Association of the Insulin Receptor with Phospholipase C-γ (PLCγ) in 3T3-L1 Adipocytes Suggests a Role for PLCγ in Metabolic Signaling by Insulin

Kayali, Ayse G.; Eichhorn, Jens; Haruta, Tetsuro; Morris, Aaron J.; Nelson, James G.; Vollenweider, Péter; Olefsky, Jerrold M.; Webster, Nicholas J. G.

doi:10.1074/jbc.273.22.13808

Cited by 65 publications

(60 citation statements)

References 92 publications

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“…In vitro kinase activity assays have demonstrated that insulin activates both pathways in adipocytes (34,41). Importantly, insulin stimulates an 18-fold increase in p44/p42 MAPK activation as well as a 2-to 3-fold increase in the activation of p38 MAPK (25).…”

Section: Discussionmentioning

confidence: 99%

“…Targets of PDK include Akt and the atypical PKC isoforms, which, when activated via phosphorylation, stimulate the translocation of the insulin-responsive glucose transporter (GLUT4)-containing vesicles to the plasma membrane. Phospholipase C-␥1 (PLC-␥1), another downstream target of PI3K in insulin signaling, also facilitates GLUT4 translocation (13,25). Although the relative contributions of PLC-␥1, Akt, and atypical PKCs to GLUT4 translocation remain controversial, studies have demonstrated the necessity of PI3K activity for insulin-stimulated glucose uptake (6, 43).…”

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confidence: 99%

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MEK inhibitors impair insulin-stimulated glucose uptake in 3T3-L1 adipocytes

Harmon¹,

Paul²,

Patel³

2004

American Journal of Physiology-Endocrinology and Metabolism

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.-In 3T3-L1 adipocytes, insulin activates three major signaling cascades, the phosphoinositide 3-kinase (PI3K) pathway, the Cbl pathway, and the mitogen-activated protein kinase (MAPK) pathway. Although PI3K and Cbl mediate insulin-stimulated glucose uptake by promoting the translocation of the insulin-responsive glucose transporter (GLUT4) to the plasma membrane, the MAPK pathway does not have an established role in insulin-stimulated glucose uptake. We demonstrate in this report that PI3K inhibitors also inhibit the MAPK pathway. To investigate the role of the MAPK pathway separately from that of the PI3K pathway in insulin-stimulated glucose uptake, we used two specific inhibitors of MAPK kinase (MEK) activity, PD-98059 and U-0126, which reduced insulin-stimulated glucose uptake by ϳ33 and 50%, respectively. Neither MEK inhibitor affected the activation of Akt or PKC/, downstream signaling molecules in the PI3K pathway. Inhibition of MEK with U-0126 did not prevent GLUT4 from translocating to the plasma membrane, nor did it inhibit the subsequent docking and fusion of GLUT4-myc with the plasma membrane. MEK inhibitors affected glucose transport mediated by GLUT4 but not GLUT1. Importantly, the presence of MEK inhibitors only at the time of the transport assay markedly impaired both insulin-stimulated glucose uptake and MAPK signaling. Conversely, removal of MEK inhibitors before the transport assay restored glucose uptake and MAPK signaling. Collectively, our studies suggest a possible role for MEK in the activation of GLUT4. p44/p42 mitogen-activated protein kinase; glucose transporter 4; glucose transport; U-0126; PD-98059 THE BINDING OF INSULIN to its receptor triggers multiple signaling pathways that participate broadly in cellular growth and differentiation and in the metabolism of lipids and glucose. To maintain glucose homeostasis, insulin not only inhibits the production of glucose in the liver but also stimulates the transport of glucose into muscle and adipose tissue for subsequent use or storage. Autophosphorylation of the insulin receptor tyrosine kinase results in the recruitment and tyrosine phosphorylation of substrates and the activation of three major pathways, the phosphoinositide 3-kinase (PI3K) pathway, the mitogen-activated protein kinase (MAPK) pathway, and the Cbl pathway (see review in Ref.3). PI3K catalyzes the formation of phosphatidylinositol-3,4,5-trisphosphate, or PIP 3 , an allosteric activator of phosphoinositide-dependent kinase (PDK). Targets of PDK include Akt and the atypical PKC isoforms, which, when activated via phosphorylation, stimulate the translocation of the insulin-responsive glucose transporter (GLUT4)-containing vesicles to the plasma membrane. Phospholipase C-␥1 (PLC-␥1), another downstream target of PI3K in insulin signaling, also facilitates GLUT4 translocation (13,25). Although the relative contributions of PLC-␥1, Akt, and atypical PKCs to GLUT4 translocation remain controversial, studies have demonstrated the necessity of PI3K activity for insulin-stimulated...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

