cd16849

DNA-binding domain of Signal Transducer and Activator of Transcription 5 (STAT5)

CDD entry
Member databaseCDD
CDD typedomain
Short nameSTAT5_DBD
SetSTAT_DBD

Description

This family consists of the DNA-binding domain (DBD) of the STAT5 proteins (Signal Transducer and Activator of Transcription 5, or Signal Transduction And Transcription 4), which include STAT5A and STAT5B, both of which are >90% identical despite being encoded by separate genes. The DNA binding domain has an Ig-like fold. STAT5A and STAT5B regulate erythropoiesis, lymphopoiesis, and the maintenance of the hematopoietic stem cell population. STAT5A and STAT5B have overlapping and redundant functions; both isoforms can be activated by the same set of cytokines, but some cytokines preferentially activate either STAT5A or STAT5B, e.g. during pregnancy and lactation, STAT5A rather than STAT5B is required for the production of luminal progenitor cells from mammary stem cells and is essential for the differentiation of milk producing alveolar cells during pregnancy. STAT5 has been found to be constitutively phosphorylated in cancer cells, and therefore constantly activated, either by aberrant cell signaling expression or by mutations. It differentially regulates cellular behavior in human mammary carcinoma. Prolactin (PRL) in the prostate gland can induce growth and survival of prostate cancer cells and tissues through the activation of STAT5, its downstream target; PRL expression and STAT5 activation correlates with disease severity. STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases, displaying unique nuclear shuttling mechanisms and having a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). In addition, STAT5A and STAT5B promote survival of leukemic stem cells. STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis via the induction of the expression of Id genes. Autosomal recessive STAT5B mutations are associated with severe growth failure, insulin-like growth factor (IGF) deficiency and growth hormone insensitivity (GHI) syndrome. STAT5B deficiency can lead to potentially fatal primary immunodeficiency.
[13, 1, 9, 11, 8, 5, 17, 2, 3, 7, 15, 14, 10, 16, 4, 12, 6]

References

1.STAT5A is regulated by DNA damage via the tumor suppressor p53. Mukhopadhyay UK, Cass J, Raptis L, Craig AW, Bourdeau V, Varma S, SenGupta S, Elliott BE, Ferbeyre G. Cytokine 82, 70-9, (2016). PMID: 26876578

2.STAT6 is amplified in a subset of dedifferentiated liposarcoma. Doyle LA, Tao D, Marino-Enriquez A. Mod Pathol 27, 1231-7, (2014). PMID: 24457460

3.Inhibition of STAT5: a therapeutic option in BCR-ABL1-driven leukemia. Berger A, Sexl V, Valent P, Moriggl R. Oncotarget 5, 9564-76, (2014). PMID: 25333255

4.Identification and characterization of five transcription factors that are associated with evolutionarily conserved immune signaling pathways in the schistosome-transmitting snail Biomphalaria glabrata. Zhang SM, Coultas KA. Mol Immunol 48, 1868-81, (2011). PMID: 21696828

5.STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis. Lee J, Seong S, Kim JH, Kim K, Kim I, Jeong BC, Nam KI, Kim KK, Hennighausen L, Kim N. Sci Rep 6, 30977, (2016). PMID: 27485735

6.Three-dimensional structure of the Stat3beta homodimer bound to DNA. Becker S, Groner B, Muller CW. Nature 394, 145-51, (1998). View articlePMID: 9671298

7.The spectrum of STAT functions in mammary gland development. Hughes K, Watson CJ. JAKSTAT 1, 151-8, (2012). PMID: 24058764

8.Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency. Sachs Z, Been RA, DeCoursin KJ, Nguyen HT, Mohd Hassan NA, Noble-Orcutt KE, Eckfeldt CE, Pomeroy EJ, Diaz-Flores E, Geurts JL, Diers MD, Hasz DE, Morgan KJ, MacMillan ML, Shannon KM, Largaespada DA, Wiesner SM. Haematologica 101, 1190-1199, (2016). PMID: 27418650

9.Syk kinase and Shp2 phosphatase inhibition cooperate to reduce FLT3-ITD-induced STAT5 activation and proliferation of acute myeloid leukemia. Richine BM, Virts EL, Bowling JD, Ramdas B, Mali R, Naoye R, Liu Z, Zhang ZY, Boswell HS, Kapur R, Chan RJ. Leukemia 30, 2094-2097, (2016). PMID: 27256702

10.Interleukin-3 signals through multiple isoforms of Stat5. Azam M, Erdjument-Bromage H, Kreider BL, Xia M, Quelle F, Basu R, Saris C, Tempst P, Ihle JN, Schindler C. EMBO J 14, 1402-11, (1995). PMID: 7537213

11.STAT5 induces miR-21 expression in cutaneous T cell lymphoma. Lindahl LM, Fredholm S, Joseph C, Nielsen BS, Jonson L, Willerslev-Olsen A, Gluud M, Blumel E, Petersen DL, Sibbesen N, Hu T, Nastasi C, Krejsgaard T, Jæhger D, Persson JL, Mongan N, Wasik MA, Litvinov IV, Sasseville D, Koralov SB, Bonefeld CM, Geisler C, Woetmann A, Ralfkiaer E, Iversen L, Odum N. Oncotarget 7, 45730-45744, (2016). PMID: 27329723

12.Ixodes scapularis JAK-STAT pathway regulates tick antimicrobial peptides, thereby controlling the agent of human granulocytic anaplasmosis. Liu L, Dai J, Zhao YO, Narasimhan S, Yang Y, Zhang L, Fikrig E. J Infect Dis 206, 1233-41, (2012). PMID: 22859824

13.Structure of the amino-terminal protein interaction domain of STAT-4. Vinkemeier U, Moarefi I, Darnell JE Jr, Kuriyan J. Science 279, 1048-52, (1998). View articlePMID: 9461439

14.STAT5A and STAT5B have opposite correlations with drug response gene expression. Lamba V, Jia B, Liang F. Biochem Biophys Res Commun 479, 117-124, (2016). PMID: 27264955

15.STAT5B deficiency: Impacts on human growth and immunity. Hwa V. Growth Horm IGF Res 28, 16-20, (2016). PMID: 26703237

16.Structure of the unphosphorylated STAT5a dimer. Neculai D, Neculai AM, Verrier S, Straub K, Klumpp K, Pfitzner E, Becker S. J. Biol. Chem. 280, 40782-7, (2005). View articlePMID: 16192273

17.A positive feedback loop between prolactin and STAT5 promotes angiogenesis. Yang X, Friedl A. Adv Exp Med Biol 846, 265-80, (2015). PMID: 25472543

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