Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Su Jun Lim
  • Willis X. LiEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_636


Historical Background

The signal transducer and activator of transcription (STAT) proteins were first identified as signaling proteins that function as second messengers and transcription factors in response to cytokines and growth factors (Santos and Costa-Pereira 2011; Li 2008). Mammals have seven STAT genes, namely, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 (Santos and Costa-Pereira 2011). All the STAT proteins are highly conserved and contain six domains including the SH2, linker, coiled -coil, and DNA- binding domain (Bromberg and Darnell 2000). Traditionally, unphosphorylated STAT is believed to reside in the cytoplasm in an inactive form; upon phosphorylation by JAK or another tyrosine kinase, the phosphorylated (active) STAT translocates into the nucleus to induce transcription of target genes (Bromberg and Darnell 2000). However,...

This is a preview of subscription content, log in to check access.


  1. Boucheron C, Dumon S, Santos SC, Moriggl R, Hennighausen L, Gisselbrecht S, et al. A single amino acid in the DNA binding regions of STAT5A and STAT5B confers distinct DNA binding specificities. J Biol Chem. 1998;273(51):33936–41.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Boyer LA, Mathur D, Jaenisch R. Molecular control of pluripotency. Curr Opin Genet Dev. 2006;16(5):455–62.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bromberg J, Darnell Jr JE. The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 2000;19(21):2468–73.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JA, Lammers JW, et al. STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. J Biol Chem. 1996;271(22):13221–7.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Dawson MA, Bannister AJ, Gottgens B, Foster SD, Bartke T, Green AR, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature. 2009;461(7265):819–22.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Hochedlinger K, Jaenisch R. Nuclear reprogramming and pluripotency. Nature. 2006;441(7097):1061–7.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Hu X, Dutta P, Tsurumi A, Li J, Wang J, Land H, Li WX. Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth. Proc Natl Acad Sci U S A. 2013;110(25):10213–8.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Huang H, Li L, Wu C, Schibli D, Colwill K, Ma S, et al. Defining the specificity space of the human SRC homology 2 domain. Mol Cell Proteomics. 2008;7(4):768–84.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Li WX. Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol. 2008;18(11):545–51.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Lim CP, Cao X. Structure, function, and regulation of STAT proteins. Mol Biosyst. 2006;2(11):536–50.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Liu L, Mcbride K, Reich NC. STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. Proc Natl Acad Sci U S A. 2005;102(23):8150–5.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Marg A, Shan Y, Meyer T, Meissner T, Brandenburg M, Vinkemeier U. Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1. J Cell Biol. 2004;165(6):823–33.PubMedPubMedCentralCrossRefGoogle Scholar
  13. O’Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov. 2004;3(7):555–64.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Park HJ, Li J, Hannah R, Biddie S, Leal-Cervantes AI, Kirschner K, Flores Santa Cruz D, Sexl V, Gottgens B, Green AR. Cytokine-induced megakaryocytic differentiation is regulated by genome-wide loss of a uSTAT transcriptional program. EMBO J. 2015;35(6):580–94.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Santos CI, Costa-Pereira AP. Signal transducers and activators of transcription-from cytokine signalling to cancer biology. Biochim Biophys Acta. 2011;1816(1):38–49.PubMedPubMedCentralGoogle Scholar
  16. Shi S, Calhoun HC, Xia F, Li J, Le L, Li WX. JAK signaling globally counteracts heterochromatic gene silencing. Nat Genet. 2006;38:1071–6.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Shi S, Larson K, Guo D, Lim SJ, Dutta P, Yan SJ, et al. Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability. Nat Cell Biol. 2008;10(4):489–96.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Silva CM. Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene. 2004;23(48):8017–23.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Watanabe S, Arai K. Roles of the JAK-STAT system in signal transduction via cytokine receptors. Curr Opin Genet Dev. 1996;6(5):587–96.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Yang J, Stark GR. Roles of unphosphorylated STATs in signaling. Cell Res. 2008;18(4):443–51.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Yang E, Wen Z, Haspel RL, Zhang JJ, Darnell Jr JE. The linker domain of Stat1 is required for gamma interferon-driven transcription. Mol Cell Biol. 1999;19(7):5106–12.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Yu H, Jove R. The STATs of cancer–new molecular targets come of age. Nat Rev Cancer. 2004;4(2):97–105.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.University of Rochester Medical CenterRochesterUSA
  2. 2.Department of MedicineUniversity of California San DiegoLa JollaUSA