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RESEARCH PAPER
Department of Embryology, Howard Hughes Medical Institute, Carnegie Institution of Washington, Baltimore, Maryland 21210, USA
Spindle assembly is subject to the regulatory controls of both the cell-cycle machinery and the Ran-signaling pathway. An important question is how the two regulatory pathways communicate with each other to achieve coordinated regulation in mitosis. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. Moreover, phosphorylation of the NLS of RCC1 is required to prevent the binding of importin 
and 
to RCC1, thereby allowing RCC1 to couple RanGTP production to chromosome binding. These findings reveal that the cell-cycle machinery directly regulates the Ran-signaling pathway by placing a high RanGTP concentration on the mitotic chromosome in mammalian cells.
[Keywords: Ran; RCC1; spindle; mitosis; chromosome; FRET]
Received December 11, 2003; revised version accepted February 4, 2004.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1177304.
E-MAIL zheng{at}ciwemb.edu; FAX (410) 243-6311.
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