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pi3-k-phosphatidylinositol-3-kinase

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Role of TRIB3 in impaired insulin metabolic signaling in endothelial cells....
Published: 17 January 2012
FIG. 1. Role of TRIB3 in impaired insulin metabolic signaling in endothelial cells. TRIB3 leads to leukocyte cell adhesion, which is an initiating event in atherogenesis. ER, endoplasmic reticulum; P, phosphorylation; PI3-K, phosphatidylinositol 3-kinase; Tyr, tyrosine. FIG. 1. Role of TRIB3 in ... More
Journal Articles
Journal: Diabetes
Diabetes 1997;46(3):494–501
Published: 01 March 1997
...Torben Hansen; Carsten B Andersen; Søren M Echwald; Søren A Urhammer; Jesper O Clausen; Henrik Vestergaard; David Owens; Lars Hansen; Oluf Pedersen Phosphatidylinositol 3-kinase (PI3-K) may regulate the basal plasma membrane glucose transporter recycling and the organization of the transporter...
Journal Articles
Journal: Diabetes
Diabetes 2002;51(12):3362–3367
Published: 01 December 2002
... is phosphatidylinositol 3-kinase (PI3-K) and Akt dependent, but the precise mechanism of PDE3B activation is not fully understood. We have identified 14-3-3 β, a critical scaffolding molecule in signal transduction, as a protein that interacts with PDE3B using the yeast two-hybrid system. The interaction between PDE3B...
Journal Articles
Journal: Diabetes
Diabetes 2002;51(6):1921–1930
Published: 01 June 2002
... with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K), and insulin-induced glucose uptake. Insulin and TNF-α each caused tyrosine phosphorylation and activation of PKCs δ and α, but when TNF-α preceded insulin, the effects were less than that produced by each substance alone. Insulin induced PKCδ...
Journal Articles
Journal: Diabetes
Diabetes 2002;51(suppl_1):S43–S49
Published: 01 February 2002
... = 9, P < 0.05) and 48 ± 10% (n = 6, P < 0.05) of control values by the phosphatidylinositol 3-kinase (PI3-K) inhibitors LY294002 (25 μmol/l) and wortmannin (100 nmol/l), respectively. In β-cells from IRS-1–/– mice, 10 μmol/l L-783,281 had no significant...
Journal Articles
Journal: Diabetes
Diabetes 2007;56(8):2093–2102
Published: 01 August 2007
...-responsive aminopeptidase (65 ± 15%, P < 0.001) increased in muscle in response to training. During hyperinsulinemia, activities of insulin receptor substrate-1 (IRS-1)–associated phosphatidylinositol 3-kinase (PI3-K) (P < 0.005), Akt1 (P < 0.05), Akt2 (P...
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IMGU in muscle. In the absence of fatty acids, when insulin (I) binds to it...
Published: 01 January 2002
FIG. 4. IMGU in muscle. In the absence of fatty acids, when insulin (I) binds to its receptor (IR), the sequence of events are as follows (dotted arrows). A: phosphorylation of the IRS-1 on a tyrosine residue, B: activation of phosphatidylinositol 3-kinase (PI3-K), and C: translocation of GLUT4 (G-4) to the membrane. In the presence of LCACoA, the insulin signaling cascade follows an abnormal pathway (solid arrows). D: generation of a diacylglycerol (DAG) pool; E: activation of PKCθ and phosphorylation of IRS-1 on a serine residue. This model is supported by work published by the laboratories of Shulman ( 18 ) and Kraegen ( 29 ). FIG. 4. IMGU in muscle. In the absence of fatty acids, when insulin (I) binds to its receptor (IR), the sequence of events are as follows (dotted arrows). A: phosphorylation of the IRS-1 on a tyrosine residue, B: activation of phosphatidylinositol 3-kinase (PI3-K), and C: translocation of GLUT4 (G-4) to the membrane. In the presence of LCACoA, the insulin signaling cascade follows an abnormal pathway (solid arrows). D: generation of a diacylglycerol (DAG) pool; E: activation of PKCθ and phosphorylation of IRS-1 on a serine residue. This model is supported by work published by the laboratories of Shulman (18) and Kraegen (29). More
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Activation of the IRS signaling cascade pathways. A peptide ligand such as ...
