Activation of Protein Kinase Cα Inhibits Signaling by Members of the Insulin Receptor Family

Danielsen, Anne; Liu, Feng; Hosomi, Yoichi; Shii, Kozui; Roth, Richard A.

doi:10.1074/jbc.270.37.21600

Cited by 75 publications

(39 citation statements)

References 66 publications

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“…Differences may include variations between Rat-1 HIR cell lines, differences in assay conditions, or other factors. The results are consistent with a previous report that PMA enhances the ability of insulin to induce MAPK activation and mitogenesis in Balb/c 3T3 fibroblasts expressing the human insulin receptor (5), but are in contrast with PMA-induced inhibition of insulinstimulated Shc tyrosine phosphorylation and mitogenesis observed in Chinese hamster ovary cells transfected with the human insulin receptor and PKC␣ (35). Thus, responses may vary with cell type, levels of PKC isoform expression, and levels of insulin receptor expression.…”

Section: Discussionsupporting

confidence: 82%

Synergistic Effects of Insulin and Phorbol Ester on Mitogen-activated Protein Kinase in Rat-1 HIR Cells

Knoepp

Wisehart-Johnson

Buse

et al. 1996

Journal of Biological Chemistry

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Regulation of the activity of the extracellular signal regulated kinase (ERK) mitogen-activated protein kinases was examined in Rat-1 HIR, a fibroblast cell line overexpressing the human insulin receptor. Insulin or phorbol ester induced partial activations of ERKs, while a combination of insulin and phorbol ester resulted in a synergistic activation. Preincubation with phorbol ester increased the subsequent response to insulin. Phorbol ester did not enhance tyrosine phosphorylation of the insulin receptor. Insulin did not enhance activation of phospholipase D in response to phorbol ester. Lysophosphatidic acid also acted synergistically with insulin to induce ERK activation. Lysophosphatidic acid alone had little effect on ERK, and did not activate phospholipase D. The combination of phorbol ester and insulin maintained tyrosine phosphorylation of focal adhesion kinase, while insulin alone decreased its tyrosine phosphorylation. Phorbol ester induced phosphorylation of Shc on serine/threonine, while insulin induced tyrosine phosphorylation of Shc and Shc-Grb2 binding. These results suggest that full activation of ERKs in fibroblasts can require the cooperation of at least two signaling pathways, one of which may result from a protein kinase C-dependent phosphorylation of effectors regulating ERK activation. In this manner, phorbol esters may enhance mitogenic signals initiated by growth factor receptors.The ERK 1 mitogen-activated protein kinases (MAPKs), which are activated in response to a wide variety of growth factors, hormones, and other mitogenic stimuli, have been linked to the induction of cell proliferation (1). The insulin receptor, a tyrosine kinase, can elicit both metabolic and mitogenic responses (2). The insulin receptor binds to several effectors, with binding to insulin receptor substrate-1 (IRS-1) mediating most of the metabolic effects of insulin. Mutation or deletion of some of the phosphorylatable tyrosines in the insulin receptor can enhance its mitogenic activity (3), suggesting that multifunctionality of the receptor may compromise its mitogenic potential. Phorbol ester tumor promoters can act additively or synergistically with insulin to induce mitogenesis (4, 5).The mitogenic activity of the insulin receptor has been correlated with its ability to activate MAPK, a response that is mediated predominantly through interaction of the insulin receptor with Shc (6). IRS-1 and Shc compete for binding to Grb2, such that IRS-1 may either inhibit (7) or enhance (8) activation of MAPK. Tyrosine-phosphorylated Shc binds to the adapter Grb2, causing disassembly of SOS from Grb2 resulting in GDP-GTP exchange on Ras (9). GTP-bound Ras promotes activation of Raf-1 kinase (1, 10). Raf-1 phosphorylates and activates MEK (mitogen-activated protein kinase kinase/ERK kinase), which phosphorylates and activates MAPK. One downstream effector of MAPK is RSK, another protein serine/threonine kinase. It is clear that the insulin receptor initiates signals that are independent of MAPK activation (reviewed in Ref...

