scholarly journals Expression and Function of IA-2 Family Proteins, Unique Neuroendocrine-specific Protein-tyrosine Phosphatases

2009 ◽  
Vol 56 (5) ◽  
pp. 639-648 ◽  
Author(s):  
Seiji TORII
Keyword(s):  
Protein Tyrosine Phosphatases ◽  
Specific Protein ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
And Function

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.

scholarly journals Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function

Blood ◽  
2013 ◽  
Vol 121 (20) ◽  
pp. 4205-4220 ◽  
Author(s):  
Alexandra Mazharian ◽  
Jun Mori ◽  
Ying-Jie Wang ◽  
Silke Heising ◽  
Benjamin G. Neel ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Platelet Production ◽  
Protein Tyrosine ◽  
Key Points ◽  
And Function ◽  
Specific Deletion

Key Points The protein-tyrosine phosphatases Shp1 and Shp2 are critical regulators of megakaryocyte development, platelet production, and function. Shp1 and Shp2 perform mainly distinct functions in megakaryocytes and platelets, with little functional overlap.

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.

Alterations in specific protein-tyrosine phosphatases accompany insulin resistance of streptozotocin diabetes

1995 ◽  
Vol 268 (5) ◽  
pp. E932-E940 ◽  
Author(s):  
F. Ahmad ◽  
B. J. Goldstein
Keyword(s):  
Insulin Resistance ◽  
Insulin Treatment ◽  
Protein Tyrosine Phosphatases ◽  
Streptozotocin Diabetes ◽  
Specific Protein ◽  
Particulate Fraction ◽  
Northern Analysis ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Ptpase Activity

To test whether protein tyrosine phosphatases (PTPases) may play a role in the insulin resistance of insulinopenic diabetes, we assessed PTPase activity as well as the protein and mRNA abundance of three major candidate PTPases in subcellular fractions of liver and skeletal muscle of streptozotocin-diabetic rats before and after insulin treatment. PTPase activity against the insulin receptor in liver and muscle cytosol increased to 120-125% of control in the diabetic animals and by an additional 5-10% after insulin treatment. In the particulate fraction, PTPase activity decreased to 65-70% of control in diabetic liver and muscle and increased to 115-120% of control after insulin treatment. Protein for the leukocyte common antigen-related PTPase paralleled the changes in the PTPase activity in the particulate fraction. SH-PTP2/syp and PTPase 1B were both significantly increased in diabetes. SH-PTP2/syp also exhibited an increased ratio of particulate to cytosol distribution in diabetic tissues (1.8-1.9) that was reversed after insulin treatment (0.79-0.95). Northern analysis suggested that the PTPases were regulated at a pretranslational level. These changes in the abundance and distribution of specific PTPases may be involved in the pathogenesis of insulin resistance in insulinopenic diabetes.

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