Published: 14 June 2013
FIG. 1. Activation of the IRS signaling cascade pathways. A peptide ligand such as insulin or insulin-like growth factor-1 (IGF-1) binds to its receptor, activating the intrinsic tyrosine kinase activity of that receptor that then tyrosine phosphorylates (pY) adaptor molecules such as IRS-1 or -2. Other receptor tyrosine kinases, or receptors that activate tyrosine kinases such as Janus kinase (JAK), can also activate IRS signaling. This leads to activation of two major signaling cascades, the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway (orange) and the phosphatidylinositol-3′-kinase (PI3’K)/protein kinase-B (PKB; also known as Akt) signaling pathway (green). For the Ras-Raf-MAPK pathway, growth factor receptor–bound protein-2 (Grb2)/son of sevenless (SOS) protein complex binds to specific phosphorylated tyrosines on IRS-1/2, activating the GTP/GDP exchange activity of SOS, which loads p21Ras (Ras) with GTP to activate Ras, leading to phosphorylation of the serine/threonine protein kinase Raf-1, which then phosphorylates the mitogen-activated protein kinase kinase (MEK1), which is then activated to phosphorylate the extracellular signal–regulated kinases-1 and -2 (Erk-1/2). Phospho-activated Erk-1/2 can then directly (or indirectly via phospho-activation of other kinases such as p90 ribosomal serine kinase [p90RSK]) serine/threonine phosphorylate certain transcription factors, such as cFos and E-twenty-six–like transcription factor 1 (Elk-1), to upregulate gene transcription. Phospho-activated Erk-1/2 can also phosphorylate MAPK–interacting kinase (Mnk) 1 and 2, leading to phosphorylation activation of the eukaryotic initiation factor-4e (eIF4e) in a complex also containing eIF4a and eIF4G to increase general protein synthesis at the level initiation phase of translational control. For the PI3’K/PKB signaling pathway, the p85 regulatory subunit of PI3’K docks to other specific phosphorylated tyrosine sites on IRS-1/2 that then activates its p110 catalytic activity. This catalyzes the phosphorylation of phosphatidylinositol-4, 5-bisphophaste [PI(4,5)P2] to phosphatidylinositol-3, 4, 5-trisphophaste [PI(3,4,5)P3], which then activates 3-phosphoinositide dependent protein kinase-1 (PDK1). PDK1 then threonine (pT) phosphorylates PKB for PKB activation, which can be amplified by serine phosphorylation (pS) of PKB by the target of rapamycin complex-2 (TORC2; which includes the protein kinase, mammalian target of rapamycin [mTOR] and associated proteins rictor and mLST8). PKB has a plethora of serine/threonine phosphorylation substrates. PKB-mediated phosphorylation of the tuberous sclerosis protein-1/2 complex (TSC1/2) inhibits its GTPase activating protein activity to then load the Ras homolog enriched in brain (Rheb) protein with GTP (RhebGTP), leading to activation of the TORC1 (which includes mTOR and associated proteins raptor and mLST8). TORC1 can then serine/threonine phosphorylate a series of substrates. This includes the eIF4e-binding protein-1 (4e-BP1) that releases it from eIF4e binding, enabling eIF4e to associate with eIF4a and eIF4G in a complex with Mnk, where Mnk then phosphorylates eIF4e to increase rates of protein synthesis translation. This also shows how the Ras/Raf/Erk and PI3’K/PKB signaling pathways can coordinate to give a tight translational control of protein synthesis. TORC1 can also phosphorylate and subsequently activate p70 S6-ribosomal kinase (p70S6K), which can lead to an increase in the elongation phase of protein synthesis translation. PDK1 can threonine phosphorylate p70S6K to amplify this effect. TORC1 also phosphorylates Unc-51–like kinases-1/2 (ULK-1/2; also known as autophagy gene-1), which results in inhibition of autophagy. Among PKB’s other phosphorylation substrates are proteins involved in the apoptotic process such as Bcl-antagonist of cell death (BAD) and X-linked inhibitor of apoptosis protein (XIAP), outlining a mechanism whereby PKB is antiapoptotic. PKB phosphorylation of the transcription factors FoxO1 and FoxO3a causes their removal from the nucleus and promotes their degradation, causing an inhibition of FoxO1/3a-mediated transcription. Phosphorylation of glycogen synthase kinase-3 (GSK3) by PKB inhibits GSK3 activity, resulting in increased glycogen deposition and cell growth. Under certain circumstances, PKB can also influence increases in cell growth by phosphorylating the cell-cycle inhibitor proteins p21 cyclin-dependent kinase inhibitor-1 (p21CIP) and p27 cyclin-dependent-kinase inhibitor (p27KIP). PKB can also phosphorylate-inhibit phosphodiesterase-3b (PDE3b) to elevate intracellular cAMP ([cAMP]i) levels. Many of these IRS signaling elements have been shown to be expressed and active and play important roles in pancreatic β-cells in terms of certain functions, growth, and survival (rev. in 2 – 4 ), and these are indicated by a yellow highlighted halo. FIG. 1. Activation of the IRS signaling cascade pathways. A peptide ligand such as insulin or insulin-like growth factor-1 (IGF-1) binds to its receptor, activating the intrinsic tyrosine kinase activity of that receptor that then tyrosine phosphorylates (pY) adaptor molecules such as IRS-1 or -2. Other receptor tyrosine kinases, or receptors that activate tyrosine kinases such as Janus kinase (JAK), can also activate IRS signaling. This leads to activation of two major signaling cascades, the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway (orange) and the phosphatidylinositol-3′-kinase (PI3’K)/protein kinase-B (PKB; also known as Akt) signaling pathway (green). For the Ras-Raf-MAPK pathway, growth factor receptor–bound protein-2 (Grb2)/son of sevenless (SOS) protein complex binds to specific phosphorylated tyrosines on IRS-1/2, activating the GTP/GDP exchange activity of SOS, which loads p21Ras (Ras) with GTP to activate Ras, leading to phosphorylation of the serine/threonine protein kinase Raf-1, which then phosphorylates the mitogen-activated protein kinase kinase (MEK1), which is then activated to phosphorylate the extracellular signal–regulated kinases-1 and -2 (Erk-1/2). Phospho-activated Erk-1/2 can then directly (or indirectly via phospho-activation of other kinases such as p90 ribosomal serine kinase [p90RSK]) serine/threonine phosphorylate certain transcription factors, such as cFos and E-twenty-six–like transcription factor 1 (Elk-1), to upregulate gene transcription. Phospho-activated Erk-1/2 can also phosphorylate MAPK–interacting kinase (Mnk) 1 and 2, leading to phosphorylation activation of the eukaryotic initiation factor-4e (eIF4e) in a complex also containing eIF4a and eIF4G to increase general protein synthesis at the level initiation phase of translational control. For the PI3’K/PKB signaling pathway, the p85 regulatory subunit of PI3’K docks to other specific phosphorylated tyrosine sites on IRS-1/2 that then activates its p110 catalytic activity. This catalyzes the phosphorylation of phosphatidylinositol-4, 5-bisphophaste [PI(4,5)P2] to phosphatidylinositol-3, 4, 5-trisphophaste [PI(3,4,5)P3], which then activates 3-phosphoinositide dependent protein kinase-1 (PDK1). PDK1 then threonine (pT) phosphorylates PKB for PKB activation, which can be amplified by serine phosphorylation (pS) of PKB by the target of rapamycin complex-2 (TORC2; which