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  • Review Article
  • Published:

Protein tyrosine phosphatases: from genes, to function, to disease

Key Points

  • The protein tyrosine phosphatase (PTP) superfamily of enzymes functions in a coordinated manner with the protein tyrosine kinases to control signalling pathways that underlie a number of fundamental physiological processes. In this review, I describe recent breakthroughs in our understanding of the role of the PTPs in the regulation of signal transduction and the aetiology of human disease.

The topics covered include:

  • An overview of the composition of the PTP superfamily.

  • The nature and function of pseudophosphatase PTPs, which maintain the PTP fold but lack crucial features that are required for enzymatic activity.

  • The regulation and function of receptor PTPs. This includes discussion of the role of ligand binding and receptor-type (RPTP) dimerization in control of activity, as well as the identity of such ligands and some of the signalling events they regulate.

  • Regulation of PTP function by reversible oxidation and its potential to represent a new tier of control of tyrosine-phosphorylation-dependent signal transduction.

  • Links between aberrant PTP function and human disease, including discussion of the potential for therapeutic intervention at the level of PTP function.

Abstract

The protein tyrosine phosphatase (PTP) superfamily of enzymes functions in a coordinated manner with protein tyrosine kinases to control signalling pathways that underlie a broad spectrum of fundamental physiological processes. In this review, I describe recent breakthroughs in our understanding of the role of the PTPs in the regulation of signal transduction and the aetiology of human disease.

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Figure 1: The classical PTPs.
Figure 2: The dual specificity phosphatases.
Figure 3: Regulation of receptor PTP function by ligands.
Figure 4: Reversible oxidation of PTPs.
Figure 5: The structural consequences of oxidation at the PTP active site.

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Acknowledgements

Work in the author's laboratory is supported by grants from the National Institutes of Health. I thank Jim Duffy for help with the art work. See 'A Web-Accessible Resource of Information on Protein Tyrosine Phosphatases' in Further information for a link to a resource that contains databases of PTP accession numbers, multiple sequence alignments, phylogenetic trees, structure files, annotated molecular graphics files, chromosomal mapping data, analyses of exon structure, pseudogenes and disease linkages.

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A Web-Accessible Resource of Information on Protein Tyrosine Phosphatases

Glossary

Lectins

Lectins are carbohydrate-binding proteins. Individual lectins show specificity for particular sugar structures.

Immunoglobulin (Ig) domain

This is a homology unit of 110 amino acids. Although there is variation in primary sequence, the structure of this domain is conserved and organized into two β-sheets, one of three and the other of four strands, which are stabilized by disulphide bonds in most of the cases. Ig domains are found in several proteins, including cell-adhesion molecules and signalling receptors, and have been implicated in protein–protein interactions.

Fibronectin type III (FNIII) domain

FNIII motifs, originally described in the extracellular matrix protein fibronectin, comprise 90 amino acids. Their three-dimensional structure is similar to that of the immunoglobulin domain. In fibronectin itself, a RGD sequence in the loop that connects the β-sheets in FNIII motif 10 has been implicated in promoting adhesion by binding to integrins. This motif is also found in a wide variety of signalling proteins.

pKα

The pKα (also known as pKa) is a measure of the uptake/release of protons by amino acids. It is the negative log to the base 10 of the acid-dissociation constant, which reflects the equilibrium between protonation and deprotonation and indicates the extent of proton dissociation. The log scale is used because this constant differs over orders of magnitude between individual acids; the smaller the pKα value, the stronger the acid.

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Tonks, N. Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 7, 833–846 (2006). https://doi.org/10.1038/nrm2039

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