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: 4.6). 09/1996; 271(33):19810-6. DOI: 10.1074/jbc.271.33.19810
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The inhibitory effects of three biguanido-oxovanadium complexes ([VO(L(1-3))(2)]·nH(2)O: HL(1) = metformin, HL(2) = phenformin, HL(3) = moroxydine) against four protein tyrosine phosphatases (PTPs) and an alkaline phosphatase (ALP) were investigated. The complexes display strong inhibition against PTP1B and TCPTP (IC(50), 80-160 nM), a bit weaker inhibition against HePTP (IC(50), 190-410 nM) and SHP-1(IC(50), 0.8-3.3 μM) and much weaker inhibition against ALP (IC(50), 17-35 μM). Complex 3 is about twofold less potent against PTP1B, TCPTP and HePTP than complexes 1 and 2, while complex 2 inhibits SHP-1 more strongly (about three to fourfold) than the other two complexes. These results suggest that the structures of the ligands slightly influence the potency and selectivity against PTPs. The complexes inhibit PTP1B and ALP with a typical competitive type.
    Biology of Metals 05/2012; 25(3):599-610. DOI:10.1007/s10534-012-9548-4
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and, often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Resistance training combined with amino acid-containing supplements is often utilized to prevent age-related muscle wasting and weakness. In this review, we summarize more recent therapeutic strategies (myostatin or proteasome inhibition, supplementation with eicosapentaenoic acid (EPA) or ursolic acid, etc.) for counteracting sarcopenia. Myostatin inhibitor is the most advanced research with a Phase I/II trial in muscular dystrophy but does not try the possibility for attenuating sarcopenia. EPA and ursolic acid seem to be effective as therapeutic agents, because they attenuate the degenerative symptoms of muscular dystrophy and cachexic muscle. The activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle by exercise and/or unknown supplementation would be an intriguing approach to attenuating sarcopenia. In contrast, muscle loss with age may not be influenced positively by treatment with a proteasome inhibitor or antioxidant.
    Journal of aging research 01/2012; 2012:251217. DOI:10.1155/2012/251217