GTP‐binding protein‐activator sequences in the insulin receptor

Okamoto, Toshimi; Okamoto, Takashi; Murayama, Yoshitake; Hayashi, Yujiro; Ogata, Etsuro; Nishimoto, Ikuo

doi:10.1016/0014-5793(93)81700-a

Cited by 33 publications

(17 citation statements)

References 48 publications

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“…Similar co-precipitation of the insulin receptor with G s , G␣ i2 , and G␤␥ has been observed, along with insulin-dependent GTP-loading of G␣ i2 in adipocyte membranes (25). Three purified peptides derived from sequences in the insulin receptor ␤ subunit have been shown to accelerate GTP exchange on purified heterotrimeric G proteins in vitro (33), although this result has not been reproduced with the intact receptor. Two of these peptides contain sites of tyrosine autophosphorylation, and the one corresponding to residues 1325-1345 of the receptor activates G i/o only when tyrosine is phosphorylated.…”

Section: Discussionmentioning

confidence: 71%

“…The first proposal is that the receptors possess the ability to directly catalyze heterotrimeric G protein guanine nucleotide exchange (32). Consistent with this, several groups have reported that heterotrimeric G protein subunits co-precipitate with the IGF-1 and insulin receptors (22,23,25) or have demonstrated that small peptides derived from the insulin and IGF-2 receptors promote a mastoparan-like acceleration of GTP exchange on purified heterotrimeric G proteins in vitro (31,(33)(34)(35). The second model advanced to explain heterotrimeric G protein-dependent signaling by non-GPCRs is that the receptors generate some signal that activates an endogenous GPCR, which in turn catalyzes G protein activation.…”

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confidence: 94%

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Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors

El‐Shewy¹,

Johnson²,

Lee³

et al. 2006

J. Biol. Chem.

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Although several studies have shown that a subset of insulin-like growth factor (IGF) signals require the activation of heterotrimeric G proteins, the molecular mechanisms underlying IGF-stimulated G protein signaling remain poorly understood. Here, we have studied the mechanism by which endogenous IGF receptors activate the ERK1/2 mitogen-activated protein kinase cascade in HEK293 cells. In these cells, treatment with pertussis toxin and expression of a G␣ q/11 -(305-359) peptide that inhibits G q/11 signaling additively inhibited IGF-stimulated ERK1/2 activation, indicating that the signal was almost completely G protein-dependent. Treatment with IGF-1 or IGF-2 promoted translocation of green fluorescent protein (GFP)-tagged sphingosine kinase (SK) 1 from the cytosol to the plasma membrane, increased endogenous SK activity within 30 s of stimulation, and caused a statistically significant increase in intracellular and extracellular sphingosine 1-phosphate (S1P) concentration. Using a GFP-tagged S1P 1 receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that IGF-1 and IGF-2 induced GFP-S1P receptor internalization and that the effect was blocked by pretreatment with the SK inhibitor, dimethylsphingosine. Treating cells with dimethylsphingosine, silencing SK1 expression by RNA interference, and blocking endogenous S1P receptors with the competitive antagonist VPC23019 all significantly inhibited IGF-stimulated ERK1/2 activation, suggesting that IGFs elicit G protein-dependent ERK1/2 activation by stimulating SK1-dependent transactivation of S1P receptors. Given the ubiquity of SK and S1P receptor expression, S1P receptor transactivation may represent a general mechanism for G protein-dependent signaling by non-G protein-coupled receptors.The insulin-like growth factors type 1 and 2 (IGF-1 and -2) 2 are single chain polypeptides that share structural homology with proinsulin. The actions of IGF-1 and IGF-2 are mediated by binding to two structurally distinct plasma membrane receptors, referred to as the IGF-1 and IGF-2/mannose 6-phosphate (M6P) receptors. Most of the metabolic and mitogenic effects of IGF-1 and IGF-2 are thought to result from binding to the IGF-1 receptor, a receptor tyrosine kinase with structural homology to the insulin receptor. It is composed of two extracellular ␣ subunits and two transmembrane ␤ subunits linked by disulfide bonds (1, 2). Ligand binding to the ␣ subunits activates the intrinsic ␤ subunit receptor tyrosine kinase activity, leading to tyrosine phosphorylation of adapter proteins, such as insulin receptor substrate 1 (IRS-1) and Shc and Gab1 (3-6). Subsequent src homology 2 or protein tyrosine-binding domaindependent recruitment of enzymes with phospholipase, phosphatase, and protein and lipid kinase activity transmits signals intracellularly, including activation of the mitogenic Ras cascade and initiation of phosphatidylinositol 3-kinase (PI3K)/Aktdependent cell survival. Adding to the diversity, in some cell types IGF-1 stimula...

