ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2020
Protein kinase A inhibitor proteins (PKIs) divert GPCR-Gαs-cAMP signaling toward EPAC and ERK activation and are involved in tumor growth.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 51 citations in OpenAlex.
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- The diverse functions of viral microproteins.bioRxiv : the preprint server for biology · 2026Article
- Deacetylforskolin ameliorates bleomycin-induced pulmonary fibrosis by suppressing inflammation and TGF-β1-induced epithelial-mesenchymal transition.Natural products and bioprospecting · 2026Article
- In-depth analysis of obesity-associated changes in adipose tissue-derived mesenchymal stromal/stem cells and primary cilia function.Communications biology · 2025Article
- Protein kinase A is a dependent factor and therapeutic target in mouse models of fibrous dysplasia.Nature communications · 2025Article
- Targeting chaperone modifications: Innovative approaches to cancer treatment.The Journal of biological chemistry · 2024Review
- Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated GMolecular pharmacology · 2024Review
- Modulation of the Oncogenic LINE-1 Regulatory Network in Non-Small Cell Lung Cancer by Exosomal miRNAs.International journal of molecular sciences · 2024Article
- Light-gated integrator for highlighting kinase activity in living cells.Nature communications · 2024Article
- Increased transcriptional elongation and RNA stability of GPCR ligand binding genes unveiled via RNA polymerase II degradation.Nucleic acids research · 2024Article
- The Effect of the cAMP Signaling Pathway on HTR8/SV-Neo Cell Line Proliferation, Invasion, and Migration After Treatment with Forskolin.Reproductive sciences (Thousand Oaks, Calif.) · 2024Article
- PKIB, a Novel Target for Cancer Therapy.International journal of molecular sciences · 2024Review
- Dronedarone Attenuates Ang II-Induced Myocardial Hypertrophy Through Regulating SIRT1/FOXO3/PKIA Axis.Korean circulation journal · 2024Article
- Light-gated Integrator for Highlighting Kinase Activity in Living Cells.bioRxiv : the preprint server for biology · 2024Article
- Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors.Pharmaceuticals (Basel, Switzerland) · 2024Review
- cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.Journal of hematology & oncology · 2024Review
- Revisiting the roles of cAMP signalling in the progression of prostate cancer.The Biochemical journal · 2023Article
- Exploring the methylation status of CFTR and PKIA genes as potential biomarkers for lung adenocarcinoma.Orphanet journal of rare diseases · 2023Article
- Human adenylyl cyclase 9 is auto-stimulated by its isoform-specific C-terminal domain.Life science alliance · 2023Article
- Edmond Fischer's kinase legacy: History of the protein kinase inhibitor and protein kinase A.IUBMB life · 2023Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The PKA-inhibitor (PKI) family members PKIα, PKIβ, and PKIγ bind with high affinity to PKA and block its kinase activity, modulating the extent, and duration of PKA-mediated signaling events. While PKA is a well-known regulator of physiological and oncogenic events, the role of PKI proteins in these pathways has remained elusive. Here, by measuring activation of the MAPK pathway downstream of GPCR-Gαs-cAMP signaling, we show that the expression levels of PKI proteins can alter the balance of activation of two major cAMP targets: PKA and EPAC. Our results indicate that PKA maintains repressive control over MAPK signaling as well as a negative feedback on cAMP concentration. Overexpression of PKI and its subsequent repression of PKA dysregulates these signaling pathways, resulting in increased intracellular cAMP, and enhanced activation of EPAC and MAPK. We also find that amplifications of PKIA are common in prostate cancer and are associated with reduced progression free survival. Depletion of PKIA in prostate cancer cells leads to reduced migration, increased sensitivity to anoikis and reduced tumor growth. By altering PKA activity PKI can act as a molecular switch, driving GPCR-Gαs-cAMP signaling toward activation of EPAC-RAP1 and MAPK, ultimately modulating tumor growth.
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Registered trials
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