NFAT proteins: emerging roles in cancer progression (original) (raw)
Crabtree, G. R. & Olson, E. N. NFAT signaling: choreographing the social lives of cells. Cell109 S67–79 (2002). CASPubMed Google Scholar
Hogan, P. G., Chen, L., Nardone, J. & Rao, A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev.17, 2205–2232 (2003). CASPubMed Google Scholar
Shaw, J. P. et al. Identification of a putative regulator of early T cell activation genes. Science241, 202–205 (1988). CASPubMed Google Scholar
Jauliac, S. et al. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nature Cell Biol.4, 540–544 (2002). This is the first study to demonstrate that NFATs are pro-migration and invasion transcription factors in breast cancer. CASPubMed Google Scholar
Medyouf, H. et al. Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nature Med.13, 736–741 (2007). CASPubMed Google Scholar
Ryeom, S. et al. Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. Cancer Cell13, 420–431 (2008). CASPubMed Google Scholar
Imamura, R. et al. Carboxyl-terminal 15-amino acid sequence of NFATx1 is possibly created by tissue-specific splicing and is essential for transactivation activity in T cells. J. Immunol.161, 3455–3463 (1998). CASPubMed Google Scholar
Chuvpilo, S. et al. Multiple NF-ATc isoforms with individual transcriptional properties are synthesized in T lymphocytes. J. Immunol.162, 7294–7301 (1999). CASPubMed Google Scholar
Chuvpilo, S. et al. Alternative polyadenylation events contribute to the induction of NF-ATc in effector T cells. Immunity10, 261–269 (1999). CASPubMed Google Scholar
Chen, L., Glover, J. N., Hogan, P. G., Rao, A. & Harrison, S. C. Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA. Nature392, 42–48 (1998). CASPubMed Google Scholar
Lopez-Rodriguez, C., Aramburu, J., Rakeman, A. S. & Rao, A. NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc. Natl Acad. Sci. USA96, 7214–7219 (1999). CASPubMedPubMed Central Google Scholar
Miyakawa, H., Woo, S. K., Dahl, S. C., Handler, J. S. & Kwon, H. M. Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. Proc. Natl Acad. Sci. USA96, 2538–2542 (1999). CASPubMedPubMed Central Google Scholar
Yang, T. T., Xiong, Q., Graef, I. A., Crabtree, G. R. & Chow, C. W. Recruitment of the extracellular signal-regulated kinase/ribosomal S6 kinase signaling pathway to the NFATc4 transcription activation complex. Mol. Cell. Biol.25, 907–920 (2005). CASPubMedPubMed Central Google Scholar
Giffin, M. J. et al. Structure of NFAT1 bound as a dimer to the HIV-1 LTR κB element. Nature Struct. Biol.10, 800–806 (2003). CASPubMed Google Scholar
Jain, J., McCaffrey, P. G., Valge-Archer, V. E. & Rao, A. Nuclear factor of activated T cells contains Fos and Jun. Nature356, 801–804 (1992). CASPubMed Google Scholar
Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell126, 375–387 (2006). ArticleCASPubMed Google Scholar
Macian, F. NFAT proteins: key regulators of T-cell development and function. Nature Rev. Immunol.5, 472–484 (2005). CAS Google Scholar
Penna, A. et al. The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature456, 116–120 (2008). CASPubMedPubMed Central Google Scholar
Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nature Immunol.9, 432–443 (2008). CAS Google Scholar
Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature443, 230–233 (2006). CASPubMed Google Scholar
Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature441, 179–185 (2006). CASPubMed Google Scholar
Yeromin, A. V. et al. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature443, 226–229 (2006). CASPubMedPubMed Central Google Scholar
Cahalan, M. D. STIMulating store-operated Ca2+ entry. Nature Cell Biol.11, 669–677 (2009). CASPubMed Google Scholar
Gwack, Y., Feske, S., Srikanth, S., Hogan, P. G. & Rao, A. Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. Cell Calcium42, 145–156 (2007). CASPubMed Google Scholar
Okamura, H. et al. Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity. Mol. Cell6, 539–550 (2000). CASPubMed Google Scholar
Zhu, J. & McKeon, F. NF-AT activation requires suppression of Crm1-dependent export by calcineurin. Nature398, 256–260 (1999). CASPubMed Google Scholar
Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P. & Crabtree, G. R. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science275, 1930–1934 (1997). The first study demonstrating that GSK3 is a nuclear export kinase for NFAT. CASPubMed Google Scholar
