The mechanism of spindle assembly: functions of Ran and its target TPX2

Abstract

Recent work has provided new insights into the mechanism of spindle assembly. Growing evidence supports a model in which the small GTPase Ran plays a central role in this process. Here, we examine the evidence for the existence of a RanGTP gradient around mitotic chromosomes and some controversial data on the role that chromosomes play in spindle assembly. We review the current knowledge on the Ran downstream targets for spindle assembly and we focus on the multiple roles of TPX2, one of the targets of RanGTP during cell division.

Figure 1.

During mitosis RanGDP is converted into RanGTP in the proximity of the chromosomes by the nucleotide exchange factor RCC1. In a first step, RanGTP binds to importin β releasing it from importin α. The affinity of importin α for NLS sequences is reduced and a complex of importin α CAS and RanGTP forms releasing TPX2. CAS functions to reexport importin α to the cytoplasm. TPX2 triggers microtubule nucleation and binds to the mitotic kinase Aurora A activating it.

Figure 2.

Factors proposed to be regulated by RanGTP during mitosis and their role in spindle assembly. (A) Nucleation: in the initial phases chromosomes generate an environment enriched in RanGTP. TPX2 is released from the importins and triggers microtubule nucleation. (B) Organization: microtubules assembled around the chromosomes coalesce and start to organize. Two proteins were suggested to be regulated by RanGTP and to participate in these events: Eg5 and Kid. (C) Pole formation: microtubule minus ends focus into spindle poles. This process involves two proteins regulated by RanGTP: NuMA and XCTK2. TPX2 may also play a role in this process.