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One RanGTP gradient builds on another to spatially guide mitotic spindle assembly, say Ma?wen Caudron, Eric Karsenti (European Molecular Biology Laboratory, Heidelberg, Germany), and colleagues.
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d0 H, b. A1 n8 n" oChromatin was known to promote spindle assembly via its effects on the Ran GTPase. RanGTP is abundant near chromosomes due to activation by a Ran–guanosine nucleotide exchange factor localized on chromosomes, but the extent of RanGTP localization and its function remained unknown. "Researchers suspected that long-range spindle effects were being mediated by chromosomes, but they couldn't prove this for certain," says Karsenti.
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) V j4 P. d' P$ B; K7 R8 xCombining mathematical modeling and fluorescent microscopy, Karsenti's group now shows that RanGTP diffusion away from chromosomes creates an interrelated series of short- and long-range protein gradients. The gradient of free RanGTP is very steep, but built upon it are shallower gradients of RanGTP–importin ? and RanGTP–importin ?–RanBP1. The RanGTP–importin ? complex helps build the spindle. But binding of RanBP1 to RanGTP–importin ? inactivates the complex.
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This inactivation helps shape the RanGTP–importin ? gradient. It is the RanGTP–importin ? that ultimately promotes two different behaviors: microtubule nucleation at chromosomes; and stabilization of growing tubules within the spindle. It does so by activating the release of nuclear localization signal (NLS)-containing proteins that regulate microtubules. "It is really the free NLS proteins that are important for driving spindle formation," says Karsenti.
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3 ?1 X5 X/ g7 j9 |0 ^. @( n8 aOne NLS protein, TPX2, facilitates microtubule nucleation in an all-or-nothing manner that occurs only when the amount of RanGTP–importin ? is above a certain threshold〞that is, right around chromosomes. Release of another yet-unidentified NLS protein increases linearly with RanGTP–importin ? concentrations and promotes microtubule stabilization. Thus, microtubules emanating from centrosomes become increasingly stabilized the closer they get to chromosomes.
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The next goal in Karsenti's view is to identify the NLS protein gradients to better understand how they promote local nucleation and biased microtubule growth toward chromosomes.
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Caudron, M., et al. 2005. Science. 309:1373–1376.(The RanGTP-importin ? gradient (red) pro) |
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发表于 2009-3-6 09:06
发表于 2015-5-22 14:16
