Pertussis toxin inhibits autophosphorylation and activation of the insulin receptor kinase

Müller‐Wieland, Dirk; White, Morris F.; Behnke, B.; Gebhardt, Angelika; Neumann, Sandra; Krone, Wilhelm; Kahn, C. Ronald

doi:10.1016/0006-291x(91)92106-t

Cited by 22 publications

(18 citation statements)

References 23 publications

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“…In an insightful recent study using human adipocyte plasma membranes and recombinant protein components in an incubation buffer lacking added MnCl 2 , this group demonstrated that insulin stimulation led to protein association between G␣i2 and the insulin receptor (128). Furthermore, insulin receptor autophosphorylation was stimulated by activated G␣i2 and blocked by pretreatment with pertussis toxin, consistent with an earlier study in Fao hepatoma cells (129). A recent report also linked the attenuation of platelet activation by insulin with both tyrosine phosphorylation of G␣i2 and complex formation between IRS-1 and G␣i2, but not other G␣ subunits (130).…”

Section: Potential Role Of G-proteins In Insulin-stimulated H 2 O 2 Asupporting

confidence: 75%

Redox Paradox

2005

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Propelled by the identification of a small family of NADPH oxidase (Nox) enzyme homologs that produce superoxide in response to cellular stimulation with various growth factors, renewed interest has been generated in characterizing the signaling effects of reactive oxygen species (ROS) in relation to insulin action. Two key observations made >30 years ago-that oxidants can facilitate or mimic insulin action and that H 2 O 2 is generated in response to insulin stimulation of its target cells-have led to the hypothesis that ROS may serve as second messengers in the insulin action cascade. Specific molecular targets of insulin-induced ROS include enzymes whose signaling activity is modified via oxidative biochemical reactions, leading to enhanced insulin signal transduction. These positive responses to cellular ROS may seem "paradoxical" because chronic exposure to relatively high levels of ROS have also been associated with functional ␤-cell impairment and the chronic complications of diabetes. The best-characterized molecular targets of ROS are the protein-tyrosine phosphatases (PTPs) because these important signaling enzymes require a reduced form of a critical cysteine residue for catalytic activity. PTPs normally serve as negative regulators of insulin action via the dephosphorylation of the insulin receptor and its tyrosinephosphorylated cellular substrates. However, ROS can rapidly oxidize the catalytic cysteine of target PTPs, effectively blocking their enzyme activity and reversing their inhibitory effect on insulin signaling. Among the cloned Nox homologs, we have recently provided evidence that Nox4 may mediate the insulin-stimulated generation of cellular ROS and is coupled to insulin action via the oxidative inhibition of PTP1B, a PTP known to be a major regulator of the insulin signaling cascade. Further characterization of the molecular components of this novel signaling cascade, including the mechanism of ROS generated by insulin and the identification of various oxidation-sensitive signaling targets in insulin-sensitive cells, may provide a novel means of facilitating insulin action in states of insulin resistance.

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Section: Potential Role Of G-proteins In Insulin-stimulated H 2 O 2 Asupporting

confidence: 75%

Redox Paradox

2005

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“…Given that the GNB3 825C>T polymorphism has been shown to be associated with enhanced G protein activation in vitro [1], there may be a relationship between this polymorphism and type 2 diabetes (attributable to insulin resistance). Furthermore, insulin action and effect on glucose transport partly depends on a G protein-sensitive mechanism [53,54]. However, we did not observe any association between the GNB3 825C>T polymorphism and quantitative traits relating to insulin resistance and/or action (Table 3).…”

Section: Discussioncontrasting

confidence: 54%

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes

et al. 2005

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Aims/hypothesis: The 825C>T polymorphism in the gene encoding the G protein β3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation. This polymorphism is also repeatedly associated with an increased risk of hypertension and has been studied in relation to obesity with divergent results. Only a few association studies have investigated whether this polymorphism is related to type 2 diabetes or the metabolic syndrome. We estimated the impact of the GNB3 825C>T polymorphism in relatively large-scale association studies of common phenotypes of the metabolic syndrome. Materials and methods: The GNB3 825C>T polymorphism was genotyped in 7,518 white Danish subjects using mass spectrometry analysis of PCR products. Case-control studies were undertaken for obesity, hypertension, type 2 diabetes and the metabolic syndrome, and a meta-analysis including data from the present study and previous studies of hypertension was performed. Quantitative trait studies of metabolic variables were carried out in 4,387 glucose-tolerant subjects. Results: We observed minor differences in 825C>T genotype distributions for type 2 diabetes (CC/CT/TT 49/41/10% (control) vs 46/46/9% (cases), respectively, p=0.007); however, after correction for multiple testing, these were not statistically significant. No association was found with hypertension, obesity or the metabolic syndrome. Curiously, the T allele was associated with nominally lower systolic and diastolic blood pressure levels-a finding in contrast with most previous studies-but not with other metabolic variables. Meta-analysis demonstrated a high degree of heterogeneity between study populations of different ethnic origin. Although there was a tendency towards an increased risk of hypertension among 825T allele carriers, this was not statistically significant. Conclusions/interpretation: The present study suggests no major involvement of the GNB3 825C>T polymorphism in components of the metabolic syndrome.

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“…In the latter case, the situation may be even more complex. Thus, GTP-binding proteins have been suggested to be involved in insulin signalling both at the receptor [9,13,24] and the post-receptor level [7,14,25]. The identity of the G-proteins and the functional implications, however, remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Regulation of cardiac insulin receptor function by guanosine nucleotides

1992

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The present study e.~amined the elTcct of [s-~S]GTP on the funct[ot~ of insulin receptors partially purified from adult rat eardiomyoeytes by WGA chromatography, [~'~S]GTP increased receptor autophosphorylation about two times and fully mimicked the stimulatory action of insulha on poly(Glu:Tyr) phosphorylatlon with no additional effect of the hormone. The effect of ["~S]GTP was specific, dose.dependent, and due to an increase in the Vm,,~ of the kinase. In the presence of ATP or AMP-PNP, insulin significantly enhanced the binding of [~SS]GTP to the partially purified insulin receptor. The findings suggest coupling of the insuli,a receptor to a G-protein which may be involved in the regulation of tyrosine klnase activity, Isolated cardiac myocyte; lnstdin receptor; Guanosine nucleotide binding protein; Tyrosine kinase

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Pertussis toxin inhibits autophosphorylation and activation of the insulin receptor kinase

Cited by 22 publications

References 23 publications

Redox Paradox

Redox Paradox

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes

Regulation of cardiac insulin receptor function by guanosine nucleotides

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