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Published on: November 11, 2018
B-type Plexins Regulate Mitosis via RanGTPase
Nicholus Mukhwana1, Ritu Garg1, Abul Azad1
1School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
Abstract:
Aberrant mitosis can result in aneuploidy and cancer. The small GTPase, Ras-related nuclear protein (Ran), is a key regulator of mitosis. B-type plexins regulate Ran activity by acting as RanGTPase-activating proteins 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 Plexin B1 functions in the control of mitosis. Depletion of Plexin B1 affects mitotic spindle assembly, significantly delaying anaphase. This leads to mitotic catastrophe in some cells and prolonged application of the spindle assembly checkpoint. Plexin B1 depletion also promoted acentrosomal microtubule nucleation and defects in spindle pole refocusing 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 Plexin B1 depletion. Plexin B1 localizes to the mitotic spindle in dividing cells. The mitotic defects observed upon Plexin B1 depletion were rescued by an RCC1 inhibitor, indicating that Plexin B1 signals, via Ran, to affect mitosis. These errors in mitosis generated multinucleate cells and nuclei of altered morphology and abnormal karyotype. Furthermore, semaphorin 4D 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.
Insights
Plexin B1 is crucial for proper cell division (mitosis). Its depletion causes mitotic errors, leading to chromosomal instability and potentially contributing to cancer progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Aberrant mitosis is linked to aneuploidy and cancer.
- The small GTPase, Ras-related nuclear protein (Ran), regulates mitosis.
- B-type plexins modulate Ran activity and are implicated in cancer.
Purpose of the Study:
- To investigate the role of B-type plexins, specifically Plexin B1, in mitosis.
- To determine if Plexin B1 influences mitotic spindle assembly and chromosome segregation.
Main Methods:
- Depletion of Plexin B1 using RNA interference.
- Analysis of mitotic spindle assembly, anaphase progression, and chromosome segregation.
- Localization studies of Plexin B1 in dividing cells.
- Rescue experiments using an RCC1 inhibitor.
- Assessment of multinucleation, abnormal karyotypes, and micronuclei formation.
Main Results:
- Plexin B1 depletion disrupts mitotic spindle assembly and delays anaphase.
- It causes acentrosomal microtubule nucleation, spindle pole defects, and aberrant spindles.
- Lagging chromosomes, chromosomal bridges, and prolonged spindle assembly checkpoint were observed.
- Plexin B1 functions via Ran signaling to control mitosis.
- Plexin B1 depletion leads to multinucleate cells, abnormal nuclei, and increased micronuclei.
Conclusions:
- Plexin B1 is a key regulator of mitosis.
- Defects in Plexin B1 contribute to chromosomal instability.
- These findings link B-type plexins to cancer progression through induced genomic instability.
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