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.

scholarly journals Protein tyrosine phosphatases and signalling

2005 ◽  
Vol 185 (1) ◽  
pp. 19-33 ◽  
Author(s):  
Andrew W Stoker
Keyword(s):  
Tyrosine Kinases ◽  
Current Knowledge ◽  
Insulin Signalling ◽  
Cell Signalling ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Kinases ◽  
Tyrosine Phosphatases ◽  
Large Protein ◽  
Protein Tyrosine ◽  
Wide Range

A cornerstone of many cell-signalling events rests on reversible phosphorylation of tyrosine residues on proteins. The reversibility relies on the coordinated actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), both of which exist as large protein families. This review focuses on the rapidly evolving field of the PTPs. We now know that rather than simply scavenging phosphotyrosine, the PTPs specifically regulate a wide range of signalling pathways. To illustrate this and to highlight current areas of agreement and contention in the field, this review will present our understanding of PTP action in selected areas and will present current knowledge surrounding the regulatory mechanisms that control PTP enzymes themselves. It will be seen that PTPs control diverse processes such as focal adhesion dynamics, cell–cell adhesion and insulin signalling, and their own actions are in turn regulated by dimerisation, phosphorylation and reversible oxidation.

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 Differential regulation of the dual-specificity protein-tyrosine phosphatases CL100, B23, and PAC1 in mesangial cells.

1997 ◽  
Vol 8 (1) ◽  
pp. 40-50
Author(s):  
D Bokemeyer ◽  
A Sorokin ◽  
M J Dunn
Keyword(s):  
Map Kinase ◽  
Intracellular Signaling ◽  
Map Kinases ◽  
Mesangial Cells ◽  
Feedback Inhibition ◽  
Protein Tyrosine Phosphatases ◽  
P38 Map Kinase ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Dual Specificity

The extracellular-signal-regulated kinase (ERK), the best described MAP kinase cascade, is a major signaling system by which cells transduce extracellular cues into intracellular responses. ERK is activated by phosphorylation both on tyrosine and threonine residues. Therefore, a new clas of protein-tyrosine phosphatases (PTPases) that exhibit dual catalytic activity toward both regulatory sites on ERK is of special interest in the control of intracellular signaling. This study examined the expression and regulation of the dual-specificity PTPases CL100, B23, and PAC1. Findings included differential expression of these phosphatases in diverse cell lines and an expression of all three dual-specificity PTPases in human mesangial cells (HMC), thereby allowing investigation of their regulation in a single cell line. The MEK antagonist PD 098059 and selective extracellular agonists of ERK were used to demonstrate the induction of CL100, PAC1, and B23 in response to activation of the ERK cascade. In contrast, anisomycin, an agonist of the recently described MAP kinases stress-activated protein kinase (SAPK) and p38 MAP kinase, stimulated CL100 gene expression but had little effect on PAC1 and B23. This effect of anisomycin was partly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. This study suggests a potential mechanism to regulate ERK activity through feedback inhibition by demonstrating the ERK cascade's induction of the dual-specificity PTPases CL100, PAC1, and B23. Moreover, this study suggests an ERK-independent induction of CL100 following stimulation of SAPK and p38 MAP kinase. This mode of induction of a phosphatase capable of inactivating ERK may play an important role in the cellular stress response.

Physiological Signaling Specificity by Protein Tyrosine Phosphatases

Physiology ◽  
2009 ◽  
Vol 24 (5) ◽  
pp. 281-289 ◽  
Author(s):  
Matthew Soulsby ◽  
Anton M. Bennett
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Physiological Responses ◽  
Cell Movement ◽  
Protein Tyrosine Phosphatases ◽  
Biological Processes ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Signaling Specificity

Protein tyrosine phosphatases (PTPs) are now recognized to be involved in a multitude of signaling events that control fundamental biological processes such as cell growth, differentiation, apoptosis, and cell movement. PTPs, which were initially thought to be less discriminating in their actions compared with their protein tyrosine kinase counterparts, are now known to regulate these various biological processes in a precise manner. This review will focus on the concept that PTPs exhibit remarkable signaling specificity through intrinsic differences between their PTP domains and through various modes of regulation that endows them with the capacity to promote unique physiological responses.

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.

Sign in / Sign up

Export Citation Format

Share Document