The p85<i>α</i> Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance

Taniguchi, Cullen M.; Alemán, José O.; Ueki, Kohjiro; Luo, Ji; Asano, Tomohiko; Kaneto, Hideaki; Stephanopoulos, Gregory; Cantley, Lewis C.; Kahn, C. Ronald

doi:10.1128/mcb.00079-07

Cited by 72 publications

(82 citation statements)

References 61 publications

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“…The activation of the IGF1-R/PI3K/Akt survival pathway may serve a protective role in the retina. In stress, insulin and p85 activates JNK via cdc42 and mitogen-activated protein kinase kinase 4; this cdc42/JNK pathway requires both an intact N-terminus and functional SH2 domains within the C terminus of the p85 ␣ regulatory subunit ( 194 ). These studies suggest that p85 ␣ plays dual roles in regulating insulin sensitivity and in mediating cross-talk between the PI3K and stress kinase pathways.…”

Section: Phosphoinositide Metabolism In the Retinamentioning

confidence: 94%

“…The p85 regulatory subunit of PI3K, a key mediator of insulin's metabolic actions, is also required for the activation of c-Jun N-terminal kinase (JNK) in states of insulin resistance including highfat-diet-induced obesity and JNK1 overexpression ( 194 ). Skeletal muscle lacking both the p85 ␣ /p55 ␣ /p50 ␣ and the p85 ␤ regulatory subunits of PI3K had reduced muscle weight and fi ber size ( 144 ).…”

Section: Light-induced Activation Of Pi3k Pathway In Rod Photoreceptomentioning

confidence: 99%

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Phosphoinositide 3-kinase signaling in the vertebrate retina

Rajala

2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org was established by Streb et al. ( 3 ) in their classic paper that showed elevations in IP 3 caused intracellular release of bound calcium. Subsequently, 1,2-DG was found to stimulate protein kinase C (PKC), a serine/threonine kinase that phosphorylates a number of cellular proteins ( 4 ). Activation of the PLC/PKC cascade affects a variety of cellular events, including secretion, phagocytosis, smooth muscle contraction, proliferation, neurotransmission, and metabolism [see reviews by Rhee ( 5 ), Rhee and Choi ( 6 ), and Berridge ( 7 ) THE PI CYCLEIn the early 1950s, Hokin and Hokin ( 1, 2 ) discovered that addition of acetylcholine to brain slices stimulated the incorporation of phosphate and inositol but not glycerol into lipids; the major products of this incorporation were phosphatidylinositol (PI) and phosphatidic acid. Subsequent studies defi ned the reactions of the PI cycle and showed that the initial event was receptor-meditated activation of a phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PI-4,5-P 2 ) to 1,2-diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP 3 ). This increase in lipid synthesis reported by the Hokins was a recovery reaction that rapidly replenished PI separate from de novo PI synthesis. The role of 1,4, This work was supported by grants

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Section: Phosphoinositide Metabolism In the Retinamentioning

confidence: 94%

Section: Light-induced Activation Of Pi3k Pathway In Rod Photoreceptomentioning

confidence: 99%

Phosphoinositide 3-kinase signaling in the vertebrate retina

Rajala

2010

Journal of Lipid Research

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“…For some studies, 6-week-old mice were subjected to a low-fat diet -14% of calories from fat, 25% from protein, and 61% from carbohydrates (Taconic) -or a HFD -55% from fat, 21% protein, and 24% carbohydrates (Harlan Teklad) -for 18 weeks prior to sacrifice. Adenoviruses encoding PKCδ or GFP as control were prepared as previously described (53) and injected at a dose of 5 × 10 8 PFU/g body weight into the tail vein 5-10 days prior to sacrifice. Adenoviruses encoding Cre recombinase were purchased from the Gene Transfer Vector Core, University of Iowa.…”

