Enhancement of post-receptor insulin signaling by trivalent chromium in hepatoma cells is associated with differential inhibition of specific protein-tyrosine phosphatases

2001 ◽  
Vol 14 (4) ◽  
pp. 393-404 ◽  
Author(s):  
Barry J. Goldstein ◽  
Li Zhu ◽  
Richard Hager ◽  
Assaf Zilbering ◽  
Yanjie Sun ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Protein Tyrosine Phosphatases ◽  
Specific Protein ◽  
Hepatoma Cells ◽  
Trivalent Chromium ◽  
Differential Inhibition ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine

scholarly journals Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases

2006 ◽  
Vol 395 (3) ◽  
pp. 483-491 ◽  
Author(s):  
Jeyanthy Eswaran ◽  
Jens Peter von Kries ◽  
Brian Marsden ◽  
Emma Longman ◽  
Judit É. Debreczeni ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Phosphorylation Site ◽  
Protein Tyrosine Phosphatases ◽  
Salt Bridge ◽  
Specific Protein ◽  
Tyrosine Phosphatases ◽  
Selective Inhibitors ◽  
Crystal Forms ◽  
Protein Tyrosine ◽  
Mitogen Activated Protein

Protein tyrosine phosphatases PTPN5, PTPRR and PTPN7 comprise a family of phosphatases that specifically inactivate MAPKs (mitogen-activated protein kinases). We have determined high-resolution structures of all of the human family members, screened them against a library of 24000 compounds and identified two classes of inhibitors, cyclopenta[c]quinolinecarboxylic acids and 2,5-dimethylpyrrolyl benzoic acids. Comparative structural analysis revealed significant differences within this conserved family that could be explored for the design of selective inhibitors. PTPN5 crystallized, in two distinct crystal forms, with a sulphate ion in close proximity to the active site and the WPD (Trp-Pro-Asp) loop in a unique conformation, not seen in other PTPs, ending in a 310-helix. In the PTPN7 structure, the WPD loop was in the closed conformation and part of the KIM (kinase-interaction motif) was visible, which forms an N-terminal aliphatic helix with the phosphorylation site Thr66 in an accessible position. The WPD loop of PTPRR was open; however, in contrast with the structure of its mouse homologue, PTPSL, a salt bridge between the conserved lysine and aspartate residues, which has been postulated to confer a more rigid loop structure, thereby modulating activity in PTPSL, does not form in PTPRR. One of the identified inhibitor scaffolds, cyclopenta[c]quinoline, was docked successfully into PTPRR, suggesting several possibilities for hit expansion. The determined structures together with the established SAR (structure–activity relationship) propose new avenues for the development of selective inhibitors that may have therapeutic potential for treating neurodegenerative diseases in the case of PTPRR or acute myeloblastic leukaemia targeting PTPN7.

Modulation of insulin signaling by protein tyrosine phosphatases

2000 ◽  
Vol 78 (9) ◽  
pp. 473-482 ◽  
Author(s):  
Mounib Elchebly ◽  
Alan Cheng ◽  
Michel L. Tremblay
Keyword(s):  
Insulin Signaling ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine

scholarly journals S -nitrosylation of endogenous protein tyrosine phosphatases in endothelial insulin signaling

2016 ◽  
Vol 99 ◽  
pp. 199-213 ◽  
Author(s):  
Ming-Fo Hsu ◽  
Kuan-Ting Pan ◽  
Fan-Yu Chang ◽  
Kay-Hooi Khoo ◽  
Henning Urlaub ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Endogenous Protein

Protein tyrosine phosphatases: the quest for negative regulators of insulin action

2003 ◽  
Vol 284 (4) ◽  
pp. E663-E670 ◽  
Author(s):  
Ernest Asante-Appiah ◽  
Brian P. Kennedy
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Fed State ◽  
Protein Tyrosine

Type 2 diabetes is increasing at an alarming rate worldwide, and there has been a considerable effort in several laboratories to identify suitable targets for the design of drugs against the disease. To this end, the protein tyrosine phosphatases that attenuate insulin signaling by dephosphorylating the insulin receptor (IR) have been actively pursued. This is because inhibiting the phosphatases would be expected to prolong insulin signaling and thereby facilitate glucose uptake and, presumably, result in a lowering of blood glucose. Targeting the IR protein tyrosine phosphatase, therefore, has the potential to be a significant disease-modifying strategy. Several protein tyrosine phosphatases (PTPs) have been implicated in the dephosphorylation of the IR. These phosphatases include PTPα, LAR, CD45, PTPε, SHP2, and PTP1B. In most cases, there is evidence for and against the involvement of the phosphatases in insulin signaling. The most convincing data, however, support a critical role for PTP1B in insulin action. PTP1B knockout mice are not only insulin sensitive but also maintain euglycemia (in the fed state), with one-half the level of insulin observed in wild-type littermates. Interestingly, these mice are also resistant to diet-induced obesity when fed a high-fat diet. The insulin-sensitive phenotype of the PTP1B knockout mouse is reproduced when the phosphatase is also knocked down with an antisense oligonucleotide in obese mice. Thus PTP1B appears to be a very attractive candidate for the design of drugs for type 2 diabetes and obesity.

scholarly journals Protein Tyrosine Phosphatases in Neuroblastoma: Emerging Roles as Biomarkers and Therapeutic Targets

2021 ◽  
Vol 9 ◽  
Author(s):  
Caroline E. Nunes-Xavier ◽  
Laura Zaldumbide ◽  
Lorena Mosteiro ◽  
Ricardo López-Almaraz ◽  
Nagore García de Andoin ◽  
...  
Keyword(s):  
Cell Growth ◽  
Intracellular Signaling ◽  
Current Knowledge ◽  
Neuroblastoma Cell ◽  
Protein Tyrosine Phosphatases ◽  
Specific Protein ◽  
Neuroendocrine Cells ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Incidence And Mortality

Neuroblastoma is a type of cancer intimately related with early development and differentiation of neuroendocrine cells, and constitutes one of the pediatric cancers with higher incidence and mortality. Protein tyrosine phosphatases (PTPs) are key regulators of cell growth and differentiation by their direct effect on tyrosine dephosphorylation of specific protein substrates, exerting major functions in the modulation of intracellular signaling during neuron development in response to external cues driving cell proliferation, survival, and differentiation. We review here the current knowledge on the role of PTPs in neuroblastoma cell growth, survival, and differentiation. The potential of PTPs as biomarkers and molecular targets for inhibition in neuroblastoma therapies is discussed.

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