Neal, J. W. & Clipstone, N. A. Glycogen synthase kinase-3 inhibits the DNA binding activity of NFATc. J. Biol. Chem.276, 3666–3673 (2000). PubMed Google Scholar
Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer9, 550–562 (2009). CAS Google Scholar
Okamura, H. et al. A conserved docking motif for CK1 binding controls the nuclear localizationof NFAT1. Mol. Cell. Biol.24, 4184–4195 (2004). CASPubMedPubMed Central Google Scholar
Zhu, J. et al. Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Cell93, 851–861 (1998). CASPubMed Google Scholar
Chow, C. W., Dong, C., Flavell, R. A. & Davis, R. J. c-Jun NH2-terminal kinase inhibits targeting of the protein phosphatase calcineurin to NFATc1. Mol. Cell. Biol.20, 5227–5234 (2000). CASPubMedPubMed Central Google Scholar
Yang, T. T., Xiong, Q., Enslen, H., Davis, R. J. & Chow, C. W. Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. Mol. Cell. Biol.22, 3892–3904 (2002). CASPubMedPubMed Central Google Scholar
Gwack, Y. et al. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature441, 646–650 (2006). CASPubMed Google Scholar
Arron, J. R. et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature441, 595–600 (2006). References 34 and 35 define DYRKs as the long-sought-after export and maintenance kinases for NFATs. CASPubMed Google Scholar
Nayak, A. et al. Sumoylation of the transcription factor NFATc1 leads to its subnuclear relocalization and interleukin-2 repression by histone deacetylase. J. Biol. Chem.284, 10935–10946 (2009). CASPubMedPubMed Central Google Scholar
Terui, Y., Saad, N., Jia, S., McKeon, F. & Yuan, J. Dual role of sumoylation in the nuclear localization and transcriptional activation of NFAT1. J. Biol. Chem.279, 28257–28265 (2004). CASPubMed Google Scholar
Yoeli-Lerner, M. et al. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol. Cell20, 539–550 (2005). This paper shows that, in breast cancer cells, NFAT1 is ubiquitylated by the E3 ligase MDM2, which targets it for degradation. CASPubMed Google Scholar
Yoeli-Lerner, M., Chin, Y. R., Hansen, C. K. & Toker, A. Akt/protein kinase B and glycogen synthase kinase-3β signaling pathway regulates cell migration through the NFAT1 transcription factor. Mol. Cancer Res.7, 425–432 (2009). CASPubMedPubMed Central Google Scholar
Neal, J. W. & Clipstone, N. A. A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts. J. Biol. Chem.278, 17246–17254 (2003). CASPubMed Google Scholar
Buchholz, M. et al. Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J.25, 3714–3724 (2006). CASPubMedPubMed Central Google Scholar
Robbs, B. K., Cruz, A. L., Werneck, M. B., Mognol, G. P. & Viola, J. P. Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol. Cell. Biol.28, 7168–7181 (2008). This paper shows that, in fibroblasts, distinct NFAT isoforms have non-overlapping roles as oncogenes and tumour suppressors, as revealed in bothin vitrostudies and mouse models. CASPubMedPubMed Central Google Scholar
Marafioti, T. et al. The NFATc1 transcription factor is widely expressed in white cells and translocates from the cytoplasm to the nucleus in a subset of human lymphomas. Br. J. Haematol.128, 333–342 (2005). CASPubMed Google Scholar
Pham, L. V., Tamayo, A. T., Yoshimura, L. C., Lin-Lee, Y. C. & Ford, R. J. Constitutive NF-κB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. Blood106, 3940–3947 (2005). CASPubMedPubMed Central Google Scholar
Horsley, V., Aliprantis, A. O., Polak, L., Glimcher, L. H. & Fuchs, E. NFATc1 balances quiescence and proliferation of skin stem cells. Cell132, 299–310 (2008). CASPubMedPubMed Central Google Scholar
Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell133, 704–715 (2008). CASPubMedPubMed Central Google Scholar
Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nature Rev. Cancer2, 442–454 (2002). CAS Google Scholar
Jonsson, M., Dejmek, J., Bendahl, P. O. & Andersson, T. Loss of Wnt-5a protein is associated with early relapse in invasive ductal breast carcinomas. Cancer Res.62, 409–416 (2002). CASPubMed Google Scholar
Dejmek, J., Safholm, A., Kamp Nielsen, C., Andersson, T. & Leandersson, K. Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1α signaling in human mammary epithelial cells. Mol. Cell. Biol.26, 6024–6036 (2006). CASPubMedPubMed Central Google Scholar
Rabinovitz, I. & Mercurio, A. M. The integrin α6β4 functions in carcinoma cell migration on laminin-1 by mediating the formation and stabilization of actin- containing motility structures. J. Cell Biol.139, 1873–1884 (1997). CASPubMedPubMed Central Google Scholar
