Ran (gene)

Ran (RAs-related Nuclear protein) also known as GTP-binding nuclear protein Ran is a is_associated_with::protein that in humans is encoded by the RAN is_associated_with::gene. Ran is a small 25 kDa protein that is involved in transport into and out of the is_associated_with::cell nucleus during is_associated_with::interphase and also involved in is_associated_with::mitosis. It is a member of the is_associated_with::Ras superfamily.

Ran is a is_associated_with::small G protein that is essential for the translocation of RNA and proteins through the is_associated_with::nuclear pore complex. The Ran protein has also been implicated in the control of DNA synthesis and cell cycle progression, as mutations in Ran have been found to disrupt DNA synthesis.

Ran cycle
Ran exists in the cell in two nucleotide-bound forms: GDP-bound and GTP-bound. RanGDP is converted into RanGTP through the action of RCC1, the is_associated_with::nucleotide exchange factor for Ran. RCC1 is also known as RanGEF (Ran Guanine nucleotide Exchange Factor). Ran's intrinsic is_associated_with::GTPase-activity is activated through interaction with Ran is_associated_with::GTPase activating protein (RanGAP), facilitated by complex formation with Ran-binding protein (RanBP). GTPase-activation leads to the conversion of RanGTP to RanGDP, thus closing the Ran cycle.

Ran can diffuse freely within the cell, but because is_associated_with::RCC1 and RanGAP are located in different places in the cell, the concentration of RanGTP and RanGDP differs locally as well, creating concentration gradients that act as signals for other cellular processes. is_associated_with::RCC1 is bound to is_associated_with::chromatin and therefore located inside the nucleus. RanGAP is is_associated_with::cytoplasmic in yeast and bound to the is_associated_with::nuclear envelope in plants and animals. In mammalian cells, it is SUMO modified and attached to the cytoplasmic side of the is_associated_with::nuclear pore complex via interaction with the is_associated_with::nucleoporin RanBP2 (Nup358). This difference in location of the accessory proteins in the Ran cycle leads to a high RanGTP to RanGDP ratio inside the nucleus and an inversely low RanGTP to RanGDP ratio outside the nucleus. In addition to a gradient of the nucleotide bound state of Ran, there is a gradient of the protein itself, with a higher concentration of Ran in the nucleus than in the cytoplasm. Cytoplasmic RanGDP is imported into the nucleus by the small protein NTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GDP for GTP on Ran.

Role in nuclear transport during interphase
'' Ran is involved in the transport of proteins across the nuclear envelope by interacting with is_associated_with::karyopherins and changing their ability to bind or release cargo molecules. Cargo proteins containing a is_associated_with::nuclear localization signal (NLS) are bound by is_associated_with::importins and transported into the nucleus. Inside the nucleus, RanGTP binds to importin and releases the import cargo. Cargo that needs to get out of the nucleus into the cytoplasm binds to is_associated_with::exportin in a ternary complex with RanGTP. Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex dissociates and export cargo is released.

Role in mitosis
During mitosis, the Ran cycle is involved in is_associated_with::mitotic spindle assembly and nuclear envelope reassembly after the chromosomes have been separated. During is_associated_with::prophase, the steep gradient in RanGTP-RanGDP ratio at the nuclear pores breaks down as the nuclear envelope becomes leaky and disassembles. RanGTP concentration stays high around the is_associated_with::chromosomes as RCC1, a nucleotide exchange factor, stays attached to is_associated_with::chromatin. RanBP2 (Nup358) and RanGAP move to the is_associated_with::kinetochores where they facilitate the attachment of spindle fibers to chromosomes. Moreover, RanGTP promotes spindle assembly by mechanisms similar to mechanisms of nuclear transport: the activity of spindle assembly factors such as NuMA and TPX2 is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the is_associated_with::mitotic spindle. In is_associated_with::telophase, RanGTP hydrolysis and nucleotide exchange are required for is_associated_with::vesicle fusion at the reforming nuclear envelopes of the daughter nuclei.

Ran and the androgen receptor
RAN is an is_associated_with::androgen receptor (AR) coactivator (ARA24) that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to is_associated_with::spinal and bulbar muscular atrophy (Kennedy's disease). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of spinal and bulbar muscular atrophy.

Interactions
Ran has been shown to interact with:


 * is_associated_with::KPNB1,
 * is_associated_with::NEK9,
 * is_associated_with::NUTF2,
 * is_associated_with::RANBP1,
 * is_associated_with::RANGAP1,
 * is_associated_with::RCC1,
 * TNPO1,
 * is_associated_with::TNPO2,
 * is_associated_with::XPO1,  and
 * is_associated_with::XPO5.

Regulation
The expression of Ran is repressed by the is_associated_with::microRNA miR-10a.