Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

An appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and maintain cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportuniti...

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Published in:Chemical reviews Vol. 118; no. 3; pp. 1069 - 1091
Main Authors: Yu, Zhi-Hong, Zhang, Zhong-Yin
Format: Journal Article
Language:English
Published: United States American Chemical Society 14-02-2018
Subjects:
Allosteric Regulation
Animals
Cells
Dual Specificity Phosphatase 6 - antagonists & inhibitors
Dual Specificity Phosphatase 6 - classification
Dual Specificity Phosphatase 6 - metabolism
Enzymes
Historical account
Homeostasis
Humans
Kinases
Modulators
Oligomerization
Oxidation-Reduction
Phosphorylation
Protein Multimerization
Protein Tyrosine Phosphatases - antagonists & inhibitors
Protein Tyrosine Phosphatases - classification
Protein Tyrosine Phosphatases - metabolism
R&D
Reactive Oxygen Species - metabolism
Regulatory mechanisms (biology)
Research & development
Signal Transduction
Signaling
Tyrosine
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Abstract An appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and maintain cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic intervention. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent to an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination of a number of regulatory mechanisms, including redox modulation, allosteric regulation, and protein oligomerization, that control PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.
AbstractList An appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and maintain cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic intervention. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent to an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination of a number of regulatory mechanisms, including redox modulation, allosteric regulation, and protein oligomerization, that control PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.
Appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and keep cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic interventions. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination on a number of regulatory mechanisms including redox modulation, allosteric regulation, and protein oligomerization, in controlling PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.
Author Zhang, Zhong-Yin
Yu, Zhi-Hong
AuthorAffiliation Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery
AuthorAffiliation_xml – name: Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery
Author_xml – sequence: 1
  givenname: Zhi-Hong
  surname: Yu
  fullname: Yu, Zhi-Hong
– sequence: 2
  givenname: Zhong-Yin
  orcidid: 0000-0001-5527-7910
  surname: Zhang
  fullname: Zhang, Zhong-Yin
  email: zhang-zy@purdue.edu
BackLink https://www.ncbi.nlm.nih.gov/pubmed/28541680$$D View this record in MEDLINE/PubMed
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Snippet An appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and maintain cellular homeostasis. Faulty...
Appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and keep cellular homeostasis. Faulty...
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SubjectTerms Allosteric Regulation
Animals
Cells
Dual Specificity Phosphatase 6 - antagonists & inhibitors
Dual Specificity Phosphatase 6 - classification
Dual Specificity Phosphatase 6 - metabolism
Enzymes
Historical account
Homeostasis
Humans
Kinases
Modulators
Oligomerization
Oxidation-Reduction
Phosphorylation
Protein Multimerization
Protein Tyrosine Phosphatases - antagonists & inhibitors
Protein Tyrosine Phosphatases - classification
Protein Tyrosine Phosphatases - metabolism
R&D
Reactive Oxygen Species - metabolism
Regulatory mechanisms (biology)
Research & development
Signal Transduction
Signaling
Tyrosine
Title Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases
URI http://dx.doi.org/10.1021/acs.chemrev.7b00105
https://www.ncbi.nlm.nih.gov/pubmed/28541680
https://www.proquest.com/docview/2009181891
https://search.proquest.com/docview/1903169441
https://pubmed.ncbi.nlm.nih.gov/PMC5812791
Volume 118
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