Mercurio, A. M. & Rabinovitz, I. Towards a mechanistic understanding of tumor invasion-lessons from the α6β4 integrin. Semin. Cancer Biol.11, 129–141 (2001). CASPubMed Google Scholar
Yiu, G. K. & Toker, A. NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J. Biol. Chem.281, 12210–12217 (2006). CASPubMed Google Scholar
Chen, M. & O'Connor, K., L., Integrin α6β4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Oncogene24, 5125–5130 (2005). CASPubMed Google Scholar
Stracke, M. L. et al. Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J. Biol. Chem.267, 2524–2529 (1992). CASPubMed Google Scholar
Yang, S. Y. et al. Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells. Clin. Exp. Metastasis19, 603–608 (2002). CASPubMed Google Scholar
Liu, S. et al. Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases. Cancer Cell15, 539–550 (2009). A recent study that highlights the potent metastatic activity of autotaxin and its product LPA in breast cancer progression. CASPubMedPubMed Central Google Scholar
Zhang, H. et al. Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration In vitro and causes tumor regression In vivo. Cancer Res.69, 5441–5449 (2009). CASPubMedPubMed Central Google Scholar
Mott, J. D. & Werb, Z. Regulation of matrix biology by matrix metalloproteinases. Curr. Opin. Cell Biol.16, 558–564 (2004). CASPubMedPubMed Central Google Scholar
Nagy, J. A., Dvorak, A. M. & Dvorak, H. F. VEGF-A and the induction of pathological angiogenesis. Annu. Rev. Pathol.2, 251–275 (2007). CASPubMed Google Scholar
Dvorak, H. F. Discovery of vascular permeability factor (VPF). Exp. Cell Res.312, 522–526 (2006). CASPubMed Google Scholar
Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med.9, 669–676 (2003). CASPubMed Google Scholar
Hernandez, G. L. et al. Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J. Exp. Med.193, 607–620 (2001). CASPubMedPubMed Central Google Scholar
Gupta, G. P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature446, 765–770 (2007). CASPubMed Google Scholar
Armesilla, A. L. et al. Vascular endothelial growth factor activates nuclear factor of activated T cells in human endothelial cells: a role for tissue factor gene expression. Mol. Cell. Biol.19, 2032–2043 (1999). CASPubMedPubMed Central Google Scholar
Cockerill, G. W. et al. Regulation of granulocyte-macrophage colony-stimulating factor and E-selectin expression in endothelial cells by cyclosporin A and the T-cell transcription factor NFAT. Blood86, 2689–2698 (1995). CASPubMed Google Scholar
Jinnin, M. et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nature Med.14, 1236–1246 (2008). NFAT activation is shown to lead to expression of VEGFRs and downstream signalling in haemangiomas, which are highly vascularized benign lesions typically seen in children. CASPubMed Google Scholar
Hasle, H., Clemmensen, I. H. & Mikkelsen, M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet355, 165–169 (2000). CASPubMed Google Scholar
Baek, K. H. et al. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature459, 1126–1130 (2009). References 69 and 6 reveal that DSCR1, a suppressor of calcineurin activity in endothelial cells, can function as a suppressor of tumour growth by attenuating NFAT activity and VEGFA induction, as observed in patients with Down's syndrome who have increased expression of DSCR1. CASPubMedPubMed Central Google Scholar
Qin, L. et al. Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. Mol. Cancer Res.4, 811–820 (2006). CASPubMed Google Scholar
Stacker, S. A., Achen, M. G., Jussila, L., Baldwin, M. E. & Alitalo, K. Lymphangiogenesis and cancer metastasis. Nature Rev. Cancer2, 573–583 (2002). CAS Google Scholar
Skobe, M. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med.7, 192–198 (2001). CASPubMed Google Scholar
Karpanen, T. et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res.61, 1786–1790 (2001). CASPubMed Google Scholar
Kulkarni, R. M., Greenberg, J. M. & Akeson, A. L. NFATc1 regulates lymphatic endothelial development. Mech. Dev.126, 350–365 (2009). CASPubMedPubMed Central Google Scholar
Norrmen, C. et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J. Cell Biol.185, 439–457 (2009). CASPubMedPubMed Central Google Scholar
Campbell, J. J. & Butcher, E. C. Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr. Opin. Immunol.12, 336–341 (2000). CASPubMed Google Scholar
