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G protein subunit phosphorylation as a regulatory mechanism in heterotrimeric G protein signaling in mammals, yeast, and plants.

ABSTRACT: Heterotrimeric G proteins composed of G?, G?, and G? subunits are vital eukaryotic signaling elements that convey information from ligand-regulated G protein-coupled receptors (GPCRs) to cellular effectors. Heterotrimeric G protein-based signaling pathways are fundamental to human health [Biochimica et Biophysica Acta (2007) 1768, 994-1005] and are the target of >30% of pharmaceuticals in clinical use [Biotechnology Advances (2013) 31, 1676-1694; Nature Reviews Drug Discovery (2017) 16, 829-842]. This review focuses on phosphorylation of G protein subunits as a regulatory mechanism in mammals, budding yeast, and plants. This is a re-emerging field, as evidence for phosphoregulation of mammalian G protein subunits from biochemical studies in the early 1990s can now be complemented with contemporary phosphoproteomics and genetic approaches applied to a diversity of model systems. In addition, new evidence implicates a family of plant kinases, the receptor-like kinases, which are monophyletic with the interleukin-1 receptor-associated kinase/Pelle kinases of metazoans, as possible GPCRs that signal via subunit phosphorylation. We describe early and modern observations on G protein subunit phosphorylation and its functional consequences in these three classes of organisms, and suggest future research directions.

SUBMITTER: Chakravorty D

PROVIDER: S-EPMC6347956 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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G protein subunit phosphorylation as a regulatory mechanism in heterotrimeric G protein signaling in mammals, yeast, and plants.

Chakravorty David D Assmann Sarah M SM

The Biochemical journal 20181109 21

Heterotrimeric G proteins composed of Gα, Gβ, and Gγ subunits are vital eukaryotic signaling elements that convey information from ligand-regulated G protein-coupled receptors (GPCRs) to cellular effectors. Heterotrimeric G protein-based signaling pathways are fundamental to human health [Biochimica et Biophysica Acta (2007) 1768, 994-1005] and are the target of >30% of pharmaceuticals in clinical use [Biotechnology Advances (2013) 31, 1676-1694; Nature Reviews Dru ...[more]

PMID: 30413679

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Project description:Serine/threonine protein phosphatase 1 regulatory subunit 12A (PPP1R12A) modulates the activity and specificity of the catalytic subunit of protein phosphatase 1, regulating various cellular processes via dephosphorylation. Nonetheless, little is known about phosphorylation events controlled by PPP1R12A in skeletal muscle insulin signaling. Here, we used quantitative phosphoproteomics to generate a global picture of phosphorylation events regulated by PPP1R12A in a L6 skeletal muscle cell line, which were engineered for inducible PPP1R12A knockdown. Phosphoproteomics revealed 3876 phosphorylation sites (620 were novel) in these cells. Furthermore, PPP1R12A knockdown resulted in increased overall phosphorylation in L6 cells at the basal condition, and changed phosphorylation levels for 698 sites (assigned to 295 phosphoproteins) at the basal and/or insulin-stimulated conditions. Pathway analysis on the 295 phosphoproteins revealed multiple significantly enriched pathways related to insulin signaling, such as mTOR signaling and RhoA signaling. Moreover, phosphorylation levels for numerous regulatory sites in these pathways were significantly changed due to PPP1R12A knockdown. These results indicate that PPP1R12A indeed plays a role in skeletal muscle insulin signaling, providing novel insights into the biology of insulin action. This new information may facilitate the design of experiments to better understand mechanisms underlying skeletal muscle insulin resistance and type 2 diabetes.Biological significanceThese results identify a large number of potential new substrates of serine/threonine protein phosphatase 1 and suggest that serine/threonine protein phosphatase 1 regulatory subunit 12A indeed plays a regulatory role in multiple pathways related to insulin action, providing novel insights into the biology of skeletal muscle insulin signaling. This information may facilitate the design of experiments to better understand the molecular mechanism responsible for skeletal muscle insulin resistance and associated diseases, such as type 2 diabetes and cardiovascular diseases.

Dataset Information

G protein subunit phosphorylation as a regulatory mechanism in heterotrimeric G protein signaling in mammals, yeast, and plants.

Publications

G protein subunit phosphorylation as a regulatory mechanism in heterotrimeric G protein signaling in mammals, yeast, and plants.

Similar Datasets

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