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Section: Discussionsupporting

confidence: 82%

Synergistic Effects of Insulin and Phorbol Ester on Mitogen-activated Protein Kinase in Rat-1 HIR Cells

Knoepp

Wisehart-Johnson

Buse

et al. 1996

Journal of Biological Chemistry

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“…This is the first report to demonstrate that PKC␣ may actually be constitutively associated with IRS-1 and that insulin causes these elements to physically dissociate. Others have shown, however, that activation of PKC␣ not only inhibits IR signaling (41,42) but also that PKC␣ may require IRS-1 for inhibition of IR tyrosine kinase activity (27). Activation of PKC␣ and its increased physical association with IRS-1 in response to TNF-␣, as reported here, are thus consistent with the involvement of IRS-1 in PKC␣ inhibition of IR signaling.…”

Section: Discussionsupporting

confidence: 77%

Differential Effects of Tumor Necrosis Factor-α on Protein Kinase C Isoforms α and δ Mediate Inhibition of Insulin Receptor Signaling

et al. 2002

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Tumor necrosis factor-␣ (TNF-␣) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-␣ inhibition of insulin signaling in primary cultures of mouse skeletal muscle. TNF-␣, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K), and insulin-induced glucose uptake. Insulin and TNF-␣ each caused tyrosine phosphorylation and activation of PKCs ␦ and ␣, but when TNF-␣ preceded insulin, the effects were less than that produced by each substance alone.

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“…Equally not surprising were findings that PKCα expressed in cells co-expressing either IR or IRS1 (3T3ir, HEK293, COSIR) induced their phosphorylation. Thus, the idea has developed and persisted that PKCα might in fact play a role in development of insulin resistance [64][65][66][67][68][69][54][55][56][57][58]. Nonetheless, a role in insulin-induced effects has not been verified.…”

Section: Conventional Pkc Isoforms Pkcαmentioning

confidence: 99%

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Sampson

Cooper

2006

Molecular Genetics and Metabolism

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Recent studies implicate specific PKC isoforms in the insulin-signaling cascade. Insulin activates PKCsα, βII, δ and ζ in several cell types. In addition, as will be documented in this review, certain members of the PKC family may also be activated and act upstream of PI3 and MAP kinases. Each of these isoforms has been shown one way or another either to mimic or to modify insulin-stimulated effects in one or all of the insulin-responsive tissues. Moreover, each of the isoforms has been shown to be activated by insulin stimulation or conditions important for effective insulin stimulation. Studies attempting to demonstrate a definitive role for any of the isoforms have been performed on different cells, ranging from appropriate model systems for skeletal muscle, liver and fat, such as primary cultures, and cell lines and even in vivo studies, including transgenic mice with selective deletion of specific PKC isoforms. In addition, studies have been done on certain expression systems such as CHO or HEK293 cells, which are far removed from the tissues themselves and serve mainly as vessels for potential protein-protein interactions. Thus, a clear picture for many of the isoforms remains elusive in spite of over two decades of intensive research. The recent intrusion of transgenic and precise molecular biology technologies into the research armamentarium has opened a wide range of additional possibilities for direct involvement of individual isoforms in the insulin signaling cascade. As we hope to discuss within the context of this review, whereas many of the long soughtafter answers to specific questions are not yet clear, major advances have been made in our understanding of precise roles for individual PKC isoforms in mediation of insulin effects. In this review, in which we shall focus our attention on isoforms in the conventional and novel categories, a clear case will be made to show that these isoforms are not only expressed but are importantly involved in regulation of insulin metabolic effects.

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Activation of Protein Kinase Cα Inhibits Signaling by Members of the Insulin Receptor Family

Cited by 75 publications

References 66 publications

Synergistic Effects of Insulin and Phorbol Ester on Mitogen-activated Protein Kinase in Rat-1 HIR Cells

Synergistic Effects of Insulin and Phorbol Ester on Mitogen-activated Protein Kinase in Rat-1 HIR Cells

Differential Effects of Tumor Necrosis Factor-α on Protein Kinase C Isoforms α and δ Mediate Inhibition of Insulin Receptor Signaling

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

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