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Review ArticleReview Article

Gαs–Protein Kinase A (PKA) Pathway Signalopathies: The Emerging Genetic Landscape and Therapeutic Potential of Human Diseases Driven by Aberrant Gαs-PKA Signaling

Dana J. Ramms, Francesco Raimondi, Nadia Arang, Friedrich W. Herberg, Susan S. Taylor and J. Silvio Gutkind
Gunnar Schulte, ASSOCIATE EDITOR
Pharmacological Reviews October 2021, 73 (4) 1326-1368; DOI: https://doi.org/10.1124/pharmrev.120.000269
Dana J. Ramms
Department of Pharmacology (D.J.R., N.A., J.S.G.), Department of Chemistry and Biochemistry (S.S.T.), and Moores Cancer Center (D.J.R., N.A., J.S.G.), University of California, San Diego, La Jolla, California; Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy (F.R.); and Department of Biochemistry, University of Kassel, Kassel, Germany (F.W.H.)
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Francesco Raimondi
Department of Pharmacology (D.J.R., N.A., J.S.G.), Department of Chemistry and Biochemistry (S.S.T.), and Moores Cancer Center (D.J.R., N.A., J.S.G.), University of California, San Diego, La Jolla, California; Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy (F.R.); and Department of Biochemistry, University of Kassel, Kassel, Germany (F.W.H.)
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Nadia Arang
Department of Pharmacology (D.J.R., N.A., J.S.G.), Department of Chemistry and Biochemistry (S.S.T.), and Moores Cancer Center (D.J.R., N.A., J.S.G.), University of California, San Diego, La Jolla, California; Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy (F.R.); and Department of Biochemistry, University of Kassel, Kassel, Germany (F.W.H.)
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Friedrich W. Herberg
Department of Pharmacology (D.J.R., N.A., J.S.G.), Department of Chemistry and Biochemistry (S.S.T.), and Moores Cancer Center (D.J.R., N.A., J.S.G.), University of California, San Diego, La Jolla, California; Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy (F.R.); and Department of Biochemistry, University of Kassel, Kassel, Germany (F.W.H.)
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Susan S. Taylor
Department of Pharmacology (D.J.R., N.A., J.S.G.), Department of Chemistry and Biochemistry (S.S.T.), and Moores Cancer Center (D.J.R., N.A., J.S.G.), University of California, San Diego, La Jolla, California; Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy (F.R.); and Department of Biochemistry, University of Kassel, Kassel, Germany (F.W.H.)
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J. Silvio Gutkind
Department of Pharmacology (D.J.R., N.A., J.S.G.), Department of Chemistry and Biochemistry (S.S.T.), and Moores Cancer Center (D.J.R., N.A., J.S.G.), University of California, San Diego, La Jolla, California; Laboratorio di Biologia Bio@SNS, Scuola Normale Superiore, Pisa, Italy (F.R.); and Department of Biochemistry, University of Kassel, Kassel, Germany (F.W.H.)
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Gunnar Schulte
Roles: ASSOCIATE EDITOR
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Abstract

Many of the fundamental concepts of signal transduction and kinase activity are attributed to the discovery and crystallization of cAMP-dependent protein kinase, or protein kinase A. PKA is one of the best-studied kinases in human biology, with emphasis in biochemistry and biophysics, all the way to metabolism, hormone action, and gene expression regulation. It is surprising, however, that our understanding of PKA’s role in disease is largely underappreciated. Although genetic mutations in the PKA holoenzyme are known to cause diseases such as Carney complex, Cushing syndrome, and acrodysostosis, the story largely stops there. With the recent explosion of genomic medicine, we can finally appreciate the broader role of the Gαs-PKA pathway in disease, with contributions from aberrant functioning G proteins and G protein–coupled receptors, as well as multiple alterations in other pathway components and negative regulators. Together, these represent a broad family of diseases we term the Gαs-PKA pathway signalopathies. The Gαs-PKA pathway signalopathies encompass diseases caused by germline, postzygotic, and somatic mutations in the Gαs-PKA pathway, with largely endocrine and neoplastic phenotypes. Here, we present a signaling-centric review of Gαs-PKA–driven pathophysiology and integrate computational and structural analysis to identify mutational themes commonly exploited by the Gαs-PKA pathway signalopathies. Major mutational themes include hotspot activating mutations in Gαs, encoded by GNAS, and mutations that destabilize the PKA holoenzyme. With this review, we hope to incite further study and ultimately the development of new therapeutic strategies in the treatment of a wide range of human diseases.

Significance Statement Little recognition is given to the causative role of Gαs-PKA pathway dysregulation in disease, with effects ranging from infectious disease, endocrine syndromes, and many cancers, yet these disparate diseases can all be understood by common genetic themes and biochemical signaling connections. By highlighting these common pathogenic mechanisms and bridging multiple disciplines, important progress can be made toward therapeutic advances in treating Gαs-PKA pathway–driven disease.

Footnotes

  • D.J.R. and this work were supported by the National Institutes of Health National Institute of General Medical Sciences Cellular and Molecular Pharmacology Training Grant [T32-GM007752], the National Science Foundation Graduate Research Fellowship Program, and the National Cancer Institute Cancer Systems Biology Consortium [U54-CA209891]. F.R. was supported by the Italian Ministry of University and Research through the Department of excellence “Faculty of Sciences” of Scuola Normale Superiore. The research leading to these results also received funding from the Italian Association for Cancer Research (AIRC) under My First AIRC Grant (MFAG) 2020 - ID. 24317 project – P.I. Raimondi Francesco. F.W.H. was supported by the Federal Ministry of Education and Research (BMBF) [16GW0270 TargetRD] and the Kassel graduate school “clocks.”

  • https://doi.org/10.1124/pharmrev.120.000269.

  • ↵Embedded ImageThis article has supplemental material available at pharmrev.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 73 (4)
Pharmacological Reviews
Vol. 73, Issue 4
1 Oct 2021
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Review ArticleReview Article

Gαs-PKA Pathway Signalopathies: Linking Genetics to Therapy

Dana J. Ramms, Francesco Raimondi, Nadia Arang, Friedrich W. Herberg, Susan S. Taylor and J. Silvio Gutkind
Pharmacological Reviews October 1, 2021, 73 (4) 1326-1368; DOI: https://doi.org/10.1124/pharmrev.120.000269

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Review ArticleReview Article

Gαs-PKA Pathway Signalopathies: Linking Genetics to Therapy

Dana J. Ramms, Francesco Raimondi, Nadia Arang, Friedrich W. Herberg, Susan S. Taylor and J. Silvio Gutkind
Pharmacological Reviews October 1, 2021, 73 (4) 1326-1368; DOI: https://doi.org/10.1124/pharmrev.120.000269
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    • I. Introduction
    • II. Gαs–Protein Kinase A Pathway Basics
    • III. Mutational Landscape of the Gαs–Protein Kinase A Pathway Signalopathies
    • IV. Human Gαs–Protein Kinase A Pathway Signalopathies
    • V. Targeting the Gαs–Protein Kinase A Pathway Signalopathies
    • VI. Conclusion
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