Systems-level analysis of a G protein mediated signaling pathway

Abstract In the filamentous fungus Aspergillus nidulans, a heterotrimeric G protein α-subunit and an RGS domain protein, encoded by fadA and flbA, respectively, regulate production of the carcinogenic metabolite sterigmatocystin (ST) and asexual spores (i.e., conidia). We investigated the genetic involvement of the cAMP-dependent protein kinase catalytic subunit (PkaA), a potential downstream target of FadA activity, in ST production and conidiation. Relative to wild type, sporulation was decreased in the pkaA overexpression strain but was not totally absent, as occurs in ΔflbA or fadAG42R (fadA-dominant active) strains. Deletion of pkaA resulted in a hyper-conidiating strain with limited radial growth. This phenotype was epistatic to mutation in flbA or fadA; the double mutants ΔpkaA; ΔflbA and ΔpkaA; fadAG42R recovered sporulation and their radial growth was severely restricted. PkaA overexpression also negatively regulated AflR, the ST biosynthesis-specific transcription factor, both transcriptionally and post-transcriptionally. Deletion of pkaA restored ST production in the ΔflbA background but not in the fadAG42R background. These data provide genetic evidence that the FlbA/FadA signaling pathway regulating ST production and morphological development is partially mediated through PkaA.

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Mot3, a Zn Finger Transcription Factor That Modulates Gene Expression and Attenuates Mating Pheromone Signaling in Saccharomyces cerevisiae

Genetics ◽

10.1093/genetics/149.2.879 ◽

1998 ◽

Vol 149 (2) ◽

pp. 879-892 ◽

Cited By ~ 1

Author(s):

Anatoly V Grishin ◽

Michael Rothenberg ◽

Maureen A Downs ◽

Kendall J Blumer

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Signaling Pathway ◽

G Protein ◽

Binding Sites ◽

Dependent Manner ◽

Pheromone Response ◽

Mating Pheromone ◽

Pheromone Signaling ◽

Yeast Genes

Abstract In the yeast Saccharomyces cerevisiae, mating pheromone response is initiated by activation of a G protein- and mitogen-activated protein (MAP) kinase-dependent signaling pathway and attenuated by several mechanisms that promote adaptation or desensitization. To identify genes whose products negatively regulate pheromone signaling, we screened for mutations that suppress the hyperadaptive phenotype of wild-type cells overexpressing signaling-defective G protein β subunits. This identified recessive mutations in MOT3, which encodes a nuclear protein with two Cys2-His2 Zn fingers. MOT3 was found to be a dosage-dependent inhibitor of pheromone response and pheromone-induced gene expression and to require an intact signaling pathway to exert its effects. Several results suggested that Mot3 attenuates expression of pheromone-responsive genes by mechanisms distinct from those used by the negative transcriptional regulators Cdc36, Cdc39, and Mot2. First, a Mot3-lexA fusion functions as a transcriptional activator. Second, Mot3 is a dose-dependent activator of several genes unrelated to pheromone response, including CYC1, SUC2, and LEU2. Third, insertion of consensus Mot3 binding sites (C/A/T)AGG(T/C)A activates a promoter in a MOT3-dependent manner. These findings, and the fact that consensus binding sites are found in the 5′ flanking regions of many yeast genes, suggest that Mot3 is a globally acting transcriptional regulator. We hypothesize that Mot3 regulates expression of factors that attenuate signaling by the pheromone response pathway.

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Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple Stimuli

Eukaryotic Cell ◽

10.1128/ec.05179-11 ◽

2011 ◽

Vol 10 (10) ◽

pp. 1306-1316 ◽

Cited By ~ 67

Author(s):

Laura H. Okagaki ◽

Yina Wang ◽

Elizabeth R. Ballou ◽

Teresa R. O'Meara ◽

Yong-Sun Bahn ◽

...

Keyword(s):

Signaling Pathway ◽

G Protein ◽

Pathogenic Fungus ◽

Cell Formation ◽

Cell Phenotype ◽

Protein Signaling ◽

Human Pathogens ◽

Morphological Form ◽

Content Type ◽

Oxidative Stresses

ABSTRACT The titan cell is a recently described morphological form of the pathogenic fungus Cryptococcus neoformans . Occurring during the earliest stages of lung infection, titan cells are 5 to 10 times larger than the normal yeast-like cells, thereby resisting engulfment by lung phagocytes and favoring the persistence of infection. These enlarged cells exhibit an altered capsule structure, a thickened cell wall, increased ploidy, and resistance to nitrosative and oxidative stresses. We demonstrate that two G-protein-coupled receptors are important for induction of the titan cell phenotype: the Ste3 a pheromone receptor (in mating type a cells) and the Gpr5 protein. Both receptors control titan cell formation through elements of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. This conserved signaling pathway, in turn, mediates its effect on titan cells through the PKA-regulated Rim101 transcription factor. Additional downstream effectors required for titan cell formation include the G 1 cyclin Pcl103, the Rho104 GTPase, and two GTPase-activating proteins, Gap1 and Cnc1560. These observations support developing models in which the PKA signaling pathway coordinately regulates many virulence-associated phenotypes in diverse human pathogens.

