Spontaneous cell polarization: Feedback control of Cdc42 GTPase breaks cellular symmetry

Martin, Sophie G.

doi:10.1002/bies.201500077

Cited by 66 publications

(74 citation statements)

References 101 publications

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“…Using these visualizations, we began by interrogating three adjacent and correlating clusters (Clusters 4, 7, and 11) contain wild-type and mutant alleles of CDC42, a gene encoding a Rho family GTPase with diverse roles in cell polarity, morphology, and migration (Melendez et al, 2011; Martin, 2015). Cluster 4 contains the constitutively active mutant CDC42 Q61L (Nobes and Hall, 1999) as well as MAP3K2 and MAP3K9.…”

Section: Resultsmentioning

confidence: 99%

Systematic morphological profiling of human gene and allele function via Cell Painting

Rohban

Singh

et al. 2017

eLife

156

152

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We hypothesized that human genes and disease-associated alleles might be systematically functionally annotated using morphological profiling of cDNA constructs, via a microscopy-based Cell Painting assay. Indeed, 50% of the 220 tested genes yielded detectable morphological profiles, which grouped into biologically meaningful gene clusters consistent with known functional annotation (e.g., the RAS-RAF-MEK-ERK cascade). We used novel subpopulation-based visualization methods to interpret the morphological changes for specific clusters. This unbiased morphologic map of gene function revealed TRAF2/c-REL negative regulation of YAP1/WWTR1-responsive pathways. We confirmed this discovery of functional connectivity between the NF-κB pathway and Hippo pathway effectors at the transcriptional level, thereby expanding knowledge of these two signaling pathways that critically regulate tumor initiation and progression. We make the images and raw data publicly available, providing an initial morphological map of major biological pathways for future study.DOI: http://dx.doi.org/10.7554/eLife.24060.001

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Section: Resultsmentioning

confidence: 99%

Systematic morphological profiling of human gene and allele function via Cell Painting

Rohban

Singh

et al. 2017

eLife

156

152

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“…In fission yeast, after treatment with the actin monomer-binding drug latrunculin A (LatA), which leads to acute depolymerization of the actin cytoskeleton, CRIB-3xGFP disperses from cell tips and forms transient ectopic patches on cell sides, as does Cdc42 itself and other components of the Cdc42 polarity module [5, 6, 10]. Because actin filaments can play a role, for example, in vectorial transport of endomembrane-associated Cdc42 or its regulators to cell tips or in endocytic recycling of Cdc42 from the plasma membrane [4, 11, 12, 13], the most straightforward interpretation of this result has been that dispersal of the Cdc42 polarity module from cell tips is a direct consequence of the loss of actin filaments [5, 6]. …”

Section: Resultsmentioning

confidence: 99%

“…In the fission yeast Schizosaccharomyces pombe , active Cdc42 and associated effectors and regulators (the “Cdc42 polarity module”) coordinate polarized growth at cell tips by controlling the actin cytoskeleton and exocytosis [2, 3, 4]. Localization of the Cdc42 polarity module to cell tips is thus critical for its function.…”

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confidence: 99%

Remodeling of the Fission Yeast Cdc42 Cell-Polarity Module via the Sty1 p38 Stress-Activated Protein Kinase Pathway

2016

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SummaryThe Rho family GTPase Cdc42 is a key regulator of eukaryotic cellular organization and cell polarity [1]. In the fission yeast Schizosaccharomyces pombe, active Cdc42 and associated effectors and regulators (the “Cdc42 polarity module”) coordinate polarized growth at cell tips by controlling the actin cytoskeleton and exocytosis [2, 3, 4]. Localization of the Cdc42 polarity module to cell tips is thus critical for its function. Here we show that the fission yeast stress-activated protein kinase Sty1, a homolog of mammalian p38 MAP kinase, regulates localization of the Cdc42 polarity module. In wild-type cells, treatment with latrunculin A, a drug that leads to actin depolymerization, induces dispersal of the Cdc42 module from cell tips and cessation of polarized growth [5, 6]. We show that latrunculin A treatment also activates the Sty1 MAP kinase pathway and, strikingly, we find that loss of Sty1 MAP kinase signaling prevents latrunculin A-induced dispersal of the Cdc42 module, allowing polarized growth even in complete absence of the actin cytoskeleton. Regulation of the Cdc42 module by Sty1 is independent of Sty1’s role in stress-induced gene expression. We also describe a system for activation of Sty1 kinase “on demand” in the absence of any external stress, and use this to show that Sty1 activation alone is sufficient to disperse the Cdc42 module from cell tips in otherwise unperturbed cells. During nitrogen-starvation-induced quiescence, inhibition of Sty1 converts non-growing, depolarized cells into growing, polarized cells. Our results place MAP kinase Sty1 as an important physiological regulator of the Cdc42 polarity module.

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“…In summary, at its core, pheromone signaling focalization relies on a positive feedback loop, similar to other symmetry-breaking systems (Motegi and Seydoux 2013;Yi et al 2013;Martin 2015) in which Fus1 promotes the delivery of the receptor and its activator, and the activated receptor promotes Fus1 function.…”

Section: How Does Focalization Of Pheromone Signaling Happen?mentioning

confidence: 92%

Spatial focalization of pheromone/MAPK signaling triggers commitment to cell–cell fusion

2016

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Cell fusion is universal in eukaryotes for fertilization and development, but what signals this process is unknown. Here, we show in Schizosaccharomyces pombe that fusion does not require a dedicated signal but is triggered by spatial focalization of the same pheromone-GPCR (G-protein-coupled receptor)-MAPK signaling cascade that drives earlier mating events. Autocrine cells expressing the receptor for their own pheromone trigger fusion attempts independently of cell-cell contact by concentrating pheromone release at the fusion focus, a dynamic actin aster underlying the secretion of cell wall hydrolases. Pheromone receptor and MAPK cascade are similarly enriched at the fusion focus, concomitant with fusion commitment in wild-type mating pairs. This focalization promotes cell fusion by immobilizing the fusion focus, thus driving local cell wall dissolution. We propose that fusion commitment is imposed by a local increase in MAPK concentration at the fusion focus, driven by a positive feedback between fusion focus formation and focalization of pheromone release and perception.

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Spontaneous cell polarization: Feedback control of Cdc42 GTPase breaks cellular symmetry

Cited by 66 publications

References 101 publications

Systematic morphological profiling of human gene and allele function via Cell Painting

Systematic morphological profiling of human gene and allele function via Cell Painting

Remodeling of the Fission Yeast Cdc42 Cell-Polarity Module via the Sty1 p38 Stress-Activated Protein Kinase Pathway

Spatial focalization of pheromone/MAPK signaling triggers commitment to cell–cell fusion

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