A Safeguard Mechanism Regulates Rho GTPases to Coordinate Cytokinesis with the Establishment of Cell Polarity

Meitinger, Franz; Richter, Heidi; Heisel, Sabrina; Hub, Birgit; Seufert, Wolfgang; Pereira, Gislene

doi:10.1371/journal.pbio.1001495

Cited by 36 publications

(63 citation statements)

References 40 publications

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“…Although haploid rga1D cells polarize preferentially at the division site [34], we found that diploid rga1D/ rga1D mutants retained a bias to polarize away from the division site. A very recent study identified a new Cdc42 antagonist present at the division site that collaborates with Rga1 to prevent budding at that site [42]. Modelling a situation with two uneven patches, competition was more effective and our simulations did evolve towards a single polarity site.…”

Section: (D) Localized Rsr1 -Gef Could Interfere With Competitionmentioning

confidence: 78%

Interaction between bud-site selection and polarity-establishment machineries in budding yeast

Savage

Lew

2013

Phil. Trans. R. Soc. B

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Saccharomyces cerevisiae yeast cells polarize in order to form a single bud in each cell cycle. Distinct patterns of bud-site selection are observed in haploid and diploid cells. Genetic approaches have identified the molecular machinery responsible for positioning the bud site: during bud formation, specific locations are marked with immobile landmark proteins. In the next cell cycle, landmarks act through the Ras-family GTPase Rsr1 to promote local activation of the conserved Rho-family GTPase, Cdc42. Additional Cdc42 accumulates by positive feedback, creating a concentrated patch of GTP-Cdc42, which polarizes the cytoskeleton to promote bud emergence. Using time-lapse imaging and mathematical modelling, we examined the process of bud-site establishment. Imaging reveals unexpected effects of the bud-site-selection system on the dynamics of polarity establishment, raising new questions about how that system may operate. We found that polarity factors sometimes accumulate at more than one site among the landmark-specified locations, and we suggest that competition between clusters of polarity factors determines the final location of the Cdc42 cluster. Modelling indicated that temporally constant landmark-localized Rsr1 would weaken or block competition, yielding more than one polarity site. Instead, we suggest that polarity factors recruit Rsr1, effectively sequestering it from other locations and thereby terminating landmark activity.

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Section: (D) Localized Rsr1 -Gef Could Interfere With Competitionmentioning

confidence: 78%

Interaction between bud-site selection and polarity-establishment machineries in budding yeast

Savage

Lew

2013

Phil. Trans. R. Soc. B

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“…This Rga1 localization is also likely to contribute to fluctuation of the Cdc42 cluster during T1 because the displacement of the Cdc42-GTP cluster is diminished in rga1Δ cells. Interestingly, Aim44/Gps1, which also prevents re-budding at the previous bud site, localizes to the division site as a disk (rather than a ring) (Meitinger et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Regulation of Cdc42 polarization by the Rsr1 GTPase and Rga1, a Cdc42 GTPase-activating protein, in budding yeast

Lee

Miller

et al. 2015

Journal of Cell Science

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Cdc42 plays a central role in establishing polarity in yeast and animals, yet how polarization of Cdc42 is achieved in response to spatial cues is poorly understood. Using live-cell imaging, we found distinct dynamics of Cdc42 polarization in haploid budding yeast in correlation with two temporal steps of the G1 phase. The position at which the Cdc42-GTP cluster develops changes rapidly around the division site during the first step but becomes stabilized in the second step, suggesting that an axis of polarized growth is determined in mid G1. Cdc42 polarization in the first step and its proper positioning depend on Rsr1 and its GTPase-activating protein (GAP) Bud2. Interestingly, Rga1, a Cdc42 GAP, exhibits transient localization to a site near the bud neck and to the division site during cytokinesis and G1, and this temporal change of Rga1 distribution is necessary for determination of a proper growth site. Mathematical modeling suggests that a proper axis of Cdc42 polarization in haploid cells might be established through a biphasic mechanism involving sequential positive feedback and transient negative feedback.

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“…The site of bud emergence (bud neck) will later be used in cytokinesis to separate the daughter from mother cell ( Figure 1A) (Park and Bi, 2007;Wloka and Bi, 2012). The remnants of the cytokinetic machinery (bud scar or cytokinesis remnant [CRM]) are retained in the mother cell and can be visualized by transmission electron microscopy (TEM) or by specific dyes ( Figure 1B) (Meitinger et al, 2013). CRMs mainly consist of extracellular matrix, which is encircled by a chitin-rich ring (Cabib et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…Different GTPase-activating proteins (GAPs) contribute to the inhibition of Cdc42 at the cell-division site (Atkins et al, 2013;Tong et al, 2007). In addition, the scaffold protein Gps1 inhibits Cdc42 at the site of cytokinesis as part of a pathway working in parallel to the Cdc42 GAP Rga1 (Meitinger et al, 2013). However, neither Cdc42 GAPs nor Gps1 accumulate at old CRMs.…”

Section: Introductionmentioning

confidence: 99%

A Memory System of Negative Polarity Cues Prevents Replicative Aging

Meitinger

Khmelinskii

Morlot

et al. 2014

Cell

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Cdc42 is a highly conserved master regulator of cell polarity. Here, we investigated the mechanism by which yeast cells never re-establish polarity at cortical sites (cytokinesis remnants [CRMs]) that have previously supported Cdc42-mediated growth as a paradigm to mechanistically understand how Cdc42-inhibitory polarity cues are established. We revealed a two-step mechanism of loading the Cdc42 antagonist Nba1 into CRMs to mark these compartments as refractory for a second round of Cdc42 activation. Our data indicate that Nba1 together with a cortically tethered adaptor protein confers memory of previous polarization events to translate this spatial legacy into a biochemical signal that ensures the local singularity of Cdc42 activation. "Memory loss" mutants that repeatedly use the same polarity site over multiple generations display nuclear segregation defects and a shorter lifespan. Our work thus established CRMs as negative polarity cues that prevent Cdc42 reactivation to sustain the fitness of replicating cells.

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A Safeguard Mechanism Regulates Rho GTPases to Coordinate Cytokinesis with the Establishment of Cell Polarity

Abstract: Gps1 provides a novel molecular polarity cue at the cell division site that guides Rho1- and Cdc42-dependent polarization during and after cytokinesis in budding yeast.

Cited by 36 publications

References 40 publications

Interaction between bud-site selection and polarity-establishment machineries in budding yeast

Interaction between bud-site selection and polarity-establishment machineries in budding yeast

Regulation of Cdc42 polarization by the Rsr1 GTPase and Rga1, a Cdc42 GTPase-activating protein, in budding yeast

A Memory System of Negative Polarity Cues Prevents Replicative Aging

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