Publications by authors named "J Silvio Gutkind"

493 Publications

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

Pharmacol Rev 2021 Oct;73(4):155-197

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 [email protected], Scuola Normale Superiore, Pisa, Italy (F.R.); and Department of Biochemistry, University of Kassel, Kassel, Germany (F.W.H.)

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 Gs-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 Gs-PKA pathway signalopathies. The Gs-PKA pathway signalopathies encompass diseases caused by germline, postzygotic, and somatic mutations in the Gs-PKA pathway, with largely endocrine and neoplastic phenotypes. Here, we present a signaling-centric review of Gs-PKA-driven pathophysiology and integrate computational and structural analysis to identify mutational themes commonly exploited by the Gs-PKA pathway signalopathies. Major mutational themes include hotspot activating mutations in Gαs, encoded by 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 Gs-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 Gs-PKA pathway-driven disease.
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http://dx.doi.org/10.1124/pharmrev.120.000269DOI Listing
October 2021

Calcium signaling induces a partial EMT.

EMBO Rep 2021 09 29;22(9):e51872. Epub 2021 Jul 29.

Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial-mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial-mesenchymal states in carcinoma cells.
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http://dx.doi.org/10.15252/embr.202051872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419705PMC
September 2021
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