scholarly journals Effect of microinjection of a low-Mr human placenta protein tyrosine phosphatase on induction of meiotic cell division in Xenopus oocytes.

1990 ◽  
Vol 10 (2) ◽  
pp. 458-463 ◽  
Author(s):  
N K Tonks ◽  
M F Cicirelli ◽  
C D Diltz ◽  
E G Krebs ◽  
E H Fischer
Keyword(s):  
Cell Division ◽  
Insulin Receptor ◽  
Human Placenta ◽  
Protein Tyrosine Phosphatase ◽  
Xenopus Oocytes ◽  
Tyrosine Phosphatase ◽  
Meiotic Cell ◽  
Protein Tyrosine ◽  
Endogenous Activity ◽  
Maturation Promoting Factor

Homogeneous preparations of a protein phosphatase that is specific for phosphotyrosyl residues (protein tyrosine phosphatase [PTPase] 1B) were isolated from human placenta and microinjected into Xenopus oocytes. This resulted in an increase in activity of up to 10-fold over control levels, as measured in homogenates with use of an artificial substrate (reduced carboxamidomethylated and maleylated lysozyme). Microinjected PTPase was stable for at least 18 h. It is distributed within the oocyte in a manner similar to the endogenous activity and is suggestive of an interaction with cellular structures or molecules located predominantly in the animal hemisphere. The phosphatase markedly retarded (by up to 5 h) maturation induced by insulin. This, in conjunction with the demonstration that PTPase 1B abolished insulin stimulation of an S6 peptide (RRLSSLRA) kinase concomitant with a decrease in the phosphorylation of tyrosyl residues in a protein with the same apparent Mr as the beta subunit of the insulin and insulinlike growth factor 1 receptors (M. F. Cicirelli, N. K. Tonks, C. D. Diltz, E. H. Fischer, and E. G. Krebs, submitted for publication), provides further support for an essential role of protein tyrosine phosphorylation in insulin action. Furthermore, maturation was significantly retarded even when the PTPase was injected 2 to 4 h after exposure of the cells to insulin. PTPase 1B also retarded maturation induced by progesterone and maturation-promoting factor, which presumably do not act through the insulin receptor. These data point to a second site of action of the PTPase in the pathway of meiotic cell division, downstream of the insulin receptor and following the appearance of active maturation-promoting factor.

Effect of microinjection of a low-Mr human placenta protein tyrosine phosphatase on induction of meiotic cell division in Xenopus oocytes

1990 ◽  
Vol 10 (2) ◽  
pp. 458-463
Author(s):  
N K Tonks ◽  
M F Cicirelli ◽  
C D Diltz ◽  
E G Krebs ◽  
E H Fischer
Keyword(s):  
Cell Division ◽  
Insulin Receptor ◽  
Human Placenta ◽  
Protein Tyrosine Phosphatase ◽  
Xenopus Oocytes ◽  
Tyrosine Phosphatase ◽  
Meiotic Cell ◽  
Protein Tyrosine ◽  
Endogenous Activity ◽  
Maturation Promoting Factor

Homogeneous preparations of a protein phosphatase that is specific for phosphotyrosyl residues (protein tyrosine phosphatase [PTPase] 1B) were isolated from human placenta and microinjected into Xenopus oocytes. This resulted in an increase in activity of up to 10-fold over control levels, as measured in homogenates with use of an artificial substrate (reduced carboxamidomethylated and maleylated lysozyme). Microinjected PTPase was stable for at least 18 h. It is distributed within the oocyte in a manner similar to the endogenous activity and is suggestive of an interaction with cellular structures or molecules located predominantly in the animal hemisphere. The phosphatase markedly retarded (by up to 5 h) maturation induced by insulin. This, in conjunction with the demonstration that PTPase 1B abolished insulin stimulation of an S6 peptide (RRLSSLRA) kinase concomitant with a decrease in the phosphorylation of tyrosyl residues in a protein with the same apparent Mr as the beta subunit of the insulin and insulinlike growth factor 1 receptors (M. F. Cicirelli, N. K. Tonks, C. D. Diltz, E. H. Fischer, and E. G. Krebs, submitted for publication), provides further support for an essential role of protein tyrosine phosphorylation in insulin action. Furthermore, maturation was significantly retarded even when the PTPase was injected 2 to 4 h after exposure of the cells to insulin. PTPase 1B also retarded maturation induced by progesterone and maturation-promoting factor, which presumably do not act through the insulin receptor. These data point to a second site of action of the PTPase in the pathway of meiotic cell division, downstream of the insulin receptor and following the appearance of active maturation-promoting factor.

