Journal article
G\textgreekas-Protein Kinase A (PKA) Pathway Signalopathies: The Emerging Genetic Landscape and Therapeutic Potential of Human Diseases Driven by Aberrant G\textgreekas-PKA Signaling
Publication Details
Authors: | Ramms, D.; Raimondi, F.; Arang, N.; Herberg, F.; Taylor, S.; Gutkind, J. |
Publication year: | 2021 |
Journal: | Pharmacological Reviews |
Pages range : | 155-197 |
Volume number: | 73 |
Issue number: | 4 |
ISSN: | 0031-6997 |
eISSN: | 1521-0081 |
DOI-Link der Erstveröffentlichung: |
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 G\textgreekas-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 G\textgreekas-PKA pathway signalopathies. The G\textgreekas-PKA pathway signalopathies encompass diseases caused by germline, postzygotic, and somatic mutations in the G\textgreekas-PKA pathway, with largely endocrine and neoplastic phenotypes. Here, we present a signaling-centric review of G\textgreekas-PKA-driven pathophysiology and integrate computational and structural analysis to identify mutational themes commonly exploited by the G\textgreekas-PKA pathway signalopathies. Major mutational themes include hotspot activating mutations in G\textgreekas, 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 G\textgreekas-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 G\textgreekas-PKA pathway-driven disease.
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 G\textgreekas-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 G\textgreekas-PKA pathway signalopathies. The G\textgreekas-PKA pathway signalopathies encompass diseases caused by germline, postzygotic, and somatic mutations in the G\textgreekas-PKA pathway, with largely endocrine and neoplastic phenotypes. Here, we present a signaling-centric review of G\textgreekas-PKA-driven pathophysiology and integrate computational and structural analysis to identify mutational themes commonly exploited by the G\textgreekas-PKA pathway signalopathies. Major mutational themes include hotspot activating mutations in G\textgreekas, 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 G\textgreekas-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 G\textgreekas-PKA pathway-driven disease.