Section: Methodsmentioning

confidence: 99%

PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

Bézy¹,

Tran²,

et al. 2011

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C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet-or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose and circulating triglycerides. Mice with global or liverspecific inactivation of the Prkcd gene displayed increased hepatic insulin signaling and reduced expression of gluconeogenic and lipogenic enzymes. This resulted in increased insulin-induced suppression of hepatic gluconeogenesis, improved glucose tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome. IntroductionObesity and type 2 diabetes (T2D) are major health problems worldwide and are projected to further increase in prevalence over the next two decades. Likewise, the closely related metabolic syndrome, with all of its complications, is increasing at epidemic rates. Indeed, nonalcoholic hepatosteatosis is now the second most common cause of chronic liver failure (1). All these disorders are the result of interactions between inherited genetic factors and varying environmental exposures.Mouse models provide a powerful tool to investigate genetic and environmental components involved in the disease susceptibility. In mice, it has been shown that different genetic backgrounds strongly modify the susceptibility to diet-induced obesity, insulin resistance, hepatic steatosis, β cell failure, and T2D, in some cases in very dramatic ways (2-6). For example, we have previously shown that C57BL/6J and 129S6/Sv (B6 and 129) mice have remarkably different metabolic responses to high-fat diet-induced (HFD-induced) insulin resistance. On regular chow diet, B6 mice gain more weight, have higher levels of insulin and leptin, and show greater glucose intolerance than 129 mice, and these phenotypic differences are further exacerbated with high-fat feeding (6). Likewise, when stressed with genetically induced insulin resistance due to heterozygous deletion of both insulin receptor and insulin receptor substrate 1 (IRS-1), more than 90% of B6 mice develop diabetes, whereas less than 5% of 129 mice carrying this form of genetic insulin resistance become diabetic (5). This difference in development of diabete...

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“…Of these isoforms, p85a is predominantly and ubiquitously expressed in most tissues and is known to play a major role in response to most stimuli (Geering et al, 2007;. Apart from forming a complex with the p110 catalytic subunit and regulating PI3K activity, p85a also serves as a crucial mediator in various physiological processes via PI3K-independent mechanisms (Brachmann et al, 2005;Taniguchi et al, 2007;Ueki et al, 2002;Ueki et al, 2003;Yin et al, 1998). However, how p85a functions in a PI3K-independent manner under stress conditions is still elusive.…”

Section: Introductionmentioning

confidence: 99%

p85 mediates NFAT3-dependent VEGF induction in the cellular UVB response

Dong¹,

et al. 2013

Journal of Cell Science

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SummaryExposure to solar ultraviolet B (UVB) radiation is known to induce several pathological reactions in the skin. In these processes, upregulation of VEGF expression has been demonstrated to be important in angiogenesis-associated photodamage and even skin cancers. However, the signaling events that are responsible for VEGF induction under UVB exposure have not been fully defined. Here, we demonstrate that the regulatory subunit of the phosphoinositide 3-kinase (PI3K), p85a, plays a role in mediating UVB-induced VEGF expression in mouse embryonic fibroblasts (MEFs) and mouse epithermal cells, the effect of which is unrelated to the PI3K activity. The transcriptional factor NFAT3 functions as a downstream target of p85a to mediate the induction of VEGF expression in the UVB response. Although lacking NFAT3-binding ability, p85a is required for the recruitment of NFAT3 to the NFAT-response element within the vegf promoter. Furthermore, by identifying the adjacent NFAT-and AP-1-binding sites within the vegf promoter, we also found an induced interaction between NFAT3 and one of the AP-1 components, c-Fos, after UVB irradiation. Without the aid of c-Fos, NFAT3 lost its vegf-promoter-binding ability. Taken together, our results reveal a novel PI3K-independent role for p85a in controlling VEGF induction during the cellular UVB response by regulating NFAT3 activity. Targeting p85a might be helpful for preventing UVBinduced angiogenesis and the associated photodamage.

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The p85α Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance

Cited by 72 publications

References 61 publications

Phosphoinositide 3-kinase signaling in the vertebrate retina

Phosphoinositide 3-kinase signaling in the vertebrate retina

PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

p85 mediates NFAT3-dependent VEGF induction in the cellular UVB response

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