a distinct physiological role in regulating energy balance. Although KSR proteins have been studied for two decades, additional analysis is required to elucidate both the regulation of these molecular scaffolds and their potent effect on the spatial and temporal control of ERK activation in health and disease.
许多癌症，包括结肠癌、肺癌和胰腺癌，都依赖于由突变的、持续激活的Ras诱导的信号通路。分子支架Ras激酶抑制因子1和2（KSR1和KSR2）在通过Raf/MEK/ERK激酶级联促进Ras介导的信号传导中发挥着重要作用。在这里，我们总结了KSR在细胞中的典型作用，包括其作为Raf/MEK/ERK激酶级联支架蛋白的核心作用、通过不同结合伴侣介导的对各种细胞途径的调节，以及KSR1或KSR2基因失活的表型后果。哺乳动物KSR蛋白在细胞和机体能量平衡中发挥作用，对癌症和肥胖有影响。使用小分子抑制剂在癌症中靶向KSR1具有对患者毒性降低的治疗潜力。以KSR1作为参考标准进行RNA干扰和小分子筛选有可能揭示并靶向癌症中的脆弱点。有趣的是，尽管KSR1和KSR2在结构上相似，但KSR2在调节能量平衡方面具有独特的生理作用。尽管对KSR蛋白的研究已有二十年，但仍需要进一步分析来阐明这些分子支架的调节及其在健康和疾病中对ERK激活的时空控制的强大影响。
