Protein Kinase C (PKC) β Modulates Serine Phosphorylation of Insulin Receptor Substrate‐1 (IRS‐1)—Effect of Overexpression of PKCβ on Insulin Signal Transduction

Ishizuka, Tatsuo; Kajita, Kazuo; Natsume, Yoshiyuki; Kawai, Yasunori; Kanoh, Yoshinori; Miura, Asako; Ishizawa, Masayoshi; Uno, Yoshihiro; Morita, Hiroyuki

doi:10.1081/erc-120039580

Cited by 22 publications

(19 citation statements)

References 30 publications

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“…PKC ␤ is one isoform that has been most directly linked to important aspects of hyperglycemia in in vivo and in vitro. PKC ␤ was also one of the earliest isoforms recognized in insulin signaling and appears to play dual roles in insulin signaling pathways (17)(18)(19)(20)(21)(22). PKC ␤ does not appear to regulate glucose-induced insulin secretion in vivo ( 23 ), even though it has been reported to undergo translocation to the plasma membrane subsequent to stimulation by glucose in primary islet cells ( 24 ).…”

Section: Western Blot Studiesmentioning

confidence: 99%

Protein kinase Cβ deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling

Huang

Bansode

Bal

et al. 2012

Journal of Lipid Research

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Section: Western Blot Studiesmentioning

confidence: 99%

Protein kinase Cβ deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling

Huang

Bansode

Bal

et al. 2012

Journal of Lipid Research

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“…Tyrosine phosphorylation of IRS could be hampered by phosphorylation of adjacent serine residues of IRS mediated by inflammatory kinase such as c-JNK or protein kinase C (16,17). Such kinases are activated through the activation of purinergic receptors by extracellular ATP (14,15).…”

Section: Decreased Tyrosine Phosphorylation Of Hepatic Irs-2 In Cd39/mentioning

confidence: 99%

“…Protein kinase C can be also activated by these pathways (15). These kinases phosphorylate serine residues of insulin receptor substrate (IRS)-1/2, resulting in impaired insulin signaling by precluding tyrosine phosphorylation required to recruit phosphoinositide 3-kinase (16,17). CD39/ENTPD1 is an ectoenzyme that hydrolyzes extracellular nucleotides and is predominantly expressed in vascular endothelial cells and immune cells.…”

Section: Conclusion-cd39/entpd1mentioning

confidence: 99%

Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance

et al. 2008

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OBJECTIVE-Extracellular nucleotides are important mediators of inflammatory responses and could also impact metabolic homeostasis. Type 2 purinergic (P2) receptors bind extracellular nucleotides and are expressed by major peripheral tissues responsible for glucose homeostasis. CD39/ENTPD1 is the dominant vascular and immune cell ectoenzyme that hydrolyzes extracellular nucleotides to regulate purinergic signaling. RESEARCH DESIGN AND METHODS-We have studiedCd39/Entpd1-null mice to determine whether any associated changes in extracellular nucleotide concentrations influence glucose homeostasis.RESULTS-Cd39/Entpd1-null mice have impaired glucose tolerance and decreased insulin sensitivity with significantly higher plasma insulin levels. Hyperinsulinemic-euglycemic clamp studies indicate altered hepatic glucose metabolism. These effects are mimicked in vivo by injection into wild-type mice of either exogenous ATP or an ecto-ATPase inhibitor, ARL-67156, and by exposure of hepatocytes to extracellular nucleotides in vitro. Increased serum interleukin-1␤, interleukin-6, interferon-␥, and tumor necrosis factor-␣ levels are observed in Cd39/Entpd1-null mice in keeping with a proinflammatory phenotype. Impaired insulin sensitivity is accompanied by increased activation of hepatic c-Jun NH 2 -terminal kinase/ stress-activated protein kinase in Cd39/Entpd1 mice after injection of ATP in vivo. This results in decreased tyrosine phosphorylation of insulin receptor substrate-2 with impeded insulin signaling. CONCLUSIONS-CD39/Entpd1is a modulator of extracellular nucleotide signaling and also influences metabolism. Deletion of Cd39/Entpd1 both directly and indirectly impacts insulin regulation and hepatic glucose metabolism. Extracellular nucleotides serve as "metabolokines," indicating further links between inflammation and associated metabolic derangements. Diabetes 57:2311-2320, 2008 P urinergic signaling elements comprise a ubiquitous sensing network within the extracellular environment. In this system, extracellular nucleotides, such as ATP, ADP, and UTP, and extracellular nucleosides, such as adenosine, trigger differential cellular responses (1,2). Purinergic signaling pathways require extracellular nucleotide release mechanisms, purinergic receptors for these mediators (type 2 purinergic [P2] receptors), and regulated expression of ectonucleotidases that hydrolyze extracellular nucleotides to generate adenosine (3-5). Extracellular nucleotides are provided by the secretion/release of intracellular substrates, and levels are increased in hypoxia, injury, mechanical stress, and inflammation.Several reports suggest roles for extracellular nucleotides and nucleosides in glucose homeostasis (e.g., stimulation of insulin secretion from islets [6 -8], modulation of glucose uptake [9,10]). P2 receptors are expressed by insulin-sensitive tissues and also by immune cells. Extracellular nucleotides activate inflammatory pathways, inducing expression of proinflammatory cytokines including interleukin-1 (11), interferon-␥ (12), and...

