Role of Ran in mitotic spindle regulation
One of the central features of mitotic cell division is the formation of the spindle that segregates chromosomes into each daughter cell. Chromosomes are not just passengers along for a ride with the spindle, but active participants in the nucleation and stabilization of spindle microtubules in their near vicinity. The ras-like GTPase Ran that regulates nucleocytoplasmic transport through the nuclear pore complex (NPC) during interphase (See “Role of Ran in Nucleocytoplasmic Transport” Pathway) also regulates the formation of the mitotic spindle. Ran plays a similar role in each of these processes, regulating downstream signaling pathways in a differential manner based on whether GDP or GTP is bound. Like other GTPases, the inherent GTPase activity of Ran is regulated by GTPase activating proteins (GAPs) and by exchange factors. An exchange factor that stimulates nucleotide exchange by the Ran GTPase is RCC1, which binds to chromatin in both interphase and mitosis. While RCC1 helps RAN drive transport between the nucleus and cytoplasm during interphase, the localization of RCC1 on chromatin during mitosis localizes Ran-GTP near chromosomes, localizing microtubule formation in these regions. Ran-BP1 and Ran-GAP1 stimulate GTP hydrolysis by Ran, converting it back to Ran-GDP further away from chromosomes. Aster promoting activities (APA) and the importin-alpha and importin-beta proteins involved with Ran in nucleocytoplasmic transport are also involved in mitotic spindle formation. Aster promoting activities stabilize microtubules during spindle formation, but binding of importins to APA neutralizes their activity in forming microtubules. The importins bind to APA when far from the chromosomes, where Ran-GDP predominates, but Ran-GTP near chromosomes causes importins to release APA factors including Tpx2 and NuMa, allowing them to stimulate microtubule formation. Tpx2 interacts with the microtubule motor protein Xklp2 and also activates the Aurora A mitotic kinase, required for spindle formation. In addition to regulating spindle formation, Ran may also help reform the nuclear envelope after cell division and may use a similar mechanism to regulate other cellular processes.
Contributor: Glenn Croston PhD
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