Insulin Activation of Mitogen-Activated Protein (MAP) Kinase and Akt Is Phosphatidylinositol 3-Kinase-Dependent in Rat Adipocytes

Liu, Hongzhi; Kublaoui, Bassil; Pilch, Paul F.; Lee, Jongsoon

doi:10.1006/bbrc.2000.3208

Cited by 16 publications

(11 citation statements)

References 39 publications

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“…Insulin on the other hand had no effect on Shc phosphorylation, neither before nor after cholesterol depletion, even at a supraphysiological insulin concentration (Fig. 12), in accordance with recent findings in rat adipocytes (44). DISCUSSION ␤-Cyclodextrin is a widely used tool for control of cellular levels of cholesterol through its ability to extract cholesterol from the plasma membrane of intact cells.…”

Section: Lack Of Effect Of Cholesterol Depletion On Map Kinasesupporting

confidence: 89%

“…Our findings demonstrate that, although Shc is present, insulin does not affect Shc in isolated adipocytes and Shc does not control ERK and the MAP kinase pathway in adipocytes. Lack of insulin effect on Shc phosphorylation in adipocytes was recently described (44). The differential effects of caveolae destruction on insulin IRS/metabolic and ERK/mitogenic control indicate that caveolae may have a role in insulin signal sorting for metabolic The dependence of the insulin receptor on intact caveolae/ cholesterol for transmission of its metabolic signals stands in contrast to other tyrosine kinase receptors, which are inhibited by cholesterol/caveolae/caveolin: Cholesterol depletion (using cyclodextrin) or caveolin-1 depletion (using caveolin-1 antisense expression) therefore constitutively activated the p42/44 MAP kinase cascade (43,64), and epidermal growth factor caused hyperactivation of ERK in cholesterol-depleted cells (43).…”

Section: Lack Of Effect Of Cholesterol Depletion On Map Kinasementioning

confidence: 88%

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Cholesterol Depletion Disrupts Caveolae and Insulin Receptor Signaling for Metabolic Control via Insulin Receptor Substrate-1, but Not for Mitogen-activated Protein Kinase Control

Parpal

Karlsson

Thorn

et al. 2001

Journal of Biological Chemistry

311

257

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Insulin controls target cells by binding to its cell surface receptor. The further intracellular transmission of the insulin signal involves phosphorylation of the receptor as well as other proteins, in particular the insulin receptor substrate (IRS), 1 on specific tyrosine residues. After tyrosine phosphorylation IRS is recognized by Src homology 2 domain-containing proteins for metabolic and glucose transport control, or activation of the mitogen-activated protein kinase (MAP kinase) pathway and mitogenic control (1-4). In type 2 diabetes target cells of the hormone are not fully responsive, which is compensated temporarily by enhanced insulin secretion. The pathogenic mechanisms for this insulin resistance are not known, but an important common feature appears to be a reduced activation/ tyrosine phosphorylation of IRS-1 (5).The insulin receptors are sequestered in the caveolae microdomains of the plasma membrane in adipocytes, and caveolae appear to be critical for insulin control (6). By thin-section electron microscopy, caveolae appear as omega-shaped invaginations of 50 -100 nm diameter in the plasma membrane (7). Caveolae invaginations are found in the plasma membrane of many cell types, but are particularly abundant in adipocytes where they increase in number in conjunction with the differentiation of 3T3-L1 fibroblasts to mature adipocytes (8 -10). Caveolae are involved in receptor-mediated uptake of solutes into the cytosol (11) and in transcytosis (12). A number of proteins, in addition to the insulin receptor, involved in signal transduction are localized to caveolae, which suggests that they may be involved in cellular signaling and control (reviewed in Refs. 13-16).Caveolae are rich in cholesterol and sphingolipids. Caveolae may indeed form from cholesterol-and sphingolipid-rich rafts in the membrane in a process requiring the caveolae-specific structural protein caveolin. Caveolin is found in the plasma membrane and intracellularly, but in the plasma membrane is confined to caveolae; it is therefore used as a marker for these structures. The function of caveolae is dependent on a sufficient level of cholesterol in the plasma membrane and caveolae (12,17). We have also demonstrated a critical dependence of the insulin receptor signal transduction on cholesterol; depletion of cholesterol from the plasma membrane of rat adipocytes reversibly inhibited insulin stimulation of glucose transport and metabolic protein phosphorylation control (6). The importance of caveolae for insulin receptor signaling is further indicated by a consensus binding site for interaction with caveolin (18), and coprecipitation of the receptor with caveolin (4) indicates that the interaction may be physiological. Moreover, the insulin receptor appears to phosphorylate caveolin (19), whereas caveolin was shown to activate the isolated receptor, although the physiological relevance of this is not known (20).Herein we examine in detail the dependence of the insulin receptor on caveolae for signal transduction: the effects of cho...