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Baicalein suppresses 17-β-estradiol-induced migration, adhesion and invasion of breast cancer cells via the G protein-coupled receptor 30 signaling pathway

Oncology Reports ◽

10.3892/or.2015.3786 ◽

2015 ◽

Vol 33 (4) ◽

pp. 2077-2085 ◽

Cited By ~ 34

Author(s):

DANDAN SHANG ◽

ZHENG LI ◽

ZHUXIA ZHU ◽

HUAMEI CHEN ◽

LUJUN ZHAO ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

G Protein ◽

Breast Cancer Cells ◽

G Protein Coupled Receptor ◽

G Protein Coupled ◽

Adhesion And Invasion

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The G-Protein-Coupled Bile Acid Receptor Gpbar1 (TGR5) Inhibits Gastric Inflammation Through Antagonizing NF-κB Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2015.00287 ◽

2015 ◽

Vol 6 ◽

Cited By ~ 41

Author(s):

Cong Guo ◽

Hui Qi ◽

Yingjie Yu ◽

Qiqi Zhang ◽

Jia Su ◽

...

Keyword(s):

Bile Acid ◽

Signaling Pathway ◽

G Protein ◽

Acid Receptor ◽

Bile Acid Receptor ◽

G Protein Coupled

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IL-17 Activates the Canonical NF-κB Signaling Pathway in Autoimmune B Cells of BXD2 Mice To Upregulate the Expression of Regulators of G-Protein Signaling 16

The Journal of Immunology ◽

10.4049/jimmunol.0903133 ◽

2010 ◽

Vol 184 (5) ◽

pp. 2289-2296 ◽

Cited By ~ 60

Author(s):

Shutao Xie ◽

Jun Li ◽

John H. Wang ◽

Qi Wu ◽

PingAr Yang ◽

...

Keyword(s):

B Cells ◽

Signaling Pathway ◽

G Protein ◽

G Protein Signaling ◽

Protein Signaling

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Role of the G-Protein-Coupled Receptor Signaling Pathway in Insecticide Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms20174300 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4300 ◽

Cited By ~ 2

Author(s):

Ting Li ◽

Nannan Liu

Keyword(s):

Insecticide Resistance ◽

Cell Line ◽

Signaling Pathway ◽

G Protein ◽

Cell Lines ◽

Sf9 Cells ◽

Camp Production ◽

G Protein Coupled Receptor ◽

G Protein Coupled

The G-protein-coupled receptor (GPCR) regulated intracellular signaling pathway is known to be involved in the development of insecticide resistance in the mosquito, Culex quinquefasciatus. To elucidate the specific role of each effector in the GPCR regulating pathway, we initially expressed a GPCR, G-protein alpha subunit (Gαs), adenylate cyclase (AC), and protein kinase A (PKA) in insect Spodoptera frugiperda (Sf9) cells and investigated their regulation function on cyclic AMP (cAMP) production and PKA activity. GPCR, Gαs, and AC individually expressed Sf9 cells showed higher cAMP production as the expression of each effector increased. All the effector-expressed cell lines showed increased PKA activity however. Moreover, Sf9 cytochrome P450 gene expression and cell tolerance to permethrin were examined. The relative expression of CYP9A32gene in Sf9 cells tested was significantly increased in all effector-expressed cell lines compared to a control cell line; these effector-expressed cell lines also showed significantly higher tolerance to permethrin. Inhibitor treatments on each effector-expressed cell line revealed that Bupivacaine HCl and H89 2HCl robustly inhibited cAMP production and PKA activity, respectively, resulting in decreased tolerance to permethrin in all cell lines. The synergistic functions of Bupivacaine HCl and H89 2HCl with permethrin were further examined in Culex mosquito larvae, providing a valuable new information for mosquito control strategies.

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Heterotrimeric G-Protein Signalers and RGSs in Aspergillus fumigatus

Pathogens ◽

10.3390/pathogens9110902 ◽

2020 ◽

Vol 9 (11) ◽

pp. 902

Author(s):

Hee-Soo Park ◽

Min-Ju Kim ◽

Jae-Hyuk Yu ◽

Kwang-Soo Shin

Keyword(s):

Aspergillus Fumigatus ◽

Signaling Pathways ◽

Signaling Pathway ◽

G Protein ◽

G Proteins ◽

Pathogenic Fungus ◽

G Protein Signaling ◽

Protein Signaling ◽

Heterotrimeric G Protein ◽

External Signals

The heterotrimeric G-protein (G-protein) signaling pathway is one of the most important signaling pathways that transmit external signals into the inside of the cell, triggering appropriate biological responses. The external signals are sensed by various G-protein-coupled receptors (GPCRs) and transmitted into G-proteins consisting of the α, β, and γ subunits. Regulators of G-protein signaling (RGSs) are the key controllers of G-protein signaling pathways. GPCRs, G-proteins, and RGSs are the primary upstream components of the G-protein signaling pathway, and they are highly conserved in most filamentous fungi, playing diverse roles in biological processes. Recent studies characterized the G-protein signaling components in the opportunistic pathogenic fungus Aspergillus fumigatus. In this review, we have summarized the characteristics and functions of GPCRs, G-proteins, and RGSs, and their regulatory roles in governing fungal growth, asexual development, germination, stress tolerance, and virulence in A. fumigatus.

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