Butcher, E. C., Williams, M., Youngman, K., Rott, L. & Briskin, M. Lymphocyte trafficking and regional immunity. Adv. Immunol.72, 209–253 (1999). CASPubMed Google Scholar
Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature410, 50–56 (2001). Chemokines and chemokine receptors are shown to be highly upregulated and functional for metastatic dissemination of breast cancer cells in this paper. CASPubMed Google Scholar
Karnoub, A. E. & Weinberg, R. A. Chemokine networks and breast cancer metastasis. Breast Dis.26, 75–85 (2006). CASPubMed Google Scholar
Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature449, 557–563 (2007). CASPubMed Google Scholar
Wyckoff, J. et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res.64, 7022–7029 (2004). CASPubMed Google Scholar
Kaufman, D. B. et al. Immunosuppression: practice and trends. Am. J. Transplant4 Suppl. 9, 38–53 (2004). PubMed Google Scholar
Martinez-Martinez, S. & Redondo, J. M. Inhibitors of the calcineurin/NFAT pathway. Curr. Med. Chem.11, 997–1007 (2004). CASPubMed Google Scholar
Matsuda, S. & Koyasu, S. Mechanisms of action of cyclosporine. Immunopharmacology47, 119–125 (2000). CASPubMed Google Scholar
Liu, J. et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell66, 807–815 (1991). CASPubMed Google Scholar
Kiani, A., Rao, A. & Aramburu, J. Manipulating immune responses with immunosuppressive agents that target NFAT. Immunity12, 359–372 (2000). CASPubMed Google Scholar
Rezzani, R. Cyclosporine A and adverse effects on organs: histochemical studies. Prog. Histochem. Cytochem.39, 85–128 (2004). CASPubMed Google Scholar
Dantal, J. & Soulillou, J. P. Immunosuppressive drugs and the risk of cancer after organ transplantation. N. Engl. J. Med.352, 1371–1373 (2005). CASPubMed Google Scholar
Aramburu, J. et al. Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Mol. Cell1, 627–637 (1998). CASPubMed Google Scholar
Aramburu, J. et al. Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science285, 2129–2133 (1999). CASPubMed Google Scholar
Noguchi, H. et al. A new cell-permeable peptide allows successful allogeneic islet transplantation in mice. Nature Med.10, 305–309 (2004). CASPubMed Google Scholar
Karanam, B. V. et al. Disposition of L-732531, a potent immunosuppressant, in rats and baboons. Drug Metab. Dispos.26, 949–957 (1998). CASPubMed Google Scholar
Abel, M. D. et al. ISATX247: a novel calcineurin inhibitor. J. Heart Lung Transplant20, 161 (2001). PubMed Google Scholar
Brundage, R. A., Fogarty, K. E., Tuft, R. A. & Fay, F. S. Calcium gradients underlying polarization and chemotaxis of eosinophils. Science254, 703–706 (1991). CASPubMed Google Scholar
Evans, J. H. & Falke, J. J. Ca2+ influx is an essential component of the positive-feedback loop that maintains leading-edge structure and activity in macrophages. Proc. Natl Acad. Sci. USA104, 16176–16181 (2007). CASPubMedPubMed Central Google Scholar
Wei, C. et al. Calcium flickers steer cell migration. Nature457, 901–905 (2009). CASPubMed Google Scholar
Yang, S., Zhang, J. J. & Huang, X. Y. Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell15, 124–134 (2009). This paper reveals that the store-operated calcium channels STIM1 and ORAI1 promote calcium signals that are required for cell migration. CASPubMed Google Scholar
Szado, T. et al. Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc. Natl Acad. Sci. USA105, 2427–2432 (2008). CASPubMedPubMed Central Google Scholar
Masuda, E. S., Imamura, R., Amasaki, Y., Arai, K. & Arai, N. Signalling into the T-cell nucleus: NFAT regulation. Cell Signal10, 599–611 (1998). CASPubMed Google Scholar
Horsley, V. & Pavlath, G. K. NFAT: ubiquitous regulator of cell differentiation and adaptation. J. Cell Biol.156, 771–774 (2002). CASPubMedPubMed Central Google Scholar
Amasaki, Y. et al. A constitutively nuclear form of NFATx shows efficient transactivation activity and induces differentiation of CD4+CD8+ T cells. J. Biol. Chem.277, 25640–25648 (2002). CASPubMed Google Scholar
Ranger, A. M., Oukka, M., Rengarajan, J. & Glimcher, L. H. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity9, 627–635 (1998). CASPubMed Google Scholar
Graef, I. A., Chen, F., Chen, L., Kuo, A. & Crabtree, G. R. Signals transduced by Ca2+/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell105, 863–875 (2001). CASPubMed Google Scholar
Rengarajan, J., Tang, B. & Glimcher, L. H. NFATc2 and NFATc3 regulate TH2 differentiation and modulate TCR-responsiveness of naive TH cells. Nature Immunol.3, 48–54 (2002). CAS Google Scholar