Nuclear transport factors: global regulation of mitosis

Abstract

The unexpected repurposing of nuclear transport proteins from their function in interphase to an equally vital and very different set of functions in mitosis was very surprising. The multi-talented cast when first revealed included the import receptors, importin alpha and beta, the small regulatory GTPase RanGTP, and a subset of nuclear pore proteins. In this review, we report that recent years have revealed new discoveries in each area of this expanding story in vertebrates: (a) The cast of nuclear transport receptors playing a role in mitotic spindle regulation has expanded: both transportin, a nuclear import receptor, and Crm1/Xpo1, an export receptor, are involved in different aspects of spindle assembly. Importin beta and transportin also regulate nuclear envelope and pore assembly. (b) The role of nucleoporins has grown to include recruiting the key microtubule nucleator the γ-TuRC complex and the exportin Crm1 to the mitotic kinetochores of humans. Together they nucleate microtubule formation from the kinetochores towards the centrosomes. (c) New research finds that the original importin beta/RanGTP team have been further co-opted by evolution to help regulate other cellular and organismal activities, ranging from the actual positioning of the spindle within the cell perimeter, to regulation of a newly discovered spindle microtubule branching activity, to regulation of the interaction of microtubule structures with specific actin structures. (d) Lastly, because of the multitudinous roles of karyopherins throughout the cell cycle, a recent large push toward testing their potential as chemotherapeutic targets has begun to yield burgeoning progress in the clinic.

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

“…The rationale behind the targeting of XPO1 is to increase the nuclear concentration of Induces G 2 cell-cycle arrest through the inhibition of CDK1, allowing the premitotic DNA repair XPO1 cargoes, in particular of tumor suppressor gene products. It must be noted, however, that XPO1 also plays a role in RNA export and in mitotic processes, such as microtubule nucleation at kinetochores (42). Thus, interference with these XPO1 functions may also contribute to the therapeutic effect of XPO1 inhibition.…”

Nuclear pore complex tethers to the cytoskeleton

“…One hint that NPC proteins could be linked to microtubules was the discovery that much of the protein transport system as well as major components of the NPC are re-purposed for a seemingly different role in control and assembly of the mitotic spindle (for review see Forbes et al, 2015). Firstly the so called Y-complex (containing Nup107, Nup160, Nup133, Nup96, Nup85, Nup43, Nup37, Sec13 and Seh1) is recruited to kinetochores before attachment of the microtubules can occur (Mishra et al, 2010).…”

“…Therefore at mitosis the Y-complex can not only be involved in microtubule nucleation but is also necessary for proper spindle formation. Other nucleoporins and transport factors such as ELYS/Mel28, CRM1 and Nup62, controlled by the RanGTP/importin β system are recruited to kinetochores and centrioles and play a role in controlling the assembly of spindle microtubules (Forbes et al, 2015).…”

Molecular mechanisms regulating plant infection in the rice blast fungus Magnaporthe oryzae

“…It has been demonstrated that some kaps bind microtubule-associated proteins promoting the inactivation of microtubule aster production during interphase, a process that regulates the entry into mitosis (Mosammaparast & Pemberton, 2004, Forbes, et al, 2015. The observed interaction of Exp5 with the tubulin alpha and beta chains (MGG_11412, MGG_00604 and MGG_06650) suggests potential links with microtubule-related processes and associated proteins.…”

“…Karyopherins are involved in the assembly of nucleopore channels and regulate the S-phase during the cell cycle (Forbes, et al, 2015). Msn5, the yeast orthologue of Exp5 is involved in the transition of cells from the G1 to the S phase of the cell cycle (Queralt & Igual, 2003).…”