Rho GTPases as regulators of mitosis and cytokinesis in mammalian cells

Chircop, Megan

doi:10.4161/sgtp.29770

Cited by 109 publications

(105 citation statements)

References 162 publications

(247 reference statements)

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“…While the major targets of these Rho-GTPases are the actomyosin and microtubule cytoskeletons (thus their importance for cytokinesis) by doing so they mediate a diverse variety of cellular processes that include not only cell cycle progression, but also cell movement, cell signaling, and cell polarity (reviewed in: Chircop, 2014;Citi et al, 2014;Mack and Georgiou, 2014). Accordingly, deregulation of Rho GTPases are linked to a number of neurodegenerative disorders (reviewed in: Stankiewicz and Linseman, 2014).…”

Section: Racgap1 and Cellular Developmentmentioning

confidence: 98%

Progressive loss of RacGAP1/ ogre activity has sequential effects on cytokinesis and zebrafish development

Warga

Wicklund

Webster

et al. 2016

Developmental Biology

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RacGAP1 is one of the two components of the centralspindlin complex essential for orchestrating cytokinesis in all animal cells. We report here that the early arrest mutant ogre is a maternal and zygotic loss of function mutation in the zebrafish homolog of racgap1. Like the other model organisms in which racgap1 is mutated, cells in the mutant stop dividing. In vivo cell recordings reveal that gradual loss of wild-type RacGAP1 leads progressively from a failure of abscission, then to cleavage furrow ingression, and finally complete absence of furrow formation. Despite the lack of cytokinesis, gross patterning occurs overtly normally in ogre mutants and cells continue to cycle slowly, some even attaining four or eight nuclei. Many multinucleate cells differentiate and survive, but the majority of cells enter apoptosis that we demonstrate is due to cumulative rounds of defective cytokinesis. Investigation of the cells that differentiate in the mutant indicate that RacGAP1 is also needed for long-term survival of motoneurons and the cytoskeletal organization of sensory axons. We conclude that while RacGAP1 function is crucial for cytokinesis and its activity at different levels controls different aspects of cytokinesis, these defects have occluded other critical roles of this interesting protein.

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Section: Racgap1 and Cellular Developmentmentioning

confidence: 98%

Progressive loss of RacGAP1/ ogre activity has sequential effects on cytokinesis and zebrafish development

Warga

Wicklund

Webster

et al. 2016

Developmental Biology

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“…Mitotic progression involves dynamic modulation of cell shape primarily through remodeling of the actin and microtubule cytoskeletons. Megan Chircop 19 reviews the molecular mechanisms regulating the spatial and temporal activation of RhoA and Cdc42 during mitosis, and how this is critical to control cell division progression.…”

Section: Cellular Signaling Network and Rho Gtpases: Major Crossroadsmentioning

confidence: 99%

Rho GTPases at the crossroad of signaling networks in mammals

Hervé

Bourmeyster

2015

Small GTPases

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“…8,9 Much is known on the molecular machinery responsible for the execution of the 'core' cytokinesis program, with particular regard to the crucial role of Rho small GTPase and of the molecules that locally modulate and/or mediate its activity at the cleavage furrow and at the midbody. [10][11][12] Much less is known on the molecules that may regulate cell type-specific aspects of cytokinesis. Citron kinase (CIT-K), a conserved ser/thr protein kinase that binds to active RhoA, 13,14 is localized at the cleavage furrow and at the midbody of dividing cells.…”

mentioning

confidence: 99%

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

et al. 2015

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Cytokinesis, the physical separation of daughter cells at the end of cell cycle, is commonly considered a highly stereotyped phenomenon. However, in some specialized cells this process may involve specific molecular events that are still largely unknown. In mammals, loss of Citron-kinase (CIT-K) leads to massive cytokinesis failure and apoptosis only in neuronal progenitors and in male germ cells, resulting in severe microcephaly and testicular hypoplasia, but the reasons for this specificity are unknown. In this report we show that CIT-K modulates the stability of midbody microtubules and that the expression of tubulin β-III (TUBB3) is crucial for this phenotype. We observed that TUBB3 is expressed in proliferating CNS progenitors, with a pattern correlating with the susceptibility to CIT-K loss. More importantly, depletion of TUBB3 in CIT-K-dependent cells makes them resistant to CIT-K loss, whereas TUBB3 overexpression increases their sensitivity to CIT-K knockdown. The loss of CIT-K leads to a strong decrease in the phosphorylation of S444 on TUBB3, a post-translational modification associated with microtubule stabilization. CIT-K may promote this event by interacting with TUBB3 and by recruiting at the midbody casein kinase-2α (CK2α) that has previously been reported to phosphorylate the S444 residue. Indeed, CK2α is lost from the midbody in CIT-K-depleted cells. Moreover, expression of the nonphosphorylatable TUBB3 mutant S444A induces cytokinesis failure, whereas expression of the phospho-mimetic mutant S444D rescues the cytokinesis failure induced by both CIT-K and CK2α loss. Altogether, our findings reveal that expression of relatively low levels of TUBB3 in mitotic cells can be detrimental for their cytokinesis and underscore the importance of CIT-K in counteracting this event.

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Rho GTPases as regulators of mitosis and cytokinesis in mammalian cells

Cited by 109 publications

References 162 publications

Progressive loss of RacGAP1/ ogre activity has sequential effects on cytokinesis and zebrafish development

Progressive loss of RacGAP1/ ogre activity has sequential effects on cytokinesis and zebrafish development

Rho GTPases at the crossroad of signaling networks in mammals

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

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