Compartmentalized signalling of Ras in cancer cells

点击翻译按钮获取中文摘要

Ras proto-oncogene(s) code for transforming GTPases that become post-translationally modified at the Golgi and endoplasmic reticulum (collectively: endomembranes) on their way to the plasma membrane (PM). Recent overexpression studies have disclosed the existence of growth-factor-activated, GTP-loaded Ras in distinct organelles of the secretory pathway, including the Golgi. However, Golgi-activation of Ras is exclusively detected in cells engineered to overexpress Ras, indicating that endomembrane activation of Ras may be a consequence of Ras overexpression, in turn raising doubts on the physiological role of endomembrane-activated Ras. Interestingly, high Ras-GTP levels are also the main attribute of Ras-dependent tumors, which leads to the hypothesis that Ras might be active at endomembranes in cancer cells. In line with this concept, we have detected active Ras at the Golgi of a N-Ras-transformed leukaemia cell line. We propose here a comprehensive study on the sub-cellular localization of Ras activity in cancer cells. Since aberrant levels of Ras-GTP also occur as a result of lesions other than activating Ras mutations, including Ras gene amplification or hypermorphic lesions upstream of Ras, we will investigate the spatial distribution of active Ras in model cell systems for all those scenarios. Moreover we will address whether signalling by Ras-GTP at endomembranes is important for oncogenic transformation in each case. In sum, we propose to determine the spatial dynamics of Ras signalling in cancer cells and close an important gap in our understanding of the pathobiochemistry of Ras.