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Inside the human cancer tyrosine phosphatome

Nature Reviews Cancer volume 11, pages 35–49 (2011)Cite this article

Subjects

Key Points

  • The protein tyrosine phosphatase (Ptp) family comprises 107 members that are classified into four classes on the basis of the amino acid sequences of their catalytic domains.

  • Recent evidence has shown that members of the Ptp family are key components of tumorigenesis in various human cancers, exerting either putative oncogenic or tumour suppressive functions, depending on the cellular context.

  • Genetic alterations such as mutation, deletion and amplification are the most important features for putative oncogenic PTPs, whereas in most cases epigenetic modifications such as DNA methylation counter the tumour suppressive functions of PTPs.

  • Recent advances have begun to decipher the molecular mechanisms by which putative oncogenic PTPs may drive tumorigenesis in human cells. Proliferation, survival, apoptosis, vesicular trafficking, adhesion, migration and invasion are all altered by the aberrant functions of PTPs during tumour development.

  • Evidence for an association between PTPs and an increased risk of developing cancer remains controversial and elusive. Here, we focus on the pertinent genetic and functional data that support the relevance of members of the Ptp family to human cancer.

  • PTP inhibitors are currently being developed. However, a better understanding of the basic biology of PTPs in human tumour development will be required to improve the therapeutic use of such inhibitors.

Abstract

Members of the protein tyrosine phosphatase (Ptp) family dephosphorylate target proteins and counter the activities of protein tyrosine kinases that are involved in cellular phosphorylation and signalling. As such, certain PTPs might be tumour suppressors. Indeed, PTPs play an important part in the inhibition or control of growth, but accumulating evidence indicates that some PTPs may exert oncogenic functions. Recent large-scale genetic analyses of various human tumours have highlighted the relevance of PTPs either as putative tumour suppressors or as candidate oncoproteins. Progress in understanding the regulation and function of PTPs has provided insights into which PTPs might be potential therapeutic targets in human cancer.

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Figure 1: The Ptp superfamily and human cancer.
Figure 2: Chromosome mapping of human PTP genes and linkage to genetic alterations in human cancer.
Figure 3: Selected PTPs and the location of mutations and SNPs reported in human cancer.
Figure 4: Proposed mechanisms of tumour suppressor functions of PTPs.
Figure 5: Mechanisms of putative oncogenic function of PTPs in cancer.

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Acknowledgements

The authors regret that, owing to space limitations, they could not mention the work of many investigators who have greatly contributed to the current knowledge of PTPs and their functions. The authors would like to thank B. P. Kennedy (Merck Frosst Center for Therapeutic Research, Canada), A. Pause (Goodman Cancer Research Centre, McGill University, Canada) and M. Meaney (Douglas Institute, McGill University, Canada and the Singapore Institute for Clinical Sciences) for discussions during the course of this work.

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  1. Sofi G. Julien

    Present address: Present address: Singapore Institute for Clinical Sciences. Growth, Development and Metabolism Programme, 30 Medical Drive, Singapore 117609.,

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  1. Goodman Cancer Research Centre and Department of Biochemistry, McGill University, 1160 Pine Avenue, Room 601, Montreal, H3A1A3, Quebec, Canada

    Sofi G. Julien, Nadia Dubé, Serge Hardy & Michel L. Tremblay

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DATABASES

National Cancer Institute Drug Dictionary

sodium stibogluconate

Glossary

DNA methylation

An addition of methyl groups to DNA, most commonly at CpG sites, to convert cytosine to 5-methylcytosine. Cytosine hypermethylation in gene promoters, leading to gene silencing, is the most frequent mechanism of tumour suppressor gene silencing in human tumours.

Loss of heterozygosity

(LOH). The loss of the normal allele of a gene in which the other allele was already inactivated, leading to a complete loss of gene expression.

Frameshift mutation

Caused by an insertion or deletion within a gene, which disrupts the reading frame and frequently results in severe malignancies or diseases.

Amplification

A type of copy number gain in which there is a copy number of more than two; amplifications are often seen for oncogenes.

Single nucleotide polymorphism

(SNP). A variation of a single nucleotide in the genomic sequence between paired chromosomes. Usually silent or does not alter gene expression or the protein, although there are numerous examples of SNPs increasing the risk of developing cancer.

Missense mutation

A point mutation in which a single nucleotide is changed that changes the encoded amino acid.

Nonsense mutation

Mutation that changes a codon that encodes an amino acid to a stop codon.

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Julien, S., Dubé, N., Hardy, S. et al. Inside the human cancer tyrosine phosphatome. Nat Rev Cancer 11, 35–49 (2011). https://doi.org/10.1038/nrc2980

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