Cooperation between Mitotic Kinesins Controls the Late Stages of Cytokinesis

Abstract

Cell division is regulated by protein kinases of the Cdk, Polo, and Aurora families. Although it has long been established that temporal control is central to the coordinated action of these kinases, the importance of spatial regulation has only recently been appreciated and is still poorly understood. The kinesin-6 family motor protein MKlp1 is a key regulator of cytokinesis and an ideal substrate for studying spatially regulated protein-phosphorylation events. MKlp1 is negatively regulated by Cdk1 phosphorylation during metaphase and becomes activated in anaphase when cleavage-furrow assembly commences. Aurora B phosphorylates MKlp1 during anaphase and is required for its function in cytokinesis. Another kinesin-6 family motor, MKlp2, mediates the relocation of Aurora B from the centromeres to the central spindle at the onset of anaphase. We now demonstrate that this process is required for the phosphorylation of MKlp1 at S911, an Aurora B consensus site overlapping a bipartite nuclear localization sequence (NLS). MKlp1(S911A) targets to the central spindle but is prematurely imported into the nucleus and fails to support cytokinesis. Spatial restriction of Aurora B to the central spindle by MKlp2 therefore regulates MKlp1 during cytokinesis in human cells.

Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line

“…The first gene we examined in this group, Kif23, is a motor molecule known to be involved in cytokinesis (Nislow et al, 1992;Raich et al, 1998;Neef et al, 2006), a process important in axolotl (Rao et al, 2009, Heber-Katz et al, 2013 and zebrafish regeneration (Poss et al, 2002(Poss et al, , 2004. Kif23, also known as MKLP1, is part of a critical complex formed at the midzone or midbody and associates with CYK-4 in the central spindlin (Glotzer, 2005).…”

Podocyte Mitosis – A Catastrophe

“…We recently demonstrated that this forced entry in mitosis is a trigger for a catastrophic mitosis (Fig. 2 ) because podocytes cannot assemble an efficient mitotic spindle due to poor expression of Aurora kinase B, which is essential for cytokinesis [75, 76]. Indeed, occurrence of abnormally mitotic podocytes and micro-multinucleation was demonstrated by electron microscopy in mice models of adriamycin nephropathy, a model of FSGS [75].…”

Polyploidization and Cancer

“…In addition, phosphorylation of MKLP1 by Aurora B is important to prevent the protein from being sequestered back in the nucleus as cells enter interphase. 252 It is interesting to note that many components required for cytokinesis are located in the nucleus or associated with Golgi apparatus during interphase (Fig. 2) and thus localization of cytokinesis components to the midbody could require sustained phosphorylation that prevents the proteins from being resequestered by these structures as cells exit mitosis.…”

“…Treatment of human cells with a small molecule inhibitor of Aurora B in early mitosis inhibits localization of MKLP1 (and its binding partner MgcRacGAP) to the central spindle. 266 However, addition of an Aurora inhibitor at later stages of mitosis inhibits phosphorylation of MKLP1 without disrupting its localization, 252,267 yet perturbs cytokinesis completion, indicating that MKLP1 must remain phosphorylated to permit abscission. How phosphorylation regulates MKLP1 is not completely clear, as MKLP1 is phosphorylated at multiple sites that may have distinct effects.…”

“…How phosphorylation regulates MKLP1 is not completely clear, as MKLP1 is phosphorylated at multiple sites that may have distinct effects. 252,267 Phosphorylation of MKLP1 could be important for stabilizing interactions between the cortex and midbody, or be important for recruiting proteins such as centriolin that are necessary for abscission. In addition, phosphorylation of MKLP1 by Aurora B is important to prevent the protein from being sequestered back in the nucleus as cells enter interphase.…”