KSR, a Modifier of Ras-Mediated Cell Transformation

描述(申请人提供)：原癌基因的激活和抑癌基因的失活驱动体内肿瘤的形成和培养细胞的转化。然而，其他有助于转导致癌信号的基因可以改变肿瘤的敏感性。RAS 1的激酶抑制因子1(KSR1)是RAS致癌和细胞转化的调节因子。这项研究的目的是解释KSR1作用的分子机制。本实验室的最新数据表明，KSR1具有预期的Raf/MEK/ERK信号盒分子支架的特性。此外，KSR1的缺失阻止了构成活性的RasV12在培养中转化细胞，并显著减少了RasV12在体内诱导的肿瘤形成。新的数据表明，KSR1与小窝蛋白-1相互作用，以对RasV12诱导的转化和肿瘤发生至关重要的方式调节Raf/MEK/ERK信号盒的亚细胞组装和激活。实验还证明，相关蛋白KSR2对细胞的增殖和代谢有明显的影响。第三组研究揭示了KSR蛋白与影响其功能的激酶家族的相互作用。这些观察表明，通过Raf/MEK/ERK信号盒和调节细胞代谢的机制，导致肿瘤发生的机制之间存在先前未知的、但在生理上重要的相互依存关系。这项提议将检验KSR蛋白通过依赖和独立于Raf/MEK/ERK激酶级联的机制影响肿瘤形成潜力的假设。这些机制的细节将被揭示如下：1)确定KSR1在ERK激活和细胞转化的空间调控中的作用；2)确定KSR2在调节KSR1功能和RasV12肿瘤发生中的作用；3)确定能量平衡效应因子在调节KSR蛋白和激活的RasV12中的作用。公共卫生相关性：原癌基因RAS是导致多种人类癌症的常见突变因素。KSR1在调节RAS的致瘤潜能方面发挥着重要作用。因此，研究KSR蛋白在肿瘤形成中的调控作用可能为研究肿瘤易感性的分子机制提供新的见解。

DESCRIPTION (provided by applicant): The activation of proto-oncogenes and the inactivation of tumor suppressors drive tumor formation in vivo and the transformation of cells in culture. However, other genes that contribute to the transduction of oncogenic signals can modify tumor susceptibility. Kinase Suppressor of Ras 1 (KSR1) is a modifier of tumorigenesis and cell transformation by oncogenic Ras. The goal of this research is to explain the molecular mechanisms underlying the action of KSR1. Recent data from this laboratory demonstrate that KSR1 has properties expected of a molecular scaffold for the Raf/MEK/ERK signaling cassette. Furthermore, deletion of KSR1 prevents constitutively active RasV12 from transforming cells in culture and markedly diminishes RasV12-induced tumor formation in vivo. New data demonstrate that KSR1 interacts with caveolin-1 to regulate the subcellular assembly and activation of the Raf/MEK/ERK signaling cassette in a manner critical to RasV12-induced transformation and tumorigenesis. Experiments also demonstrate that the related protein, KSR2, has a distinct effect on cell proliferation and metabolism. A third set of studies reveal the interaction of KSR proteins with a kinase family that affects their function. These observations suggest a previously unidentified, but physiologically important, interdependence of mechanisms contributing to tumorigenesis via the Raf/MEK/ERK signaling cassette and mechanisms regulating cellular metabolism. This proposal will test the hypothesis that KSR proteins affect tumorigenic potential via mechanisms that are dependent and independent of the Raf/MEK/ERK kinase cascade. The details of those mechanisms will be revealed by: 1) determining the contribution of KSR1 in the spatial regulation of ERK activation and cell transformation, 2) determining the role of KSR2 in regulating KSR1 function and RasV12 tumorigenesis, and 3) determining the role of effectors of energy balance in regulating KSR proteins and activated RasV12. PUBLIC HEALTH RELEVANCE: The proto-oncogene Ras is a commonly mutated contributor to multiple human cancers. KSR1 plays a potent role in regulating the tumorigenic potential of Ras. Thus, study of KSR proteins in the regulation of tumor formation is likely to provide novel insights into the molecular mechanisms regulating cancer susceptibility.