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Protein-tyrosine phosphatases and cancer

Key Points

  • Protein-tyrosine phosphatases (PTPs) constitute a structurally diverse family of tightly regulated enzymes that are characterized by a conserved catalytic domain with an oxidation-sensitive active-site cysteine residue.

  • Different PTPs function as negative or positive mediators of signalling triggered by receptor-tyrosine kinases, integrins and cell-adhesion molecules.

  • The tumour-suppressive function of PTPs is indicated by frequent inactivating mutations of PTPs in colon cancer, and the identification of Ptprj as the gene that confers colon cancer susceptibility in STS/A mice. Also, inactivation of the genes that encode SHP1 and glomerular epithelial protein 1 (GLEPP1) by methylation has been described in haematological malignancies and solid tumours, respectively.

  • The oncogenic activity of a PTP is best characterized for the mutational activation of SHP2, which occurs in hereditary and sporadic leukaemias and, less frequently, in solid tumours.

  • Despite technical challenges, recent advances in the design of PTP inhibitors are encouraging with respect to the possibilities of developing novel cancer drugs that function by inhibiting oncogenic PTPs.

  • Other aspects of PTP biology that might be relevant to cancer research in the future are the regulation of PTPs by oxidation and the putative role of PTPs in angiogenesis.

Abstract

Tyrosine phosphorylation is an important signalling mechanism in eukaryotic cells. In cancer, oncogenic activation of tyrosine kinases is a common feature, and novel anticancer drugs have been introduced that target these enzymes. Tyrosine phosphorylation is also controlled by protein-tyrosine phosphatases (PTPs). Recent evidence has shown that PTPs can function as tumour suppressors. In addition, some PTPs, including SHP2, positively regulate the signalling of growth-factor receptors, and can be oncogenic. An improved understanding of how these enzymes function and how they are regulated might aid the development of new anticancer agents.

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Figure 1: Schematic representation of some of the protein-tyrosine phosphatase subfamilies.
Figure 2: Schematic illustration of the dual aspects of protein-tyrosine phosphatases in controlling cell proliferation, cell–matrix and cell–cell adhesion.
Figure 3: Schematic illustration of different mechanisms for protein-tyrosine phosphatase inactivation in cancer.
Figure 4: Mechanism of SHP2-mediated signal transduction and the effect of SHP2 mutations in leukaemia.

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Acknowledgements

Work in the authors' laboratories is supported by grants from the Swedish Cancer Society (Cancerfonden) the Deutsche Krebshilfe (F.D.B.) and Karolinska Institutet (A.Ö.) the Swedish Research Council (C.H and A.Ö.), the Deutsche Forschungsgemeinschaft (F.D.B.), the Deutsche Krebshilfe (F.D.B.), and the German Ministry for Education and Research (F.D.B.). We are grateful to the colleagues mentioned in the text for sharing with us their unpublished results, and to A. Uecker and C. H. Heldin for critical reading of the manuscript.

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Box: Selected inhibitors for protein-tyrosine phosphatases (PDF 189 kb)

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DATABASES

National Cancer Institute

ALL

AML

breast cancer

colorectal cancer

lung cancer

lymphomas

thyroid cancer

OMIM

Noonan syndrome

FURTHER INFORMATION

Arne Östman's home page

Carina Hellberg's home page

Entry for PTPN11 in The Human Gene Mutation Database, Cardiff

Frank D. Böhmer's home page

GeneCards

InterPro

Novo Nordisk Science PTPs

Pfam database of protein families and hidden Markov models

Phosphobase

PTP resource

Uniprot

Glossary

Immunoglobulin-like domain

Protein domain of approximately 100 amino-acids that was originally identified in antibodies. Structural features include 7–10 β–strands and an internal disulphide bridge. One or more of these domains commonly occur in the extracellular parts of growth-factor receptors and other transmembrane cell surface proteins, where they are involved in protein–protein interactions.

Fibronectin type III domain

Protein domain with structural similarities to immunoglobulin-like domains, but lacking the internal disulphide. This domain is found in extracellular-matrix proteins, cell-surface receptors and enzymes, and often contains surface-exposed stretches of amino acids that are involved in protein–protein interactions, such as the prototypical RGD sequence in fibronectin that mediates integrin binding.

K M

The Michaelis constant, KM, is defined as the substrate concentration at which half the maximum reaction velocity is attained. A small KM indicates that the enzyme requires only a small amount of substrate to become saturated, and a large KM indicates the need for high substrate concentrations to achieve maximum reaction velocity. The substrate with the lowest KM on which the enzyme acts is frequently assumed to be the enzyme's natural substrate.

Substrate-trapping PTP

Variants of PTPs that have been experimentally altered so that they still bind their substrates but do not dephosphorylate them, which allows the identification of PTP substrates. This is most commonly achieved by substituting the active site cysteine residue with a serine (C/S mutant), or by substituting the conserved aspartic acid residue in the active site with an alanine residue (D/A mutant).

FAB-M5

M5 subgroup of acute myeloid leukaemia of the French–American–British group-classification system.

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Östman, A., Hellberg, C. & Böhmer, F. Protein-tyrosine phosphatases and cancer. Nat Rev Cancer 6, 307–320 (2006). https://doi.org/10.1038/nrc1837

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