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Section: Lack Of Effect Of Cholesterol Depletion On Map Kinasesupporting

confidence: 89%

Section: Lack Of Effect Of Cholesterol Depletion On Map Kinasementioning

confidence: 88%

Cholesterol Depletion Disrupts Caveolae and Insulin Receptor Signaling for Metabolic Control via Insulin Receptor Substrate-1, but Not for Mitogen-activated Protein Kinase Control

Parpal

Karlsson

Thorn

et al. 2001

Journal of Biological Chemistry

311

257

View full text Add to dashboard Cite

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“…Results of the present study confirm this observation and show that the PI 3-kinase inhibitor wortmannin (partially) and the PKC inhibitor GF109203X (completely), blocked insulinstimulated ERK1/2 phosphorylation. Although a nonspecific effect of these inhibitors on MEK1/2 cannot be excluded, this finding is in agreement with a growing number of reports suggesting that PI 3-kinase, through atypical PKCs, is involved in ERK activation (45)(46)(47). Importantly, GF109203X, used at a concentration that inhibits only conventional and novel PKCs, had no effect on insulin-stimulated ERK1/2 phosphorylation.…”

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confidence: 90%

ERK1/2 Mediates Insulin Stimulation of Na,K-ATPase by Phosphorylation of the α-Subunit in Human Skeletal Muscle Cells

Al-Khalili

Kotova

Tsuchida

et al. 2004

Journal of Biological Chemistry

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“…The same finding is also reported from rat adipocytes stimulated with insulin and inhibited with wortmannin [103][104][105]. One of the reports, [103], also show that the Shc pathway is not involved in the activation of ERK in response to insulin in rat adipocytes. Instead the IRS1/PI3K pathway is exclusively used for ERK activation in these adipocytes.…”

Section: Insulin Control Of Erk Signalingsupporting

confidence: 78%

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Nyman¹

2014

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Type 2 diabetes is characterized by raised blood glucose levels caused by an insufficient insulin control of glucose homeostasis. This lack of control is expressed both through insufficient release of insulin by the pancreatic beta-cells, and through insulin resistance in the insulin-responding tissues. We find insulin resistance of the adipose tissue particularly interesting since it appears to influence other insulin-responding tissues, such as muscle and liver, to also become insulin resistant.The insulin signaling network is highly complex with cross-interacting intermediaries, positive and negative feedbacks, etc. To facilitate the mechanistic understanding of this network, we obtain dynamic, information-rich data and use model-based analysis as a tool to formally test different hypotheses that arise from the experimental observations. With dynamic mathematical models, we are able to combine knowledge and experimental data into mechanistic hypotheses, and draw conclusions such as rejection of hypotheses and prediction of outcomes of new experiments.We aim for an increased understanding of adipocyte insulin signaling and the underlying mechanisms of the insulin resistance that we observe in adipocytes from subjects diagnosed with type 2 diabetes. We also aim for a complete picture of the insulin signaling network in primary human adipocytes from normal and diabetic subjects with a link to relevant clinical parameters: plasma glucose and insulin. Such a complete picture of insulin signaling has not been presented before. Not for adipocytes and not for other types of cells.In this thesis, I present the development of the first comprehensive insulin signaling model that can simulate both normal and diabetic data from adipocytes -and that is linked to a whole-body glucose-insulin model. In the linking process we conclude that at least two glucose uptake parameters differ between the in vivo and in vitro conditions (Paper I). We also perform a model analysis of the early insulin signaling dynamics in rat adipocytes and conclude that internalization is important for an apparent reversed order of phosphorylation seen in these cells (Paper II). In the development of the first version of the comprehensive insulin signaling model, we introduce a key parameter for the diabetic state -an attenuated feedback (Paper III). We finally continue to build on the comprehensive model and include signaling to nuclear transcription via ERK and report substantial crosstalk in the insulin signaling network (Paper IV). Populärvetenskaplig sammanfattningTyp 2-diabetes är en vanligt förekommande sjukdom där kroppens vävnader förlorar sin känslighet mot hormonet insulin. Insulinets uppgift är att hålla en jämn blodsockernivå dygnet runt. Insulin utsöndras i samband med måltider och påverkar muskel-och fettvävnader att ta upp socker och levern att sluta producera socker. Det är viktigt att hålla en jämn blodsockernivå eftersom låga nivåer kan vara direkt dödligt och höga nivåer är skadligt för blodkärlen, vilket i sin tur kan led...

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Insulin Activation of Mitogen-Activated Protein (MAP) Kinase and Akt Is Phosphatidylinositol 3-Kinase-Dependent in Rat Adipocytes

Cited by 16 publications

References 39 publications

Cholesterol Depletion Disrupts Caveolae and Insulin Receptor Signaling for Metabolic Control via Insulin Receptor Substrate-1, but Not for Mitogen-activated Protein Kinase Control

Cholesterol Depletion Disrupts Caveolae and Insulin Receptor Signaling for Metabolic Control via Insulin Receptor Substrate-1, but Not for Mitogen-activated Protein Kinase Control

ERK1/2 Mediates Insulin Stimulation of Na,K-ATPase by Phosphorylation of the α-Subunit in Human Skeletal Muscle Cells

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

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