B-type plexins regulate mitosis via RanGTPase.

Abstract

Aberrant mitosis can result in aneuploidy and cancer. The small GTPase, Ran, is a key regulator of mitosis. B-type Plexins regulate Ran activity by acting as RanGTPase activating proteins (GAPs) and have been implicated in cancer progression. However, whether B-type plexins have a role in mitosis has not so far been investigated. We show here that PlexinB1 functions in the control of mitosis. Depletion of PlexinB1 affects mitotic spindle assembly, significantly delaying anaphase. This leads to mitotic catastrophe in some cells, and prolonged application of the spindle assembly checkpoint. PlexinB1 depletion also promoted acentrosomal microtubule nucleation and defects in spindle pole refocussing and increased the number of cells with multipolar or aberrant mitotic spindles. An increase in lagging chromosomes or chromosomal bridges at anaphase was also found upon PlexinB1 depletion. PlexinB1 localises to the mitotic spindle in dividing cells. The mitotic defects observed upon PlexinB1 depletion were rescued by an RCC1 inhibitor, indicating that PlexinB1 signals, via Ran, to affect mitosis. These errors in mitosis generated multinucleate cells, and nuclei of altered morphology and abnormal karyotype. Furthermore, Semaphorin4D-treatment increased the percentage of cells with micronuclei, precursors of chromothripsis. Implications: Defects in B-type plexins may contribute to the well-established role of plexins in cancer progression by inducing chromosomal instability.