Abstract
Ran (Ras-related nuclear protein) GTPase is a member of the Ras superfamily. Like all the GTPases, Ran cycles between an active (GTP-bound) and inactive (GDP-bound) state. However, Ran lacks the CAAX motif at its C-terminus, a feature of other small GTPases that ensures a plasma membrane localization, and largely traffics between the nucleus and the cytoplasm. Ran regulates nucleo-cytoplasmic transport of molecules through the nuclear pore complex and controls cell cycle progression through the regulation of microtubule polymerization and mitotic spindle formation. The disruption of Ran expression has been linked to cancer at different levels – from cancer initiation to metastasis. In the present review, we discuss the contribution of Ran in the acquisition of three hallmarks of cancer, namely, proliferative signaling, resistance to apoptosis, and invasion/metastasis, and highlight its prognostic value in cancer patients. In addition, we discuss the use of this GTPase as a therapeutic target in cancer.
Highlights
Ran (Ras-related nuclear protein) is a member of the RAS superfamily of small GTPases
Another study has shown that RanBP9, a presumed interacting partner of Ran (Nakamura et al, 1998), is an adaptor of the Met-receptor that allows the recruitment of the Son of Sevenless (SoS) protein, resulting in the activation of the proliferative mitogen-activated protein kinase (MAPK) signaling pathway (Wang et al, 2002). These findings suggest that Ran may regulate the phosphoinositide 3-kinase (PI3K) and MAPK pathways at two levels: upstream by stabilizing Met-receptor and recruiting SoS protein through RanBP9 and downstream by ensuring the traffic of transcription factors controlled by these pathways
Since no activating mutation of Ran has been reported in patient samples, this raises the question on how Ran is activated in the context of cancer
Summary
Ran (Ras-related nuclear protein) is a member of the RAS superfamily of small GTPases. Importin β forms a complex with cargo proteins displaying NLS (directly or through the adaptor importin α) and moves actively into the nucleus through the nuclear pores This process involves the interaction of importin β with the phenylalanine/glycine repeat domains displayed by nucleoporins of the NPC to overcome the size limit of the barrier and to rapidly cross the NE (Joseph, 2006; Matchett et al, 2014). We examine the involvement of Ran in tumor progression and metastasis, and we provide insights on the use of this GTPase as a therapeutic target in cancer
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