Ran Proteins in Health and Disease

Ras-related nuclear protein (Ran), a member of the Ras superfamily of small GTPases, plays a critical role in the transport of macromolecules between the nucleus and the cytoplasm that occurs through nuclear pores. More recently, research has shown that Ran participates in the coordination of mitosis, with specific roles in mitotic spindle assembly, centrosome duplication, microtubule dynamics, and chromosome alignment.¹

Ran acts as a molecular switch, cycling between GTP-bound and GDP-bound conformations. RanGTP is generated in the nucleus by the guanine nucleotide exchange factor RCC1, while GTP is hydrolyzed to produce RanGDP in the cytoplasm by GTP-hydrolysis activating protein 1 (RanGAP1) with the help of Ran-binding protein 1 (RanBP1).² Additional effectors of Ran include other Ran-binding proteins, such as RanBP3 that enhances the rate of nuclear export³, and importins alpha and beta, critical mediators of nuclear import.²

Ran and its binding proteins are implicated in a variety of diseases. For example, elevated levels of Ran and RanBP1 are found in many cancers, including ovarian, colon, esophageal, lung, and lymphoma². RanBP2 is also implicated in cancer, as mice lacking the gene are prone to spontaneous tumors⁴. In addition, a mutation in RanBP2 causes a familial form of acute necrotizing encephalopathy, a rare and often-fatal neurological disorder that affects otherwise healthy children after a viral infection such as influenza⁵. Both RanBP3 and RanBP5 are involved in influenza virus replication⁶. RanBP9 is elevated in the brains of patients with Alzheimer disease, where it is thought to promote generation of the toxic neuropeptide amyloid beta and enhance mitochondrial-mediated apoptosis^7,8.

Ran and its wide range of effector proteins play a significant role in many functions in the cell, providing insights into a number of different processes, especially in cell division and the life cycle. However, because of the wide breadth of activities, these proteins also critical players in multiple disease processes, rendering the knowledge gained from these proteins critical for both cell biology and human health.