scholarly journals Double Knockouts Reveal that Protein Tyrosine Phosphatase 1B Is a Physiological Target of Calpain-1 in Platelets

2007 ◽  
Vol 27 (17) ◽  
pp. 6038-6052 ◽  
Author(s):  
Shafi M. Kuchay ◽  
Nayoung Kim ◽  
Elizabeth A. Grunz ◽  
William P. Fay ◽  
Athar H. Chishti
Keyword(s):  
Platelet Aggregation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cysteine Proteases ◽  
Arterial Injury ◽  
Protein Tyrosine Phosphatase 1B ◽  
Clot Retraction ◽  
Double Knockout ◽  
Protein Tyrosine

ABSTRACT Calpains are ubiquitous calcium-regulated cysteine proteases that have been implicated in cytoskeletal organization, cell proliferation, apoptosis, cell motility, and hemostasis. Gene targeting was used to evaluate the physiological function of mouse calpain-1 and establish that its inactivation results in reduced platelet aggregation and clot retraction potentially by causing dephosphorylation of platelet proteins. Here, we report that calpain-1 null (Capn1 −/−) platelets accumulate protein tyrosine phosphatase 1B (PTP1B), which correlates with enhanced tyrosine phosphatase activity and dephosphorylation of multiple substrates. Treatment of Capn1 −/− platelets with bis(N,N-dimethylhydroxamido)hydroxooxovanadate, an inhibitor of tyrosine phosphatases, corrected the aggregation defect and recovered impaired clot retraction. More importantly, platelet aggregation, clot retraction, and tyrosine dephosphorylation defects were rescued in the double knockout mice lacking both calpain-1 and PTP1B. Further evaluation of mutant mice by the ferric chloride-induced arterial injury model suggests that the Capn1 −/− mice are relatively resistant to thrombosis in vivo. Together, our results demonstrate that PTP1B is a physiological target of calpain-1 and suggest that a similar mechanism may regulate calpain-1-mediated tyrosine dephosphorylation in other cells.

Double Knockouts Reveal That Protein Tyrosine Phosphatase 1B Is a Physiological Substrate of Calpain-1 in Platelets.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 396-396 ◽  
Author(s):  
Shafi M. Kuchay ◽  
William P. Fay ◽  
Athar H. Chishti
Keyword(s):  
Platelet Aggregation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Wild Type Mouse ◽  
Cysteine Proteases ◽  
Protein Tyrosine Phosphatase 1B ◽  
Dependent Manner ◽  
Wild Type ◽  
Clot Retraction ◽  
Protein Tyrosine

Abstract Calpains are ubiquitous calcium-regulated cysteine proteases that have been implicated in cytoskeletal organization, cell proliferation, apoptosis, cell motility, and hemostasis. Previously we used gene-targeting to evaluate the physiological function of mouse calpain-1, and established that its inactivation results in reduced platelet aggregation and clot retraction, potentially by causing dephosphorylation of platelet proteins. Here, we present data showing that calpain-1 null platelets accumulate protein tyrosine phosphatase 1B (PTP1B) that correlates with enhanced tyrosine phosphatase activity and dephosphorylation of multiple substrates in platelets. Using antibodies specific for phosphotyrosines 747 and 759 of the b3 subunit of αIibβ3 integrin, we show that the tyrosine phosphorylation of both tyrosine residues at positions 747 and 759 in the cytoplasmic domain of b3 subunit is reduced by approximately 60–70% in the calpain-1 null platelets. Treatment of calpain-1 null platelets with DMHV, an inhibitor of tyrosine phosphatases, corrected the aggregation defect and recovered impaired clot retraction. Importantly, platelet aggregation, clot retraction, and tyrosine dephosphorylation defects were rescued in the double knockout mice lacking both calpain-1 and PTP1B. Consistent with this paradigm, treatment of wild type mouse platelets as well as human platelets with the tyrosine phosphatase inhibitor DMHV enhanced their aggregation at low doses of thrombin. Conversely, MDL, a cell permeable inhibitor of calpains, potently inhibited aggregation of wild type mouse platelets in a dose-dependent manner upon thrombin activation. Further evaluation of mutant mice by ferric chloride induced arterial injury model suggests that the calpain-1 null mice are relatively resistant to thrombosis in vivo. Finally, the calpain-1 mediated regulation of PTP1B appears to be a systemic event as evident by the enhanced tyrosine dephosphorylation of B lymphocytes and their resistance to apoptosis in calpain-1 null mice. Together, our results demonstrate that PTP1B is a physiological substrate of calpain-1 and suggest that a similar mechanism may regulate calpain-1 mediated tyrosine dephosphorylation in other cells.

