scholarly journals Local and global Cdc42 GEFs for fission yeast cell polarity are coordinated by microtubules and the Tea1/Tea4/Pom1 axis

2017 ◽  
Author(s):  
Ye Dee Tay ◽  
Marcin Leda ◽  
Andrew B. Goryachev ◽  
Kenneth E. Sawin
Keyword(s):  
Fission Yeast ◽  
Cell Polarity ◽  
Eukaryotic Cell ◽  
Guanine Nucleotide Exchange Factors ◽  
Polarized Growth ◽  
Nucleotide Exchange ◽  
Gtpase Activating Protein ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Rho Family

ABSTRACTThe conserved Rho-family GTPase Cdc42 plays a central role in eukaryotic cell polarity. The rod-shaped fission yeast Schizosaccharomyces pombe has two Cdc42 guanine-nucleotide exchange factors (GEFs), Scd1 and Gef1, but little is known about how they are coordinated in polarized growth. Although the microtubule cytoskeleton is normally not required for polarity maintenance in fission yeast, here we show that when scdl function is compromised, disruption of microtubules or the polarity landmark proteins Tea1, Tea4, or Pom1 leads to isotropic rather than polarized growth. Surprisingly, this isotropic growth is due to spatially inappropriate activity of Gef1, which is a cytosolic protein rather than a membrane-associated protein at cell tips like Scd1. Microtubules and the Tea1/Tea4/Pom1 axis counteract inappropriate Gef1 activity by regulating the localization of the Cdc42 GTPase-activating protein Rga4. Our results thus demonstrate coordination of “local” (Scd1) and “global” (Gef1) Cdc42 GEFs via microtubules and microtubule-dependent polarity landmarks.

scholarly journals The Multiple Functions of Rho GTPases in Fission Yeasts

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1422
Author(s):  
Jero Vicente-Soler ◽  
Teresa Soto ◽  
Alejandro Franco ◽  
José Cansado ◽  
Marisa Madrid
Keyword(s):  
Fission Yeast ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Model Organism ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Physiological Processes ◽  
Evolutionary Changes ◽  
Rho Family

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another fission yeast species, Schizosaccharomyces japonicus, has come into focus offering insight into evolutionary changes within the genus. Both fission yeasts contain only six Rho-type GTPases that are spatiotemporally controlled by multiple guanine–nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and whose intricate regulation in response to external cues is starting to be uncovered. In the present review, we will outline and discuss the current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes such as morphogenesis and polarity, cellular integrity, cytokinesis and cellular differentiation.

scholarly journals Essential Role of Vav Family Guanine Nucleotide Exchange Factors in EphA Receptor-Mediated Angiogenesis

2006 ◽  
Vol 26 (13) ◽  
pp. 4830-4842 ◽  
Author(s):  
Sonja G. Hunter ◽  
Guanglei Zhuang ◽  
Dana Brantley-Sieders ◽  
Wojciech Swat ◽  
Christopher W. Cowan ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Rac1 Gtpase ◽  
Rho Family ◽  
Epha Receptor

ABSTRACT Angiogenesis, the process by which new blood vessels are formed from preexisting vasculature, is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Prior studies from our laboratory demonstrate that the EphA2 receptor tyrosine kinase is a key regulator of angiogenesis in vivo. The EphA receptor-mediated angiogenic response is dependent on activation of Rho family GTPase Rac1 and is regulated by phosphatidylinositol 3-kinase. Here we report the identification of Vav2 and Vav3 as guanine nucleotide exchange factors (GEFs) that link the EphA2 receptor to Rho family GTPase activation and angiogenesis. Ephrin-A1 stimulation recruits the binding of Vav proteins to the activated EphA2 receptor. The induced association of EphA receptor and Vav proteins modulates the activity of Vav GEFs, leading to activation of Rac1 GTPase. Overexpression of either Vav2 or Vav3 in primary microvascular endothelial cells promotes Rac1 activation, cell migration, and assembly in response to ephrin-A1 stimulation. Conversely, loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo. In addition, embryonic fibroblasts derived from Vav2−/− Vav3−/− mice fail to spread on an ephrin-A1-coated surface and exhibit a significant decrease in the formation of ephrin-A1-induced lamellipodia and filopodia. These findings suggest that Vav GEFs serve as a molecular link between EphA2 receptors and the actin cytoskeleton and provide an important mechanism for EphA2-mediated angiogenesis.

scholarly journals Stress-dependent inhibition of cell polarity through unbalancing the GEF/GAP regulation of Cdc42

2021 ◽  
Author(s):  
Clàudia Salat-Canela ◽  
Mercè Carmona ◽  
Rebeca Martín-García ◽  
Pilar Pérez ◽  
José Ayté ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Gtp Hydrolysis ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Dependent Inhibition ◽  
Stress Dependent

Cdc42 rules cell polarity and growth in fission yeast. It is negatively and positively regulated by GTPase-activating proteins (GAPs) and by Guanine-nucleotide Exchange factors (GEFs), respectively. Active Cdc42-GTP localizes to the poles, where it associates with numerous proteins constituting the polarity module. However, little is known about its down-regulation. We describe here that oxidative stress causes Sty1 kinase-dependent Cdc42 inactivation at cell poles. Both the amount of active Cdc42 at poles and cell length inversely correlate with Sty1 activity, explaining the elongated morphology of Δsty1 cells. We have created stress-blinded cell poles by either eliminating two Cdc42 GAPs or through the constitutive tethering of a GEF to the cell tips, and biochemically demonstrate that Rga3 is a direct substrate of Sty1. We propose that stress-activated Sty1 promotes GTP hydrolysis and prevents GEF activity at the cell tips, thus leading to the inhibition of Cdc42 and polarized growth cessation.

scholarly journals Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration

2016 ◽  
Author(s):  
Assaf Zaritsky ◽  
Yun-Yu Tseng ◽  
M. Angeles Rabadan ◽  
Shefali Krishna ◽  
Michael Overholtzer ◽  
...  
Keyword(s):  
Intercellular Communication ◽  
Guanine Nucleotide Exchange Factors ◽  
Collective Cell Migration ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Collective Migration ◽  
Knock Down ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Rho Family

AbstractEfficient collective migration depends on a balance between contractility and cytoskeletal rearrangements, adhesion, and mechanical cell-cell communication, all controlled by GTPases of the RHO family. By comprehensive screening of guanine nucleotide exchange factors (GEFs) in human bronchial epithelial cell monolayers, we identified GEFs that are required for collective migration at large, such as SOS1 and β-PIX, and RHOA GEFs that are implicated in intercellular communication. Downregulation of the latter GEFs differentially enhanced front-to-back propagation of guidance cues through the monolayer, and was mirrored by downregulation of RHOA expression and myosin-II activity. Phenotype-based clustering of knock-down behaviors identified RHOA-ARHGEF18 and ARHGEF3-ARHGEF28-ARHGEF11 clusters, indicating that the latter may signal through other RHO-family GTPases. Indeed, knock-down of RHOC produced an intermediate between the two phenotypes. We conclude that for effective collective migration the RHOA-GEFs-→ARHOA/C→ actomyosin pathways must be optimally tuned to compromise between generation of motility forces and restriction of intercellular communication.

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