Identification and Functional Characterization of Protein Kinase A Phosphorylation Sites in the Major Lipolytic Protein, Adipose Triglyceride Lipase

Pagnon, Joanne; Matzaris, Maria; Stark, Romana; Meex, Ruth C. R.; Macaulay, S. Lance; Brown, Wendy A.; O'Brien, Paul Edmond; Tiganis, Tony; Watt, Matthew J.

doi:10.1210/en.2012-1127

Cited by 130 publications

(107 citation statements)

References 49 publications

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“…Given that PKA acts upstream from ATGL-1 and LID-1 in fasting-induced lipolysis, we asked the question whether PKA might directly phosphorylate ATGL-1 and/or LID-1. Recently, it has been demonstrated that mammalian ATGL is phosphorylated by PKA at multiple sites (55). In vitro kinase assays revealed that PKA phosphorylated C. elegans ATGL-1 but not LID-1 (data not shown).…”

Section: Atgl-1 As Shown Inmentioning

confidence: 90%

Lipid Droplet Protein LID-1 Mediates ATGL-1-Dependent Lipolysis during Fasting in Caenorhabditis elegans

Lee

Kong

Jang

et al. 2014

Molecular and Cellular Biology

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Lipolysis is a delicate process involving complex signaling cascades and sequential enzymatic activations. In Caenorhabditis elegans, fasting induces various physiological changes, including a dramatic decrease in lipid contents through lipolysis. Interestingly, C. elegans lacks perilipin family genes which play a crucial role in the regulation of lipid homeostasis in other species. Here, we demonstrate that in the intestinal cells of C. elegans, a newly identified protein, lipid droplet protein 1 (C25A1.12; LID-1), modulates lipolysis by binding to adipose triglyceride lipase 1 (C05D11.7; ATGL-1) during nutritional deprivation. In fasted worms, lipid droplets were decreased in intestinal cells, whereas suppression of ATGL-1 via RNA interference (RNAi) resulted in retention of stored lipid droplets. Overexpression of ATGL-1 markedly decreased lipid droplets, whereas depletion of LID-1 via RNAi prevented the effect of overexpressed ATGL-1 on lipolysis. In adult worms, short-term fasting increased cyclic AMP (cAMP) levels, which activated protein kinase A (PKA) to stimulate lipolysis via ATGL-1 and LID-1. Moreover, ATGL-1 protein stability and LID-1 binding were augmented by PKA activation, eventually leading to increased lipolysis. These data suggest the importance of the concerted action of lipase and lipid droplet protein in the response to fasting signals via PKA to maintain lipid homeostasis.

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Section: Atgl-1 As Shown Inmentioning

confidence: 90%

Lipid Droplet Protein LID-1 Mediates ATGL-1-Dependent Lipolysis during Fasting in Caenorhabditis elegans

Lee

Kong

Jang

et al. 2014

Molecular and Cellular Biology

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“…3C). PKA promotes lipolysis by phosphorylating several proteins including lipid droplet-associated protein perilipin A (Miyoshi et al 2007), hormone-sensitive lipase (HSL) (Krintel et al 2008), and adipose triglyceride lipase (ATGL) (Pagnon et al 2012). In normal fed condition, insulin promotes lipogenesis and suppresses lipolysis partially through inhibition of cAMP/PKA signaling by activation of PDE3B in adipocyte (Eriksson et al 1995, Kitamura et al 1999.…”

Section: Camp/pka In Adipose Tissuesmentioning

confidence: 99%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

151

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In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMPdependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

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“…For instance, major components of lipolytic pathways, including hormone-sensitive lipase (Hsl) 2 and perilipin 1 (Plin1), are direct targets of PKA (10,11). Recently, adipose triglyceride lipase (Atgl) was also reported to be a target of PKA (12,13). Upon receiving activation signals from molecules such as catecholamine and glucagon, activated PKA phosphorylates Plin1 and HSL to promote the recruitment of HSL to lipid droplets (14,15).…”

mentioning

confidence: 99%

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

Lee

Han

Kong

et al. 2016

Journal of Biological Chemistry

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Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent protein kinase composed of catalytic and regulatory subunits and involved in various physiological phenomena, including lipid metabolism. Here we demonstrated that the stoichiometric balance between catalytic and regulatory subunits is crucial for maintaining basal PKA activity and lipid homeostasis. To uncover the potential roles of each PKA subunit, Caenorhabditis elegans was used to investigate the effects of PKA subunit deficiency. In worms, suppression of PKA via RNAi resulted in severe phenotypes, including shortened life span, decreased egg laying, reduced locomotion, and altered lipid distribution. Similarly, in mammalian adipocytes, suppression of PKA regulatory subunits RI␣ and RII␤ via siRNAs potently stimulated PKA activity, leading to potentiated lipolysis without increasing cAMP levels. Nevertheless, insulin exerted anti-lipolytic effects and restored lipid droplet integrity by antagonizing PKA action. Together, these data implicate the importance of subunit stoichiometry as another regulatory mechanism of PKA activity and lipid metabolism.Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent serine/threonine kinase that mediates various cellular responses, including lipolysis. Since its discovery in the 1950s (1-4), the cAMP-PKA system has become one of the best understood signaling pathways in terms of biochemical properties. PKA is composed of catalytic subunits and cAMP-binding regulatory subunits (5). In the absence of cAMP stimulation, PKA forms an inactive tetramer composed of four subunits with two regulatory and two catalytic subunits. Upon nutritional deprivation or hormonal stimulation, activated adenylyl cyclase produces cAMP from ATP. Then, the regulatory subunit of PKA binds cAMP, causing a conformational change that decreases its affinity for catalytic subunits by ϳ10 4 -fold and leads to the release of active catalytic subunits to phosphorylate target proteins (6, 7).PKA has a wide range of substrates that regulate a number of physiological processes. To date, several hundred PKA target proteins have been identified, and yet new PKA substrates are continually being reported (8, 9). In mammalian adipocytes, numerous studies over the last 40 years have revealed that the cAMP-PKA axis forms a critical node in the regulation of lipolysis. For instance, major components of lipolytic pathways, including hormone-sensitive lipase (Hsl) 2 and perilipin 1 (Plin1), are direct targets of PKA (10, 11). Recently, adipose triglyceride lipase (Atgl) was also reported to be a target of PKA (12, 13). Upon receiving activation signals from molecules such as catecholamine and glucagon, activated PKA phosphorylates Plin1 and HSL to promote the recruitment of HSL to lipid droplets (14, 15). In addition, phosphorylated Plin1 releases comparative gene identification-58 (CGI-58; Abhd5), a coactivator of Atgl, to mediate lipolysis upon PKA activation (16 -20). On the contrary, insulin can activate phosphodiesterase 3B (Pde3b) and reduce cAMP levels (1...

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Identification and Functional Characterization of Protein Kinase A Phosphorylation Sites in the Major Lipolytic Protein, Adipose Triglyceride Lipase

Cited by 130 publications

References 49 publications

Lipid Droplet Protein LID-1 Mediates ATGL-1-Dependent Lipolysis during Fasting in Caenorhabditis elegans

Lipid Droplet Protein LID-1 Mediates ATGL-1-Dependent Lipolysis during Fasting in Caenorhabditis elegans

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

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