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“…For instance, PKC␤ is activated by insulin and acts upstream of PI 3-kinase and mitogen-activated protein kinase (18). In contrast, activation of PKC␤ results in increased serine/ * This work was supported, in whole or in part, by National Institutes of Health threonine phosphorylation of insulin receptor substrate-1 (19), and its excessive phosphorylation has been proposed to be one of the mechanisms whereby dietary lipids and tumor necrosis factor induce insulin resistance (20,21).…”

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confidence: 99%

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Huang¹,

Bansode

Rowland

et al. 2011

Journal of Biological Chemistry

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The protein kinase C (PKC) family of Ca 2؉ and/or lipid-activated serine-threonine protein kinases is implicated in the pathogenesis of obesity and insulin resistance. We recently reported that protein kinase C␤ (PKC␤), a calcium-, diacylglycerol-, and phospholipid-dependent kinase, is critical for maintaining whole body triglyceride homeostasis. We now report that PKC␤ deficiency has profound effects on murine hepatic cholesterol metabolism, including hypersensitivity to diet-induced gallstone formation. The incidence of gallstones increased from 9% in control mice to 95% in PKC␤ ؊/؊ mice. Gallstone formation in the mutant mice was accompanied by hyposecretion of bile acids with no alteration in fecal bile acid excretion, increased biliary cholesterol saturation and hydrophobicity indices, as well as hepatic p42/44 MAPK activation, all of which enhance susceptibility to gallstone formation. Lithogenic diet-fed PKC␤ ؊/؊ mice also displayed decreased expression of hepatic cholesterol-7␣-hydroxylase (CYP7A1) and sterol 12␣-hydroxylase (CYP8b1). Finally, feeding a modified lithogenic diet supplemented with milk fat, instead of cocoa butter, both increased the severity of and shortened the interval for gallstone formation in PKC␤ ؊/؊ mice and was associated with dramatic increases in cholesterol saturation and hydrophobicity indices. Taken together, the findings reveal a hitherto unrecognized role of PKC␤ in fine tuning diet-induced cholesterol and bile acid homeostasis, thus identifying PKC␤ as a major physiological regulator of both triglyceride and cholesterol homeostasis.

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Protein Kinase C (PKC) β Modulates Serine Phosphorylation of Insulin Receptor Substrate‐1 (IRS‐1)—Effect of Overexpression of PKCβ on Insulin Signal Transduction

Cited by 22 publications

References 30 publications

Protein kinase Cβ deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling

Protein kinase Cβ deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling

Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

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