Protein-tyrosine Phosphatase 1B Is a Negative Regulator of Insulin- and Insulin-like Growth Factor-I-stimulated Signaling

Department of Physiology, Tulane University Medical Center, New Orleans, Louisiana 70112-2699, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/1996; 271(33):19810-6. DOI: 10.1074/jbc.271.33.19810
Source: PubMed


To understand the physiological role of protein-tyrosine phosphatase 1B (PTPase 1B) in insulin and insulin-like growth factor-I (IGF-I) signaling, we established clonal cell lines overexpressing wild type or inactive mutant (C215S) PTPase 1B in cells overexpressing insulin (Hirc) or IGF-I (CIGFR) receptors. PTPase 1B overexpression in transfected cells was verified by immunoblot analysis with a monoclonal PTPase 1B antibody. Subfractionation of parental cells demonstrated that greater than 90% of PTPase activity was localized in the Triton X-100-soluble particulate (P1) cell fraction. PTPase activity in the P1 fraction of cells overexpressing wild type PTPase 1B was 3-6-fold higher than parental cells but was unaltered in all fractions from C215S PTPase 1B-containing cells. The overexpression of wild type and C215S PTPase 1B had no effects on intrinsic receptor kinase activity, growth rate, or general cell morphology. The effects of PTPase 1B overexpression on cellular protein tyrosine phosphorylation were examined by anti-phosphotyrosine immunoblot analysis. No differences were apparent under basal conditions, but hormone-stimulated receptor autophosphorylation and/or insulin receptor substrate tyrosine phosphorylation were inhibited in cells overexpressing wild type PTPase 1B and increased in cells expressing mutant PTPase 1B, in comparison with parental cells. Metabolic signaling, assessed by ligand-stimulated [14C]glucose incorporation into glycogen, was also inhibited in cells overexpressing active PTPase 1B and enhanced in cells containing C215S PTPase 1B. These data strongly suggest that PTPase 1B acts as a negative regulator of insulin and IGF-I signaling.

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    • "By virtue of these signaling actions insulin regulates glucose homeostasis in the liver, muscle, and adipose tissues by promoting glucose uptake and glycogen synthesis and inhibiting glycogenolysis and gluconeogenesis (Litherland et al., 2001). Several previous studies have suggested that PTP1B is a phosphatase that targets the tyrosine-phosphorylated insulin receptor b and IRS-1 and thereby functions as a negative regulator of insulin signaling (Kenner et al., 1996; Asante-Appiah and Kennedy, 2003). "
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    ABSTRACT: Type-2 diabetes is growing at epidemic proportions and pharmacological interventions are being actively sought. This study examined the effect of a novel neuroprotective curcuminoid, CNB001 [4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl)vinyl)-2- methoxy-phenol), on glucose intolerance and insulin signaling in high fat diet (HFD)-fed mice. C57BL6 mice (5-6 week old) were randomly assigned to receive either a HFD (45% fat) or a low fat diet (LFD, 10% fat) for 24-weeks, together with CNB001 (40mg/kg/d, ip). Glucose tolerance test revealed that that the area under the curve of post-challenge glucose concentration was elevated on HF-feeding, which was attenuated by CNB001. CNB001 attenuated body weight gain, serum triglycerides and IL-6, augmented insulin signaling (elevated p-Akt, p-IRβ, lowered ER-stress, PTP1B) and glucose uptake in gastrocnemius muscle of HFD-fed mice. Respiratory quotient, measured using metabolic chamber, was elevated in HFD-fed mice, which was unaltered by CNB001, although CNB001 treatment resulted in higher energy expenditure. In cultured myotubes, CNB001 reversed palmitate-induced impairment of insulin signaling and glucose-uptake. Docking studies suggest a potential interaction between CNB001 and PTP1B. Taken together, CNB001 alleviates obesity-induced glucose intolerance and represents a potential candidate for further development as an antidiabetic agent.
    Journal of Pharmacology and Experimental Therapeutics 02/2014; 349(2). DOI:10.1124/jpet.113.208728 · 3.97 Impact Factor
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    • "In 1996, Becker and his associates proved the efficacy of sodium selenate in enhancing glucose homeostasis and partly reversing the expression of liver glycolytic and gluconeogenic enzymes in diabetic rats [9]. Recently, many studies have focused particularly on the cytoplasmic phosphatase PTP1B as an important antagonist or negative regulator of insulin signaling owing to its ability to dephosphorylate the insulin receptor substrates (IRSs) 1 and 2 as well as the intracellular β subunit of the insulin receptor [10]. Interestingly; it was found that supranutritional sodium selenate doses can influence PTPs, involved in insulin-resistant DM, which in turn can be assumed as being responsible for the changes in intermediary metabolism such as gluconeogenesis and lipid metabolism [11]. "
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    ABSTRACT: Metformin is widely regarded as the standard first-line antidiabetic agent, in terms of efficacy and safety profiles. However, in most patients with type II diabetes mellitus (T2DM), it was found that metformin alone is not enough to adequately control hyperglycemia. Thus, we designed this study with the aim to investigate the effect of sodium selenate, a protein tyrosine phosphatase (PTP) inhibitor, individually and as an adjunct to metformin, on a rat model that simulates the metabolic characteristics of human T2DM. T2DM model was achieved by feeding the rats with high-fat, high-fructose diet (HFFD) for 8 weeks followed by a low dose of streptozotocin (STZ) (35 mg/kg/day, i.p.). Changes in serum glucose, insulin, adiponectin, homeostasis model assessment of insulin resistance (HOMA-IR) index, and the lipid profile were assessed. In addition, the level of reduced glutathione (GSH) and the activity of PTP were determined in the liver. Results showed that the addition of sodium selenate to metformin was able to restore hepatic GSH back to normal levels. Also, this combination therapy corrected the altered serum total cholesterol (TC), triglycerides (TG), and adiponectin levels. In conclusion, additive therapeutic effect was recorded when sodium selenate was used as an adjunct to metformin.
    09/2013; 2013:231378. DOI:10.1155/2013/231378
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    • "Another possible component of the insulin receptor signaling pathway that could be affected in insulin resistance is PTP1B. PTP1B is the canonical member of protein tyrosine phosphatases and serves an important role in insulin signaling regulation [29]. Overexpression of PTP1B has been linked to insulin resistance in peripheral tissues of ob/ob mice [26] and PTP1B knockout mice display increased insulin sensitivity [48]. "
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    ABSTRACT: Background A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. Results The results indicate that insulin signaling abnormalities documented in other “insulin sensitive” tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. Conclusions These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy.
    05/2013; 1(1). DOI:10.1186/2051-5960-1-15
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