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 94%

Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors

El‐Shewy¹,

Johnson²,

Lee³

et al. 2006

J. Biol. Chem.

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“…One possibility might involve the phosphorylation of G i by the PDGFR kinase, although there is no evidence to support this. Others have shown that peptides derived from another growth-factor receptor, insulin-receptor β subunit, activate G i in lipid vesicles [19], suggesting direct protein-protein interaction. Direct interaction between growth-factor receptors and G-proteins has been demonstrated [20][21][22].…”

Section: Role Of C-srcmentioning

confidence: 99%

Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase

Conway

Rakhit

Pyne

et al. 1999

Biochemical Journal

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The mechanism used by the platelet-derived growth factor receptor (PDGFR) to activate the mitogen-activated-proteinkinase (p42\p44 MAPK) pathway was investigated in cultured airway smooth muscle (ASM) cells. We have found that pertussis toxin (PTX, which was used to inactivate the heterotrimeric Gprotein G i ) induced an approx. 40-50 % decrease in the activation of c-Src and p42\p44 MAPK by PDGF. An essential role for c-Src was confirmed using the c-Src inhibitor, PP1, which abolished p42\p44 MAPK activation (PP1 and PTX were without effect on PDGFR tyrosine phosphorylation). Furthermore, the PTX-dependent decrease in c-Src and p42\p44 MAPK activation appeared correlated. These findings suggest that the PDGFR can utilize the PTX-sensitive G-protein, G i , to regulate c-Src and subsequent p42\p44 MAPK activation. Phosphoinositide 3-kinase (PI3K) has been shown by others to be involved in p42\p44 MAPK activation. This is confirmed here

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“…The insulin-like growth factor II receptor has a single transmembrane domain and couples directly to G i2 in a manner similar to that of conventional G-protein-coupled receptors (7). Studies have been reported suggesting that the insulin receptor binds G i ␣ 2 (8,9).…”

mentioning

confidence: 99%

IRS-1 Mediates Inhibition of Ca2+ Mobilization by Insulin via the Inhibitory G-protein Gi

Ferreira

Eybrechts

Mocking

et al. 2004

Journal of Biological Chemistry

103

116

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Patients with diabetes mellitus have a 2-4-fold increased risk for coronary artery disease. They suffer from both microvascular (nephropathy and retinopathy) and macrovascular (peripheral artery disease) complications (1). Apart from increased concentrations of certain coagulation factors (2), patients with diabetes mellitus type I and II have platelets that show increased adhesion, aggregation, thromboxane production, and P-selectin expression (3). The hyperactivity might be caused by the absence of insulin inhibition, since intensive insulin treatment in diabetic patients reduced platelet aggregation (4).The insulin receptor is a heterotetrameric transmembrane glycoprotein composed of two extracellular ␣ subunits (135 kDa each) and two transmembrane ␤ subunits (95 kDa each) that function as allosteric enzymes in which the ␣ subunit inhibits the tyrosine kinase activity of the ␤ subunit. Insulin binding to the ␣ subunit relieves the inhibition of the kinase activity in the ␤ subunit leading to autophosphorylation of the ␤ subunits and a conformational change that further increases the kinase activity. The insulin receptor tyrosine kinase phosphorylates proteins such as Shc and the insulin receptor substrates IRS-1 (165-185 kDa) and . IRS-1 and IRS-2 have a highly conserved amino terminus, which contains a pleckstrin homology domain, a phosphotyrosine binding domain, and a carboxyl terminus with several tyrosine phosphorylation sites. IRS-1 and IRS-2 are complementary and act as "docking sites" to several Src homology 2 domains containing proteins, such as the regulatory subunits of phosphatidylinositol 3-kinase (PI3K) 1 (5). GTP-binding proteins (G-proteins) can also act as signal transducers for the insulin receptor. G-proteins are guanine nucleotide-binding regulatory proteins that function as molecular switches between a GTP-bound "on state" and a GDPbound "off state." These proteins amplify, transmit, and integrate signals. The major G-proteins involved in platelet aggregation and secretion are G q ␣, which mediates increases in cytosolic Ca 2ϩ concentration, [Ca 2ϩ ] i , and G i ␣, which inhibits adenylyl cyclase thereby suppressing cAMP that is an inhibitor of platelets (6). Receptors that couple to G-proteins are generally seven-transmembrane proteins, but there are important exceptions. The insulin-like growth factor II receptor has a single transmembrane domain and couples directly to G i2 in a manner similar to that of conventional G-protein-coupled receptors (7). Studies have been reported suggesting that the insulin receptor binds G i ␣ 2 (8, 9).The insulin receptor is present on muscle, liver, and adipose tissue but also on endothelial cells, lymphocytes, erythrocytes, and platelets. A human platelet contains ϳ570 insulin receptors (10). Insulin binding induces phosphorylation of the ␤ subunits (11,12), demonstrating that the receptor is func-

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GTP‐binding protein‐activator sequences in the insulin receptor

Cited by 33 publications

References 48 publications

Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors

Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors

Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase

IRS-1 Mediates Inhibition of Ca2+ Mobilization by Insulin via the Inhibitory G-protein Gi

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