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 Endocytosis mechanism of a novel proteoglycan, extracted from Ganoderma lucidum, in HepG2 cells

RSC Advances ◽  
2017 ◽  
Vol 7 (66) ◽  
pp. 41779-41786 ◽  
Author(s):  
Zhou Yang ◽  
Fan Wu ◽  
Hongjie Yang ◽  
Ping Zhou
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Hepg2 Cells ◽  
Ganoderma Lucidum ◽  
Tyrosine Phosphatase ◽  
Hypoglycemic Effect ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Novel Protein

A novel protein tyrosine phosphatase 1B (PTP1B) inhibitor,FYGL, extracted fromGanoderma lucidum, was first reported to have an efficient hypoglycemic effect and high safetyin vivoin our previous study.

scholarly journals PROTEIN TYROSINE PHOSPHATASE 1B (PTP1B) IN OBESITY AND TYPE 2 DIABETES

2009 ◽  
Vol 38 (1) ◽  
pp. 2-7 ◽  
Author(s):  
Mirela Delibegovic ◽  
Nimesh Mody
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Developed Countries ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
The Developed Countries

Increased incidence in obesity is reaching epidemic proportions and is placing a major burden on the healthcare systems in the developed countries. Obesity is a major risk factor for the development of type 2 diabetes, metabolic syndrome, cardiovascular disease and cancer. Thus, the search for molecules that regulate the development of obesity and its associated pathologies is ongoing. Protein tyrosine phosphatase 1B (PTP1B) has been found to be a major regulator of body fat stores, energy balance, and insulin sensitivity in vivo. Increased expression of PTP1B is associated with insulin resistance in rodents and humans and deletion of PTP1B leads to leanness and insulin sensitivity in rodents, suggesting that PTP1B may be a very attractive molecular target for anti-obesity, anti-diabetic agents.

scholarly journals Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo

2008 ◽  
Vol 283 (21) ◽  
pp. 14230-14241 ◽  
Author(s):  
Janice M. Zabolotny ◽  
Young-Bum Kim ◽  
Laura A. Welsh ◽  
Erin E. Kershaw ◽  
Benjamin G. Neel ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine

Design, synthesis and biological evaluation of 3-(2-(benzo[d]thiazol-2- ylthio)acetamido)benzoic acid derivatives as inhibitors of protein tyrosine phosphatase 1B

2020 ◽  
Vol 17 ◽  
Author(s):  
Monika Rakse ◽  
Chandrabose Karthikeyan ◽  
Narayana Subbiah Hari Narayana Moorthy ◽  
Ram Kishore Agrawal
Keyword(s):  
Benzoic Acid ◽  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Tyrosine Phosphatase ◽  
Docking Studies ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Benzoic Acid Derivatives

Background: Protein Tyrosine Phosphatase 1B (PTP1B) is an attractive target for antidiabetic drug discovery owing to its pivotal role as a negative regulator of insulin and leptin signaling. Objective: The objective of this research is to design, synthesize, and evaluate some acetamido benzoic acid derivatives as a novel class of protein tyrosine phosphatase 1B inhibitors with therapeutic potential for Type II diabetes. Methods: 3-(2-(benzo[d]thiazol-2-ylthio)acetamido)benzoic acid derivatives 4(a-j) were synthesized and characterized by employing spectral studies. All the synthesized compounds were screened for in vitro PTP1B inhibitory activity and the most potent compound in the series was also evaluated for in vivo anti-hyperglycemic activity using STZ induced diabetic Wistar rat model. Molecular docking studies were also performed with the most potent analog using FlexX docking algorithm to delineate its binding mode to the active site of the PTP1B. Results and Discussion: Among all the synthesized compounds, 3-(2-(benzo[d]thiazol-2-ylthio)acetamido)-4- methylbenzoic acid (4f) displayed good PTP1B inhibitory activity with an IC50 value of 11.17 μM. The compound also exhibited good anti-hyperglycemic efficacy in streptozotocin induced diabetic Wistar rats. Docking studies with 4f revealed the compound bound in the catalytic and second aryl binding site of the PTP1B. Conclusion: Overall, compound 4f with good in vitro PTP1B inhibitory potency and in vivo antihyperglycemic efficacy would be a valuable lead molecule for the development of acetamido benzoic acid based PTP1B inhibitors with antidiabetic potential.

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