Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101)
ABSTRACT Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. The protein kinase C (PKC) is activated by free-fatty acids, and its activity is higher in muscle from obese diabetic patients. However, a molecular link between PKC and insulin resistance has not been defined yet. Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1 tyrosine phosphorylation and downstream activation of the Akt pathway. Mutation of Ser(1101) to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. These results provide a novel mechanism linking the activation of PKC to the inhibition of insulin signaling.
- SourceAvailable from: Greg M Kowalski
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- "Indeed, extensive evidence demonstrates that accumulation of triacylglycerol (TG) in skeletal muscle is associated with insulin resistance (Perseghin et al., 1999). TG itself directly interfering with insulin action is unlikely, but the general consensus is that accumulation of bioactive lipids, particularly diacylglycerol (DG), causes insulin resistance (Itani et al., 2002; Li et al., 2004; Yu et al., 2002). In addition to being an important metabolic intermediate for TG, DG is a precursor for the synthesis of phospholipids. "
ABSTRACT: Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis. Copyright © 2015 Elsevier Inc. All rights reserved.Cell metabolism 05/2015; 21(5):718-30. DOI:10.1016/j.cmet.2015.04.001 · 16.75 Impact Factor
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- "In type II diabetes, activation of some PKCs, including PKCq, with fatty acids or diacylglycerol can induce insulin resistance via inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) (Griffin et al., 1999; Li et al., 2004). Phosphorylated IRS1 dissociates from the insulin receptor, leading to decreased signaling via PI3K/AKT and reduced glucose uptake (Li et al., 2004; Griffin et al., 1999). PKC isozymes are divided into three groups: conventional PKCs (PKCa, PKCbI, PKCbII, and PKCg), novel PKCs (PKCd, PKCq, PKCε, and PKCh), and atypical PKCs (PKCz and PKCi). "
ABSTRACT: The natural product englerin A (EA) binds to and activates protein kinase C-θ (PKCθ). EA-dependent activation of PKCθ induces an insulin-resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKCθ-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction, while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors.Cancer cell 01/2013; 23(2):228-237. DOI:10.1016/j.ccr.2012.12.007 · 23.89 Impact Factor
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- "Ser-29 Krasel et al. (2001); Malhotra et al. (2010) PKCα GTPase activating protein (GAP) p190A Ser-1221 and Thr-1226 Lévay et al. (2009) PKCδ Heat-shock protein-25/27 Ser-15 and Ser-86 Maizels et al. (1998) PKCζ Heterogeneous ribonucleoprotein A1 Ser-199 + three unknown sites Municio et al. (1995) cPKCs and PKCδ High-mobility-group protein-1 Ser-44 and Ser-64 Xiao et al. (2000) PKCβΙ Histone H3 Thr-6 Metzger et al. (2010) PKCε and β Ser-10 Huang et al. (2004) PKCζ Insulin-responsive aminopeptidase (IRAP) Ser-80 and Ser-91 Ryu et al. (2002) PKCδ Insulin receptor substrate-1 (IRS-1) (human) Ser-24, Ser-307, Ser-323, and Ser-574 Greene et al. (2004) (2006) PKCθ IRS-1 (human) Ser-1101 Li et al. (2004) PKCβII IRS-1 (mouse) Ser-336 Liberman et al. (2008) PKCδ IRS-1 (rat) Ser 357 Waraich et al. (2008) PKCζ IRS-1 (rat) Ser-318, Ser-498, Ser-570, and Ser-612 (a major phosphorylation site is Ser-318) Beck et al. (2003); Moeschel et al. (2004) "
ABSTRACT: Protein kinase C (PKC), a phospholipid-dependent serine/threonine kinase, appears to be involved in the signal transduction response to many hormones and growth factors; there are 11 different PKC isozymes. Because PKC isozymes directly and/or indirectly participate in signal transduction pathways of normal and transformed cells through phosphorylation of target proteins, it is critical to understand the diversity of the intracellular signaling pathways regulated by each PKC isozyme. Thus, PKC isozyme-specific substrates are useful to understand the characterization of the intracellular signaling pathways for each PKC isozyme. Consensus sequences and sequence information obtained from PKC target proteins are very important to design PKC isozyme-specific peptide substrates. Moreover, computational prediction programs of phosphorylation sites using a library of peptide substrates aid in the fast design of PKC isozyme-specific peptide substrates. Although a large number of target proteins and synthetic peptides for PKCs are known, only two peptide substrates (peptide 422-426 of murine elongation factor-1α and Alphatomega peptide) have been reported as PKC isozyme-specific peptide substrates. This discussion will review the literature concerning these native and synthetic PKC isozyme-specific peptide substrates and their design.Biotechnology advances 07/2012; 30(6):1662-72. DOI:10.1016/j.biotechadv.2012.07.004 · 8.91 Impact Factor