Rho protein crosstalk: another social network?

Guilluy, Christophe; Garcı́a-Mata, Rafael; Burridge, Keith

doi:10.1016/j.tcb.2011.08.002

Cited by 285 publications

(327 citation statements)

References 97 publications

(144 reference statements)

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“…Although hyperactivation of Rac1 is an accepted pathogenetic model in podocyte disease verified by several independent studies (40,41), there is an ambiguous perception regarding the role of RhoA. Nevertheless, an emerging body of evidence supports the concept of a required balance of these GTPases to maintain cellular function (42). Therefore, our findings exemplify the interdependent and reciprocal interplay of small GTPases and demonstrate their essential role for podocyte spreading and adhesion maturation (Fig.…”

Section: Discussionsupporting

confidence: 53%

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

Schell

Rogg

Suhm

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Podocytes form the outer part of the glomerular filter, where they have to withstand enormous transcapillary filtration forces driving glomerular filtration. Detachment of podocytes from the glomerular basement membrane precedes most glomerular diseases. However, little is known about the regulation of podocyte adhesion in vivo. Thus, we systematically screened for podocyte-specific focal adhesome (FA) components, using genetic reporter models in combination with iTRAQ-based mass spectrometry. This approach led to the identification of FERM domain protein EPB41L5 as a highly enriched podocyte-specific FA component in vivo. Genetic deletion of Epb41l5 resulted in severe proteinuria, detachment of podocytes, and development of focal segmental glomerulosclerosis. Remarkably, by binding and recruiting the RhoGEF ARGHEF18 to the leading edge, EPB41L5 directly controls actomyosin contractility and subsequent maturation of focal adhesions, cell spreading, and migration. Furthermore, EPB41L5 controls matrixdependent outside-in signaling by regulating the focal adhesome composition. Thus, by linking extracellular matrix sensing and signaling, focal adhesion maturation, and actomyosin activation EPB41L5 ensures the mechanical stability required for podocytes at the kidney filtration barrier. Finally, a diminution of EPB41L5-dependent signaling programs appears to be a common theme of podocyte disease, and therefore offers unexpected interventional therapeutic strategies to prevent podocyte loss and kidney disease progression.focal adhesion | actomyosin | podocyte | FSGS

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Section: Discussionsupporting

confidence: 53%

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

Schell

Rogg

Suhm

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…It is not clear why the cell recruits two distinct GEFs to the same site in a sequential manner, given that they both activate Cdc42. Previous reports have demonstrated crosstalk between GTPases via the modulation of their regulators (Guilluy et al, 2011). While there is no report of GEFs of the same GTPase regulating each other, such an interaction may explain the temporal relationship detected between Gef1 and Scd1 localization at the division site.…”

Section: Gef1 Promotes Scd1 Recruitment To the Division Sitementioning

confidence: 84%

“…During cell migration, these GTPases form bands or 'zones' in the leading and trailing regions of the cell (Ridley, 2015). Their spatial separation is mediated by the organization of their GEFs and GAPs, as well as by regulatory signaling between these GTPases (Guilluy et al, 2011). Cdc42 and Rho are mutually antagonistic, explaining how such zones of GTPase activity can be established and maintained (Guilluy et al, 2011;Kutys and Yamada, 2014;Warner and Longmore, 2009).…”

Section: Significance Of Gef Coordination In Other Systemsmentioning

confidence: 99%

“…Their spatial separation is mediated by the organization of their GEFs and GAPs, as well as by regulatory signaling between these GTPases (Guilluy et al, 2011). Cdc42 and Rho are mutually antagonistic, explaining how such zones of GTPase activity can be established and maintained (Guilluy et al, 2011;Kutys and Yamada, 2014;Warner and Longmore, 2009). Similarly, Cdc42 can refine Rac activity (Guilluy et al, 2011).…”

Section: Significance Of Gef Coordination In Other Systemsmentioning

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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“…The different Rho GTPases might operate in a coordinated fashion to affect the actin cytoskeleton. In particular, RhoA often acts as an antagonist of Rac1 and Cdc42 (Kozma et al, 1997;Tsuji et al, 2002;Ohta et al, 2006; reviewed by Brown et al, 2006;Guilluy et al, 2011). Moreover, the small GTPases regulate the activity of effector enzymes, such as the protein kinases Rho-associated coiled-coil forming kinase (ROCK) (activated by RhoA) and p21-activated kinase (PAK) (activated by Rac and Cdc42).…”

Section: Rho Gtpases -Mechanisms Of Action and Localizationmentioning

confidence: 99%

Cell surface dynamics – how Rho GTPases orchestrate the interplay between the plasma membrane and the cortical cytoskeleton

Curtis

Meldolesi

2012

Journal of Cell Science

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SummarySmall GTPases are known to regulate hundreds of cell functions. In particular, Rho family GTPases are master regulators of the cytoskeleton. By regulating actin nucleation complexes, Rho GTPases control changes in cell shape, including the extension and/or retraction of surface protrusions and invaginations. Protrusion and invagination of the plasma membrane also involves the interaction between the plasma membrane and the cortical cytoskeleton. This interplay between membranes and the cytoskeleton can lead to an increase or decrease in the plasma membrane surface area and its tension as a result of the fusion (exocytosis) or internalization (endocytosis) of membranous compartments, respectively. For a long time, the cytoskeleton and plasma membrane dynamics were investigated separately. However, studies from many laboratories have now revealed that Rho GTPases, their modulation of the cytoskeleton, and membrane traffic are closely connected during the dynamic remodeling of the cell surface. Arf-and Rab-dependent exocytosis of specific vesicles contributes to the targeting of Rho GTPases and their regulatory factors to discrete sites of the plasma membrane. Rho GTPases regulate the tethering of exocytic vesicles and modulate their subsequent fusion. They also have crucial roles in the different forms of endocytosis, where they participate in the sorting of membrane domains as well as the sculpting and sealing of membrane flasks and cups. Here, we discuss how cell surface dynamics depend on the orchestration of the cytoskeleton and the plasma membrane by Rho GTPases.

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Rho protein crosstalk: another social network?

Cited by 285 publications

References 97 publications

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier

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

Cell surface dynamics – how Rho GTPases orchestrate the interplay between the plasma membrane and the cortical cytoskeleton

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