Potential Inhibitors of Protein Tyrosine Phosphatase (PTP1B) Enzyme: Promising Target for Type-II Diabetes Mellitus

2020 ◽  
Vol 20 (29) ◽  
pp. 2692-2707
Author(s):  
Sisir Nandi ◽  
Mridula Saxena
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Type Ii Diabetes ◽  
Tyrosine Phosphatase ◽  
Type Ii Diabetes Mellitus ◽  
Type Ii ◽  
Insulin Effect ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
Insulin Dependent Diabetic

Background: There has been growing interest in the development of highly potent and selective protein tyrosine phosphatase (PTP1B) inhibitors for the past 2-3 decades. Though most PTPs share a common active site motif, the interest in selective inhibitors, particularly against PTP1B is increasing to discover new chemical entities as antidiabetic agents. In the current paradigm to find potent and selective PTP1B inhibitors, which is currently considered as one of the best validated biological targets for non-insulin-dependent diabetic and obese individuals, resistance to insulin due to decreased sensitivity of the insulin receptor is a pathological factor and is also genetically linked, causing type II diabetes. Objectives: Insulin receptor sensitization is performed by a signal transduction mechanism via a selective protein tyrosine phosphatase (PTP1B). After the interaction of insulin with its receptor, autophosphorylation of the intracellular part of the receptor takes place, turning it into an active kinase (sensitization). PTP1B is involved in the desensitization of the receptor by dephosphorylation. PTP1b inhibitors delay the receptor desensitization, prolonging insulin effect and making PTP1B as a drug target for the treatment of diabetes II. Therefore, it has become a major target for the discovery of potent drugs for the treatment of type II diabetes and obesity. An attempt has been made in the present study to discuss the latest design and discovery of protein tyrosine phosphatase (PTP1B) inhibitors. Methods: Many PTP1B inhibitors such as diaminopyrroloquinazoline, triazines, pyrimido triazine derivatives, 2-(benzylamino)-1-phenylethanol, urea, acetamides and piperazinylpropanols, phenylsulphonamides and phenylcarboxamide, benzamido, arylcarboxylic acid derivatives, arylsupfonyl derivatives, thiazoles, isothiozolidiones and thiazolodinones have been discussed, citing the disease mechanisms. Results: The reader will gain an overview of the structure and biological activity of recently developed PTPs inhibitors. Conclusion: The co-crystallized ligands and the screened inhibitors could be used as a template for the further design of potent congeners.

scholarly journals Regulation of Insulin Receptor Signaling by the Protein Tyrosine Phosphatase TCPTP

2003 ◽  
Vol 23 (6) ◽  
pp. 2096-2108 ◽  
Author(s):  
Sandra Galic ◽  
Manuela Klingler-Hoffmann ◽  
Michelle T. Fodero-Tavoletti ◽  
Michelle A. Puryer ◽  
Tzu-Ching Meng ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Periphery ◽  
Β Subunit ◽  
Insulin Stimulation ◽  
Protein Tyrosine ◽  
Akt Activation ◽  
Insulin Receptor Signaling

ABSTRACT The human protein tyrosine phosphatase TCPTP exists as two forms: an endoplasmic reticulum-targeted 48-kDa form (TC48) and a nuclear 45-kDa form (TC45). Although targeted to the nucleus, TC45 can exit in response to specific stimuli to dephosphorylate cytoplasmic substrates. In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A “substrate-trapping” mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR β-subunit in 293 cells. Moreover, in response to insulin stimulation, the TC45-D182A mutant accumulated in the cytoplasm of cells overexpressing the IR and in part colocalized with the IR β-subunit at the cell periphery. These results indicate that the IR may serve as a cellular substrate for both TC48 and TC45. In immortalized TCPTP−/− murine embryo fibroblasts, insulin-induced IR β-subunit tyrosine phosphorylation and protein kinase PKB/Akt activation were enhanced relative to the values in TCPTP+/+ cells. Importantly, the expression of TC45 or TC48 to physiological levels suppressed the enhanced insulin-induced signaling in TCPTP−/− cells. These results indicate that the differentially localized variants of TCPTP may dephosphorylate the IR and downregulate insulin-induced signaling in vivo.

scholarly journals Interaction of protein tyrosine phosphatase (PTP) 1B with its substrates is influenced by two distinct binding domains

2002 ◽  
Vol 364 (2) ◽  
pp. 377-383 ◽  
Author(s):  
Shrikrishna DADKE ◽  
Jonathan CHERNOFF
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Insulin Signalling ◽  
Tyrosine Phosphatase ◽  
Rich Region ◽  
Protein Tyrosine ◽  
Binding Domains ◽  
C Terminus ◽  
Ptp 1B ◽  
Proline Rich Region

We have shown previously that protein tyrosine phosphatase (PTP) 1B interacts with insulin receptor and negatively regulates insulin signalling by an N-terminal binding domain [Dadke, Kusari and Chernoff (2000) J. Biol. Chem. 275, 23642–23647] and it also negatively regulates integrin signalling through a proline-rich region present in the C-terminus [Liu, Hill and Chernoff (1996) J. Biol. Chem. 271, 31290–31295; Liu, Sells and Chernoff (1998) Curr. Biol. 8, 173–176]. Here we show that PTP1B mutants that are defective in Src homology 3 domain binding fully retain the ability to inhibit insulin signalling, whereas mutants defective in insulin-receptor binding fully retain the ability to inhibit integrin signalling. In contrast, both the C-terminal proline-rich region and the tandem tyrosine residues present in the N-terminal region are required for the activation of Src family kinases. These data show that PTP1B can independently regulate insulin and integrin signals, and that Src might represent a convergence point for regulating signal transduction by this phosphatase.

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