The nuts and bolts of AGC protein kinases
01 Jan 2010-Nature Reviews Molecular Cell Biology (Nature Publishing Group)-Vol. 11, Iss: 1, pp 9-22
TL;DR: The AGC kinase subfamily of protein kinases contains 60 members, including PKA, PKG and PKC, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes.
Abstract: The AGC kinase subfamily of protein kinases contains 60 members, including PKA, PKG and PKC. The family comprises some intensely examined protein kinases (such as Akt, S6K, RSK, MSK, PDK1 and GRK) as well as many less well-studied enzymes (such as SGK, NDR, LATS, CRIK, SGK494, PRKX, PRKY and MAST). Research has shed new light onto the architecture and regulatory mechanisms of these kinases. In addition, AGC kinases mediate diverse and important cellular functions, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes.
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Journal Article•
TL;DR: In this article, S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation, but on a high fat diet, levels of glucose and free fatty acids still rise in S6k1-dependent mice, resulting in insulin receptor desensitization.
Abstract: Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K Ay and ob/ob (also known as Lep/Lep) micetwo genetic models of obesityhave markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.
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TL;DR: In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease, which are essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications.
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1,039 citations
Cites background from "The nuts and bolts of AGC protein k..."
...…and glucocorticoid-induced protein kinase (SGK), as well as several isoforms of protein kinase C (PKC), particularly the atypical PKCs. AGC kinase family members share similar structure and mechanisms of activation via phosphorylation of two serine and threonine residues (Pearce et al. 2010)....
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...AGC kinase family members share similar structure and mechanisms of activation via phosphorylation of two serine and threonine residues (Pearce et al. 2010)....
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References
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TL;DR: The protein kinase complement of the human genome is catalogued using public and proprietary genomic, complementary DNA, and expressed sequence tag sequences to provide a starting point for comprehensive analysis of protein phosphorylation in normal and disease states and a detailed view of the current state of human genome analysis through a focus on one large gene family.
Abstract: We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
7,486 citations
"The nuts and bolts of AGC protein k..." refers background in this paper
...It is now appreciated that the AGC family contains 60 of the 518 human protein kinase...
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TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.
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"The nuts and bolts of AGC protein k..." refers background in this paper
...Akt promotes tumorigenesis by phosphorylating substrates involved in apoptosis (for example, BCL-2 antagonist of cell death (BAD)) and the cell cycle (for example, p27 cyclin-dependent kinase inhibitor (p27 KIP )), and by phosphorylating FOXO, which prevents the transcription of genes that promote apoptosis and cell cycle arrest (for example, BCL-2-interacting mediator of cell death (BIM; also known as BCL-2L11) and CD95 ligand (also known as FASL)...
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TL;DR: In this paper, the rictor-mTOR complex was used to identify compounds which modulate Akt activity mediated by the Rictor mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activation.
Abstract: In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.
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TL;DR: It is described that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis.
3,647 citations
"The nuts and bolts of AGC protein k..." refers background in this paper
...A rise in cellular AMP levels causes activation of the AMP-activated protein kinase (AMPK), which suppresses mTORC1 activity by phosphorylating TSC2 and RAPTO...
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TL;DR: AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor, uncovering a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.
3,328 citations
"The nuts and bolts of AGC protein k..." refers background in this paper
...A rise in cellular AMP levels causes activation of the AMP-activated protein kinase (AMPK), which suppresses mTORC1 activity by phosphorylating TSC2 and RAPTO...
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