Phosphorylation-dependent inhibition of Cdc42 GEF Gef1 by 14-3-3 protein Rad24 spatially regulates Cdc42 GTPase activity and oscillatory dynamics during cell morphogenesis

Das, Maitreyi; Nuñez, Illyce; Rodriguez, Marbelys; Wiley, David J.; Rodríguez, Juan Prieto; Sarkeshik, Ali; Yates, John R.; Buchwald, Péter; Verde, Fulvia

doi:10.1091/mbc.e15-02-0095

Cited by 43 publications

(116 citation statements)

References 85 publications

(132 reference statements)

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“…Interaction with a 14-3-3 protein sequesters Gef1 to the cytoplasm and away from the cortex. The gef1S112A mutation eliminates the Orb6 phosphorylation site, thus enabling excessive Gef1S112A localization to both cell ends, where it activates Cdc42 to promote premature bipolar growth (Das et al, 2015). Consistent with these findings, we report that Scd1 is significantly more bipolar in gef1S112A mutants.…”

Section: Gef1 Establishes Polarized Growth At a Nascent Sitesupporting

confidence: 86%

“…http://dx.doi.org/10.1101/364786 doi: bioRxiv preprint first posted online Taken together, our findings suggest that Gef1 helps promote bipolar growth by enabling Scd1 localization to the new end. This is further supported by our previous observation that the hyperactive gef1 mutant allele gef1S112A shows premature bipolar growth (Das et al, 2015). Gef1 sparsely localizes to cell ends and instead remains mainly cytoplasmic.…”

Section: Gef1 Establishes Polarized Growth At a Nascent Sitesupporting

confidence: 84%

“…However, previous reports have shown that while gef1Δ mutants are mainly monopolar, about 40% of interphase cells show bipolar growth ( Figure 5B) (Coll et al, 2003;Das et al, 2012;Das et al, 2015). If Gef1 is required for Scd1 localization to the new end, how does bipolar growth occur in some gef1Δ cells?…”

Section: Gef1 Establishes Polarized Growth At a Nascent Sitementioning

confidence: 87%

“…Gef1 sparsely localizes to cell ends and instead remains mainly cytoplasmic. Gef1 is phosphorylated by the NDR kinase Orb6 (Das et al, 2009), resulting in a 14-3-3 binding site (Das et al, 2015). Interaction with a 14-3-3 protein sequesters Gef1 to the cytoplasm and away from the cortex.…”

Section: Gef1 Establishes Polarized Growth At a Nascent Sitementioning

confidence: 99%

“…Furthermore, Cdc42 activity is reduced at the new end in gef1 mutants (Das et al, 2012). Gef1 shows sparse localization at the cortex, making it difficult to determine whether it oscillates between cell ends (Das et al, 2015). Understanding how two different Cdc42 GEFs yield distinct phenotypes will provide valuable insights into Cdc42 regulation.…”

Section: Introductionmentioning

confidence: 99%

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A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis

Hercyk

Rich

Das

2018

Preprint

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Cdc42, a conserved regulator of cell polarity, is activated by two GEFs, Gef1 and Scd1, in fission yeast. While gef1 and scd1 mutants exhibit distinct phenotypes, how they do so is unclear given that they activate the same GTPase. Using the GEF localization pattern during cytokinesis as a paradigm, we report a novel interplay between Gef1 and Scd1 that spatially modulates Cdc42. We find that Gef1 promotes Scd1 localization to the division site during cytokinesis and to the new end during polarized growth through the recruitment of the scaffold Scd2 via a Cdc42 feedforward pathway. Gef1-mediated Scd1 recruitment at the new end enables the transition from monopolar to bipolar growth. Reciprocally, Scd1 restricts Gef1 localization to prevent ectopic Cdc42 activation during cytokinesis to promote cell separation and during interphase to maintain cell shape. Our findings reveal an elegant regulatory pattern in which Gef1 establishes new sites of Scd1-mediated Cdc42 activity, while Scd1 restricts Gef1 to functional sites. We propose that crosstalk between GEFs is a conserved mechanism that orchestrates Cdc42 activation during complex cellular processes.Summary StatementCdc42 GEFs Gef1 and Scd1 crosstalk to fine-tune Cdc42 activity. This crosstalk promotes bipolar growth and maintains cell shape in fission yeast.

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Section: Gef1 Establishes Polarized Growth At a Nascent Sitesupporting

confidence: 86%

Section: Gef1 Establishes Polarized Growth At a Nascent Sitesupporting

confidence: 84%

Section: Gef1 Establishes Polarized Growth At a Nascent Sitementioning

confidence: 87%

Section: Gef1 Establishes Polarized Growth At a Nascent Sitementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis

Hercyk

Rich

Das

2018

Preprint

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Functional interaction between Cdc42 and the stress MAPK signaling pathway during the regulation of fission yeast polarized growth

et al. 2019

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Cell polarization can be defined as the generation and maintenance of directional cellular organization. The spatial distribution and protein or lipid composition of the cell are not symmetric but organized in specialized domains which allow cells to grow and acquire a certain shape that is closely linked to their physiological function. The establishment and maintenance of polarized growth requires the coordination of diverse processes including cytoskeletal dynamics, membrane trafficking, and signaling cascade regulation. Some of the major players involved in the selection and maintenance of sites for polarized growth are Rho GTPases, which recognize the polarization site and transmit the signal to regulatory proteins of the cytoskeleton. Additionally, cytoskeletal organization, polarized secretion, and endocytosis are controlled by signaling pathways including those mediated by mitogen-activated protein kinases (MAPKs). Rho GTPases and the MAPK signaling pathways are strongly conserved from yeast to mammals, suggesting that the basic mechanisms of polarized growth have been maintained throughout evolution. For this reason, the study of how polarized growth is established and regulated in simple organisms such as the fission yeast Schizosaccharomyces pombe has contributed to broaden our knowledge about these processes in multicellular organisms. We review here the function of the Cdc42 GTPase and the stress activated MAPK (SAPK) signaling pathways during fission yeast polarized growth, and discuss the relevance of the crosstalk between both pathways.

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Integrin-Dependent Regulation of Small GTPases: Role in Cell Migration

Pawar

Balasubramanian

2017

J Indian Inst Sci

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Phosphorylation-dependent inhibition of Cdc42 GEF Gef1 by 14-3-3 protein Rad24 spatially regulates Cdc42 GTPase activity and oscillatory dynamics during cell morphogenesis

Cited by 43 publications

References 85 publications

A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis

A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis

Functional interaction between Cdc42 and the stress MAPK signaling pathway during the regulation of fission yeast polarized growth

Integrin-Dependent Regulation of Small GTPases: Role in Cell Migration

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