scholarly journals Protein kinase A inhibitor proteins (PKIs) divert GPCR‐Gαs‐cAMP signaling toward EPAC and ERK activation and are involved in tumor growth

2020 ◽  
Vol 34 (10) ◽  
pp. 13900-13917 ◽  
Author(s):  
James J. Hoy ◽  
Natalia Salinas Parra ◽  
Jeannie Park ◽  
Skyler Kuhn ◽  
Ramiro Iglesias‐Bartolome
Keyword(s):  
Protein Kinase ◽  
Tumor Growth ◽  
Protein Kinase A ◽  
Camp Signaling ◽  
Erk Activation ◽  
Kinase A

scholarly journals Analysis of the Protein Kinase A-Regulated Proteome ofCryptococcus neoformansIdentifies a Role for the Ubiquitin-Proteasome Pathway in Capsule Formation

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
J. M. H. Geddes ◽  
M. Caza ◽  
D. Croll ◽  
N. Stoynov ◽  
L. J. Foster ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Camp Signaling ◽  
Ubiquitin Proteasome Pathway ◽  
Capsule Production ◽  
Life Threatening ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Kinase A

ABSTRACTThe opportunistic fungal pathogenCryptococcus neoformanscauses life-threatening meningitis in immunocompromised individuals. The expression of virulence factors, including capsule and melanin, is in part regulated by the cyclic-AMP/protein kinase A (cAMP/PKA) signal transduction pathway. In this study, we investigated the influence of PKA on the composition of the intracellular proteome to obtain a comprehensive understanding of the regulation that underpins virulence. Through quantitative proteomics, enrichment and bioinformatic analyses, and an interactome study, we uncovered a pattern of PKA regulation for proteins associated with translation, the proteasome, metabolism, amino acid biosynthesis, and virulence-related functions. PKA regulation of the ubiquitin-proteasome pathway inC. neoformansshowed a striking parallel with connections between PKA and protein degradation in chronic neurodegenerative disorders and other human diseases. Further investigation of proteasome function with the inhibitor bortezomib revealed an impact on capsule production as well as hypersusceptibility for strains with altered expression or activity of PKA. Parallel studies with tunicamycin also linked endoplasmic reticulum stress with capsule production and PKA. Taken together, the data suggest a model whereby expression of PKA regulatory and catalytic subunits and the activation of PKA influence proteostasis and the function of the endoplasmic reticulum to control the elaboration of the polysaccharide capsule. Overall, this study revealed both broad and conserved influences of the cAMP/PKA pathway on the proteome and identified proteostasis as a potential therapeutic target for the treatment of cryptococcosis.IMPORTANCEFungi cause life-threatening diseases, but very few drugs are available to effectively treat fungal infections. The pathogenic fungusCryptococcus neoformanscauses a substantial global burden of life-threatening meningitis in patients suffering from HIV/AIDS. An understanding of the mechanisms by which fungi deploy virulence factors to cause disease is critical for developing new therapeutic approaches. We employed a quantitative proteomic approach to define the changes in the protein complement that occur upon modulating the cAMP signaling pathway that regulates virulence inC. neoformans. This approach identified a conserved role for cAMP signaling in the regulation of the ubiquitin-proteasome pathway and revealed a link between this pathway and elaboration of a major virulence determinant, the polysaccharide capsule. Targeting the ubiquitin-proteasome pathway opens new therapeutic options for the treatment of cryptococcosis.

Abstract 954: COX-2 inhibition reduces bone tumor growth in animal models:A role for celecoxib treatment in cAMP/protein kinase A-induced tumors

2012 ◽  
Author(s):  
Emmanouil Saloustros ◽  
Edward Mertz ◽  
Maria Nesterova ◽  
Meg Keil ◽  
Anelia Horvath ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tumor Growth ◽  
Protein Kinase A ◽  
Bone Tumor ◽  
Induced Tumors ◽  
Cox 2 ◽  
Kinase A

scholarly journals The cAMP Signaling Pathway and Direct Protein Kinase A Phosphorylation Regulate Polycystin-2 (TRPP2) Channel Function

2015 ◽  
Vol 290 (39) ◽  
pp. 23888-23896 ◽  
Author(s):  
María del Rocío Cantero ◽  
Irina F. Velázquez ◽  
Andrew J. Streets ◽  
Albert C. M. Ong ◽  
Horacio F. Cantiello
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Signaling Pathway ◽  
Camp Signaling ◽  
Channel Function ◽  
Camp Signaling Pathway ◽  
Kinase A

scholarly journals The G Protein-coupled Receptor Gpr1 and the Gα Protein Gpa2 Act through the cAMP-Protein Kinase A Pathway to Induce Morphogenesis inCandida albicans

2005 ◽  
Vol 16 (4) ◽  
pp. 1971-1986 ◽  
Author(s):  
Mykola M. Maidan ◽  
Larissa De Rop ◽  
Joke Serneels ◽  
Simone Exler ◽  
Steffen Rupp ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
G Protein ◽  
Mitogen Activated Protein Kinase ◽  
Camp Signaling ◽  
G Protein Coupled Receptor ◽  
Gene Encoding ◽  
Pka Pathway ◽  
G Protein Coupled ◽  
Kinase A

We investigated the role in cell morphogenesis and pathogenicity of the Candida albicans GPR1 gene, encoding the G protein-coupled receptor Gpr1. Deletion of C. albicans GPR1 has only minor effects in liquid hypha-inducing media but results in strong defects in the yeast-to-hypha transition on solid hypha-inducing media. Addition of cAMP, expression of a constitutively active allele of the Gα protein Gpa2 or of the catalytic protein kinase A subunit TPK1 restores the wild-type phenotype of the CaGPR1-deleted strain. Overexpression of HST7, encoding a component of the mitogen-activated protein kinase pathway, does not suppress the defect in filamentation. These results indicate that CaGpr1 functions upstream in the cAMP–protein kinase A (PKA) pathway. We also show that, in the presence of glucose, CaGpr1 is important for amino acid-induced transition from yeast to hyphal cells. Finally, as opposed to previous reports, we show that CaGpa2 acts downstream of CaGpr1 as activator of the cAMP–PKA pathway but that deletion of neither CaGpr1 nor CaGpa2 affects glucose-induced cAMP signaling. In contrast, the latter is abolished in strains lacking CaCdc25 or CaRas1, suggesting that the CaCdc25-CaRas1 rather than the CaGpr1-CaGpa2 module mediates glucose-induced cAMP signaling in C. albicans.

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