includes the protein kinase, mammalian target of rapamycin [mTOR] and associated proteins rictor and mLST8). PKB has a plethora of serine/threonine phosphorylation substrates. PKB-mediated phosphorylation of the tuberous sclerosis protein-1/2 complex (TSC1/2) inhibits its GTPase activating protein activity to then load the Ras homolog enriched in brain (Rheb) protein with GTP (RhebGTP), leading to activation of the TORC1 (which includes mTOR and associated proteins raptor and mLST8). TORC1 can then serine/threonine phosphorylate a series of substrates. This includes the eIF4e-binding protein-1 (4e-BP1) that releases it from eIF4e binding, enabling eIF4e to associate with eIF4a and eIF4G in a complex with Mnk, where Mnk then phosphorylates eIF4e to increase rates of protein synthesis translation. This also shows how the Ras/Raf/Erk and PI3’K/PKB signaling pathways can coordinate to give a tight translational control of protein synthesis. TORC1 can also phosphorylate and subsequently activate p70 S6-ribosomal kinase (p70S6K), which can lead to an increase in the elongation phase of protein synthesis translation. PDK1 can threonine phosphorylate p70S6K to amplify this effect. TORC1 also phosphorylates Unc-51–like kinases-1/2 (ULK-1/2; also known as autophagy gene-1), which results in inhibition of autophagy. Among PKB’s other phosphorylation substrates are proteins involved in the apoptotic process such as Bcl-antagonist of cell death (BAD) and X-linked inhibitor of apoptosis protein (XIAP), outlining a mechanism whereby PKB is antiapoptotic. PKB phosphorylation of the transcription factors FoxO1 and FoxO3a causes their removal from the nucleus and promotes their degradation, causing an inhibition of FoxO1/3a-mediated transcription. Phosphorylation of glycogen synthase kinase-3 (GSK3) by PKB inhibits GSK3 activity, resulting in increased glycogen deposition and cell growth. Under certain circumstances, PKB can also influence increases in cell growth by phosphorylating the cell-cycle inhibitor proteins p21 cyclin-dependent kinase inhibitor-1 (p21CIP) and p27 cyclin-dependent-kinase inhibitor (p27KIP). PKB can also phosphorylate-inhibit phosphodiesterase-3b (PDE3b) to elevate intracellular cAMP ([cAMP]i) levels. Many of these IRS signaling elements have been shown to be expressed and active and play important roles in pancreatic β-cells in terms of certain functions, growth, and survival (rev. in 2–4), and these are indicated by a yellow highlighted halo. More
Journal Articles
Journal: Diabetes
Diabetes 2012;61(2):265–266
Published: 17 January 2012
...FIG. 1. Role of TRIB3 in impaired insulin metabolic signaling in endothelial cells. TRIB3 leads to leukocyte cell adhesion, which is an initiating event in atherogenesis. ER, endoplasmic reticulum; P, phosphorylation; PI3-K, phosphatidylinositol 3-kinase; Tyr, tyrosine. FIG. 1. Role of TRIB3...
Meeting Abstracts
Journal: Diabetes
Diabetes 2000;49(10):1700–1708
Published: 01 October 2000
... glucose observed in 3T3-L1 adipocytes [13,14]) because IRS-1 plays oxidase for 2 h), 2 mmol/l 5-aminoimidazole-4-carbox- a major role in the activation of phosphatidylinositol amide ribonucleoside for 30 min, and osmotic shock 3-kinase (PI3-K), which is essential for GLUT4 translocation (600 mmol/l...
Journal Articles
Journal: Diabetes
Diabetes 2001;50(4):882–885
Published: 01 April 2001
... IAUC, insulin area under the curve, IRS, insulin receptor substrate ISI, insulin sensitivity index IVGTT, intravenous glucose tolerance test MCR, metabolic clearance rate of glucose OGTT, oral glucose tolerance tests PI3-K, phosphatidylinositol 3-kinase The pathogenesis of type 2 diabetes...
