Ran in Mitosis - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 130

RCC1

RanGTP

T PX2

imp

RanGDP

RanGTP

TPX2

imp

importin

RCC1

imp

TPX2

RanGDP

TPX2:
Microtubule associated protein

Microtubules

Fig. 7.1 Tight binding and ongoing activity of RCC1 on M-phase chromatin generate RanGTP
from RanGDP in the vicinity of chromatin. As it diffuses away from chromatin, with time, the
probability for GTP hydrolysis on Ran by RanBP1/BP2 and RanGAP increases. As a result, a
diffusible gradient of RanGTP becomes established around M-phase chromatin. RanGTP, by a
mechanism analogous to its function in the interphase nucleus, releases microtubule-associated
proteins, such as TPX2 (targeting protein for Xklp2), microtubule motors or other spindle
assembly factors from importins (importin or importin 7). Factors released from

importins can then function in, for example, microtubule nucleation as shown for TPX2

ʱ , importin ʲ

(Tegha-Dunghu et al. 2008 )], which is required for proper mitosis in human cells
(Chang et al. 2004 , 2005 ). Interestingly, also PARP functions together with NuMA
(Chang et al. 2009 ).
Bundling of MT in the vicinity of chromatin requires the activity of chromatin-
bound NuSAP (Ribbeck et al. 2006 , 2007 ; Vanden Bosch et al. 2010 ), a nucleolar
protein in interphase nuclei of somatic cells, which, consistently, is under the
control of RanGTP in the Xenopus system. Interestingly, NuSAP functions could
be modulated by binding to importins

ʱ ʲ

and 7 (Ribbeck et al. 2006 , 2007 )
indicating a complicated set of regulatory inputs. In a cell cycle-dependent manner,
the chromatin protein ISWI dissociates from mitotic chromatin, binds MTs and
stabilises spindle MTs in particular during anaphase. Apart from regulation by the
cell cycle machinery, ISWI's MT binding stays under the control of RanGTP to
ensure high local activity of ISWI on spindle MTs and proper chromosome segre-
gation (Yokoyama et al. 2009 ). In contrast, it is the release from importin

,

that
mediates proper association of the chromokinesin motor protein Xkid on chromatin
(Tahara et al. 2008 ).
The activity of RanGTP to form complete spindles also seems to trigger the
association of TPX2 with the Xenopus chTOG (colonic and hepatic tumour
overexpressed gene) ortholog XMAP215 (Xenopus MT-associated protein of

ʲ