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NFAT proteins: emerging roles in cancer progression

Nature Reviews Cancer volume 9, pages 810–820 (2009)Cite this article

Key Points

  • Nuclear factor of activated T cells (NFAT) is a family of closely related transcription factors that are ubiquitously expressed in mammalian cells and tissues. NFAT1–4 are regulated by the calcium-sensitive phosphatase calcineurin, which induces nuclear translocation and transcriptional activation.

  • The transcriptional activity of NFATs is primarily regulated by phosphorylation that in turn determines subcellular localization. Maintenance kinases such as dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and casein kinase 1 phosphorylate cytoplasmic NFATs and prevent nuclear translocation, whereas export kinases such as DYRK1 and glycogen synthase kinase 3 phosphorylate nuclear NFATs and promote their export.

  • Overexpression and increased transcriptional activity of NFAT isoforms has been detected in various human solid tumours and cell lines, as well as haematological malignancies. This leads to the induction of genes that promote cellular phenotypes that are associated with tumour progression, such as proliferation, survival, migration and invasion phenotypes.

  • NFAT isoforms promote the migration and invasion of tumour cells, prerequisites for metastatic dissemination. These phenotypes are mediated by the transcriptional induction of NFAT target genes in tumour cells, such as prostaglandin E2 and lysophosphatidic acid.

  • NFATs are directly implicated in promoting tumour angiogenesis. In endothelial cells NFATs are activated by vascular endothelial growth factor A and promote vessel formation by inducing pro-angiogenic genes such as cyclooxygenase 2.

  • The activation of NFATs in tumour cells and the tumour microenvironment induces soluble factors that function through both paracrine and autocrine mechanisms to promote tumour progression.

  • Inactivation of NFATs decreases tumour formation. This is consistent with pathophysiological settings of increased expression of the calcineurin inhibitor Down syndrome candidate region 1, which attenuates the activation of NFATs and reduces tumour incidence.

  • Inhibition of NFAT activation using small-molecule inhibitors is predicted to suppress tumorigenesis. Paradoxically, patients receiving immunosuppressive therapy that blocks NFAT activity have a higher incidence of cancer.

  • Future cancer therapy targeting NFATs must take into account the cell type-specific phenotypes associated with deregulated the activation of NFATs.

Abstract

The roles of nuclear factor of activated T cells (NFAT) transcription factors have been extensively studied in the immune system. However, ubiquitous expression of NFAT isoforms in mammalian tissues has recently been observed, and a role for these transcription factors in human cancer is emerging. Various NFAT isoforms are functional in tumour cells and multiple compartments in the tumour microenvironment, including fibroblasts, endothelial cells and infiltrating immune cells. How do NFAT isoforms regulate the complex interplay between these compartments during carcinoma progression? The answers lie with the multiple functions attributed to NFATs, including cell growth, survival, invasion and angiogenesis. In addition to elucidating the complex role of NFATs in cancer, we face the challenge of targeting this pathway therapeutically.

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Figure 1: Primary structure of NFAT.
Figure 2: Calcium signalling and activation of NFATs.
Figure 3: NFATs promote tumour cell migration through paracrine and autocrine mechanisms.
Figure 4: NFATs promote tumour angiogenesis.
Figure 5: Multiple roles for NFATs in the heterotypic interactions of the tumour microenvironment.

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Acknowledgements

We thank members of the Toker laboratory for many useful discussions and suggestions. We apologize to colleagues whose work could not be cited owing to space limitations. The Toker laboratory is funded by grants from the US National Institutes of Health and National Cancer Institute, the Department of Defense and the Susan G. Komen Breast Cancer Foundation.

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  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Maria Mancini & Alex Toker

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  1. Maria Mancini
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Correspondence to Alex Toker.

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DATABASES

National Cancer Institute Drug Dictionary

cyclosporin A

FK506

Pathway Interaction Database

canonical pathway

PI3K–Akt pathway

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Glossary

Store-operated channels

Calcium channels in the plasma membrane that allow the influx of extracellular calcium in response to the emptying of intracellular calcium stores such as the ER. Also known as CRAC channels.

Rel family transcription factors

Transcription factors with an N-terminal Rel-homology domain that is responsible for nuclear localization, dimerization and DNA binding.

Priming kinase

A serine/threonine kinase (such as a casein kinase) that, by phosphorylating specific residues in proteins, enables the subsequent phosphorylation of additional residues downstream of the priming sites, typically mediated by distinct kinases.

Sumoylation

Similar to ubiquitylation in that proteins are post-translationally modified with small ubiquitin-like modifier (SUMO). Unlike ubiquitylation, sumoylation does not target proteins for degradation, instead it facilitates nuclear–cytoplasmic shuttling, transcription and cell cycle progression.

EMT

A complex process in which genetic and epigenetic events lead to epithelial cells acquiring a mesenchymal architecture concomitant with increased cell motility. Typically associated with the loss of E-cadherin expression.

Hemidesmosomes

Rivet-like structures found in epithelial cells and also keratinocytes that attach these cells to the extracellular matrix. In epithelial cells, hemidesmosomes couple to integrins.

Haemangioma

A benign self-involuting mass of proliferating endothelial cells that typically presents in children.

VEGFR

A receptor tyrosine kinase on the surface of endothelial cells that activates downstream signalling pathways subsequent to binding VEGF. VEGFR1 is also known as FLT-1, and VEGFR2 is also known as KDR and FLK1.

Chemokines

A family of secreted cytokines that regulate both immune surveillance and inflammatory responses on infection.

Epstein-Barr virus

EBV. Herpesvirus that can transform B cells. It is implicated in the aetiology of several different lymphoid malignancies, such as Burkitt's lymphoma.

Angiogenic switch

The transition of a non-vascularized solid tumour to a highly vascularized state following recruitment of blood vessels.

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Mancini, M., Toker, A. NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 9, 810–820 (2009). https://doi.org/10.1038/nrc2735

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