Self-Organizing Molecular Field Analysis on Pyridazine Analogues as Protein Tyrosine Phosphatase 1B (PTP 1B) Inhibitors

2010 ◽  
Vol 7 (6) ◽  
pp. 395-401 ◽  
Author(s):  
Suresh Thareja ◽  
Saurabh Aggarwal ◽  
Tilak Raj Bhardwaj ◽  
Manoj Kumar
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Field Analysis ◽  
Molecular Field ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Molecular Field Analysis ◽  
Ptp 1B ◽  
Self Organizing

scholarly journals Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice

2000 ◽  
Vol 20 (15) ◽  
pp. 5479-5489 ◽  
Author(s):  
Lori D. Klaman ◽  
Olivier Boss ◽  
Odile D. Peroni ◽  
Jason K. Kim ◽  
Jennifer L. Martino ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B ◽  
Tissue Specific ◽  
Protein Tyrosine ◽  
Ptp 1B ◽  
Deficient Mice

ABSTRACT Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.

scholarly journals Protein Tyrosine Phosphatase 1B Attenuates Growth Hormone-Mediated JAK2-STAT Signaling

2003 ◽  
Vol 23 (11) ◽  
pp. 3753-3762 ◽  
Author(s):  
Feng Gu ◽  
Nadia Dubé ◽  
Jin Wook Kim ◽  
Alan Cheng ◽  
Maria de Jesus Ibarra-Sanchez ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cytokine Signaling ◽  
Tyrosine Kinase Domain ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ptp 1B

ABSTRACT Protein tyrosine phosphatase-1B (PTP-1B) attenuates insulin, PDGF, EGF, and IGF-I signaling by dephosphorylating tyrosine residues located in the tyrosine kinase domain of the corresponding receptors. More recently, PTP-1B was shown to modulate the action of cytokine signaling via the nonreceptor tyrosine kinase JAK2. Transmission of the growth hormone (GH) signal also depends on JAK2, raising the possibility that PTP-1B modulates GH action. Consistent with this hypothesis, GH increased the abundance of tyrosine-phosphorylated JAK2 associated with a catalytically inactive mutant of PTP-1B. GH-induced JAK2 phosphorylation was greater in knockout (KO) than in wild-type (WT) PTP-1B embryonic fibroblasts and resulted in increased tyrosine phosphorylation of STAT3 and STAT5, while overexpression of PTP-1B reduced the GH-mediated activation of the acid-labile subunit gene. To evaluate the in vivo relevance of these observations, mice were injected with GH under fed and fasted conditions. As expected, tyrosine phosphorylation of JAK2 and STAT5 occurred readily in the livers of fed WT mice and was almost completely abolished during fasting. In contrast, resistance to the action of GH was severely impaired in the livers of fasted KO mice. These results indicate that PTP-1B regulates GH signaling by reducing the extent of JAK2 phosphorylation and suggest that PTP-1B is essential for limiting the action of GH during metabolic stress such as fasting.

Sign in / Sign up

Export Citation Format

Share Document