Journal Articles
Journal: Diabetes
Diabetes 2006;55(4):1148–1156
Published: 01 April 2006
... PI3-K, phosphatidylinositol 3-kinase STZ, streptozotocin A second approach to evaluate retinal insulin receptor signaling utilized ex vivo retina cultures to examine the specific effects of hormone stimulation on the retina. In agreement with our previous report ( 6 ), 10 nmol/l insulin...
Journal Articles
Journal: Diabetes
Diabetes 2006;55(7):2067–2076
Published: 01 July 2006
..., extensor digitorum longus GAP, GTPase-activating protein PAS, phospho-Akt substrate PI3-K, phosphatidylinositol 3-kinase Insulin and exercise share the capacity to increase glucose uptake into skeletal muscle and positively regulate glucose homeostasis in healthy individuals and people with type 2...
Journal Articles
Journal: Diabetes
Diabetes 2004;53(12):3057–3066
Published: 01 December 2004
... of insulin receptor substrate-1 (IRS-1) and insulin-stimulated phosphatidylinositol 3-kinase (PI3-K) activity ( 3 – 6 ). Tissue levels of PTP-1B have been reported to be increased in insulin-resistant diabetes in humans ( 7 ). Increased PTP-1B expression has also been observed in the fa/fa genetic...
Journal Articles
Journal: Diabetes
Diabetes 2004;53(12):3217–3225
Published: 01 December 2004
...-mouse CD36 monoclonal antibody (clone 63; Cascade Bioscience, Winchester, MA) at 2.5 μg/ml. Mouse IgA (Sigma) was used as a control. Phosphatidylinositol 3-kinase (PI3-K) was inhibited by wortmannin (100 nmol/l). The extracellular signal-regulated kinase (ERK) pathway was inhibited by PD98059 (2 μmol/l...
Journal Articles
Journal: Diabetes
Diabetes 2006;55(12):3372–3380
Published: 01 December 2006
...-P, glucose-6-phosphate HGP, hepatic glucose production HR-dGTT, hepatic recycling deuterated glucose tolerance test HR-GTT, hepatic recycling glucose tolerance test ipGTT, intraperitoneal glucose tolerance test ITT, insulin tolerance test PI3-K, phosphatidylinositol 3-kinase PPAR, peroxisome...
Includes: Supplementary data
Journal Articles
Journal: Diabetes
Diabetes 1997;46(5):735–741
Published: 01 May 1997
... that the MAP kinase cascade in growth factor signaling diverges and cross-talks with other signaling pathways. In the present study, we examined the effects of wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), on the activation of Ras, Raf-1 kinase, and MAP kinase by insulin...
Journal Articles
Journal: Diabetes
Diabetes 2002;51(4):1052–1059
Published: 01 April 2002
... that was roughly 30–50% less than that from control subjects. This insulin resistance was associated with impaired insulin receptor substrate (IRS)-2–associated phosphatidylinositol 3′ (PI3) kinase activation and IRS-2 tyrosine phosphorylation as well as significantly decreased protein kinase C (PKC)-ζ/λ...
Journal Articles
Journal: Diabetes
Diabetes 2006;55(10):2688–2697
Published: 01 October 2006
... carboxylase AMPK, AMP-activated protein kinase DG, deoxyglucose EGP, endogenous glucose production FFA, free fatty acid GIR, glucose infusion rate IL-6, interleukin-6 IRS, insulin receptor substrate PI3-K, phosphatidylinositol 3-kinase rhIL-6, recombinant human IL-6 rmIL-6, recombinant mouse IL-6...
Journal Articles
Journal: Diabetes
Diabetes 2006;55(8):2371–2378
Published: 01 August 2006
.... In response to hyperthermia, the activation of serine/threonine kinase Akt depending on phosphatidylinositol 3 (PI3) kinase was necessary for cardiac expression of HSP72. Hyperthermia-induced activation of Akt and HSP72 expression were depressed in OLETF rat hearts. Pioglitazone but not glibenclamide improved...