MEK inhibitors impair insulin-stimulated glucose uptake in 3T3-L1 adipocytes

Harmon¹,

Paul²,

Patel³

2004

American Journal of Physiology-Endocrinology and Metabolism

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“…PLC-γ has been reported to be activated and up-regulated in response to external signals [13,15,[40][41][42][43][44] . Most of these previous studies focused on PLC-γ2 phosphorylation and the relevant growth factor receptor(s), but its physiologic function and signaling pathway were rarely concerned.…”

Section: Discussionmentioning

confidence: 99%

“…PLC-γ has been implicated in mitogenic signaling by plateletderived growth factor (PDGF) receptor. Through the pleiotropic actions of IP 3 and DAG, PLC-γ could participate in regulation of cell proliferation and differentiation [13] . PLC-γ overexpression could favor cell survival in response to acute oxidative stress [14,15] .…”

Section: Introductionmentioning

confidence: 99%

Roles of PLC-γ2 and PKCα in TPA-induced apoptosis of gastric cancer cells

Zhang¹,

Wu²,

Ye³

et al. 2003

WJG

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“…Moreover, overexpression of a kinase-deficient mutant of PKC-resulted in a 50% reduction in insulin-stimulated glucose transport (32). We recently reported that the insulin receptor interacts with PLC-␥1 and that the disruption of this interaction blocks GLUT4 translocation (33). Inhibition of phospholipase activity has also been shown to decrease maximal glucose transport in 3T3-L1 cells stimulated by insulin or by epidermal growth factor (EGF) in 3T3-L1 cells overexpressing the EGF receptor (34).…”

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confidence: 99%

Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes.

Kayali¹,

Austin²,

Webster³

2000

Diabetes

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Osmotic shock and insulin stimulate GLUT4 translocation and glucose transport via mechanisms that are for the most part distinct yet convergent. In this article, we investigated the effect of osmotic shock and insulin on the activation of the mitogen-activated protein kinase (MAPK) cascades in differentiated 3T3-L1 adipocytes. The MAPKs are activated by phosphorylation on conserved tyrosine and threonine residues. Both sorbitol and insulin strongly stimulated extracellular regulated kinase (ERK) 1 and 2 phosphorylation (8-and 18-fold, respectively). In contrast, c-jun-NH 2 -terminal kinase (JNK)/stress-activated protein kinase (SAPK) phosphorylation was stimulated only by sorbitol (sevenfold) and not by insulin. Phosphorylation of p38 MAPK was stimulated strongly by sorbitol (22-fold) but weakly by insulin (2.7-fold). Measurement of intrinsic JNK and p38 MAPK activity confirmed the phosphorylation studies. JNK and p38 MAPK were activated only significantly by sorbitol. (1-3). The ERKs are strongly activated by polypeptide growth factors and phorbol esters but are weakly activated by environmental stresses, such as osmotic or heat shock, UV light, and inhibitors of protein synthesis. In contrast, JNK and p38 MAPKs are strongly activated by cytokines and adverse stimuli, but are poorly activated by growth factors.All MAPKs are activated by phosphorylation on both threonine and tyrosine residues within the motif Thr-Xaa-Tyr. The Xaa represents Glu in the ERK subfamily, Pro in the JNK subfamily, and Gly in the p38 MAPK subfamily. Both the threonine and tyrosine residues are phosphorylated by a dualspecificity kinase or MAPK (mitogen-activated ERK-activating kinase [MEK] or MAPK kinase [MKK]). The central residue in the Thr-Xaa-Tyr motif allows for selective activation by different MKKs, such that MEK1 and MEK2 selectively phosphorylate and activate the ERKs; MKK4/SAPK kinase (SEK) 1 and MKK7 phosphorylate and activate JNK; MKK3 and MKK6 phosphorylate and activate p38 MAPK (4-9). Despite the prevailing view of the selectivity of these kinases, a growing body of evidence indicates that these pathways overlap. In a study examining interleukin-1␤-induced cyclooxygenase-2 expression in rat renal mesangial cells, Guan et al. (10) have found that overexpressing the dominant negative form of MKK4 inhibited both JNK and p38 MAPK phosphorylation in their system. This finding indicates that MKK4 can act upstream of p38 in certain systems (10). In another study, the investigators coexpressed p38␦ and MKK3, MKK4, and MKK6 in 293 cells and found that, although MKK3 and MKK6 were the dominant regulators, MKK4 could also phosphorylate p38␦ (11).

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Association of the Insulin Receptor with Phospholipase C-γ (PLCγ) in 3T3-L1 Adipocytes Suggests a Role for PLCγ in Metabolic Signaling by Insulin

Cited by 65 publications

References 92 publications

MEK inhibitors impair insulin-stimulated glucose uptake in 3T3-L1 adipocytes

MEK inhibitors impair insulin-stimulated glucose uptake in 3T3-L1 adipocytes

Roles of PLC-γ2 and PKCα in TPA-induced apoptosis of gastric cancer cells

Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes.

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