Serine phosphorylation of the Stat5a C-terminus is a driving force for transformation

Frontiers in Bioscience

Volumn 16, Issue 7, 2011, Pages 3043-3056

  Friedbichler, Katrin ^a   Hoelbl, Andrea ^b   Li, Geqiang ^c   Bunting, Kevin D ^d   Sexl, Veronika ^b   Gouilleux, Fabrice ^e   Moriggl, Richard ^a  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

^b MEDICAL UNIVERSITY OF VIENNA   (Austria)

^c BOSTON CHILDREN S HOSPITAL   (United States)

^d EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITÉ DE TOURS   (France)

Author keywords

Review; Serine phosphorylation; Serine threonine kinase; Stat5a; Stat5b; Transformation

Indexed keywords

VERTEBRATA;

PROTEIN SERINE THREONINE KINASE; SERINE; STAT5 PROTEIN;

AMINO ACID SEQUENCE; ANIMAL; BLOOD DISEASE; CELL TRANSFORMATION; CHEMISTRY; GENETICS; HUMAN; METABOLISM; MOLECULAR GENETICS; NUCLEOTIDE SEQUENCE; PHOSPHORYLATION; PROTEIN PROCESSING; REVIEW; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION;

AMINO ACID SEQUENCE; ANIMALS; CELL TRANSFORMATION, NEOPLASTIC; CONSERVED SEQUENCE; HEMATOLOGIC NEOPLASMS; HUMANS; MOLECULAR SEQUENCE DATA; PHOSPHORYLATION; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEIN-SERINE-THREONINE KINASES; SEQUENCE HOMOLOGY, AMINO ACID; SERINE; SIGNAL TRANSDUCTION; STAT5 TRANSCRIPTION FACTOR;

EID: 79959557151     PISSN: 27686701     EISSN: 27686698     Source Type: Journal    
DOI: 10.2741/3897     Document Type: Article

References (122)

1. Cui, Y., M. Li, K. D. Walton, K. Sun, J. A. Hanover, P. A. Furth & L. Hennighausen: The Stat3/5 locus encodes novel endoplasmic reticulum and helicase-like proteins that are preferentially expressed in normal and neoplastic mammary tissue. Genomics, 78, 129-34 (2001) (Pubitemid 34001416)
2. Hennighausen, L. & G. W. Robinson: Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev, 22, 711-21 (2008) (Pubitemid 351439101)
3. Schindler, C., D. E. Levy & T. Decker: JAK-STAT signaling: from interferons to cytokines. J Biol Chem, 282, 20059-63 (2007) (Pubitemid 47099977)
4. Kornfeld, J. W., F. Grebien, M. A. Kerenyi, K. Friedbichler, B. Kovacic, B. Zankl, A. Hoelbl, H. Nivarti, H. Beug, V. Sexl, M. Muller, L. Kenner, E. W. Mullner, F. Gouilleux & R. Moriggl: The different functions of Stat5 and chromatin alteration through Stat5 proteins. Front Biosci, 13, 6237-54 (2008)
5. O'Shea, J. J. & P. J. Murray: Cytokine signaling modules in inflammatory responses. Immunity, 28, 477-87 (2008) (Pubitemid 351467044)
6. Ferbeyre, G. & R. Moriggl: The role of Stat5 transcription factors as tumor suppressors or oncogenes. Biochim Biophys Acta (2010)
7. Yu, H., M. Kortylewski & D. Pardoll: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol, 7, 41-51 (2007) (Pubitemid 46020826)
8. Levy, D. E. & J. E. Darnell, Jr.: Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol, 3, 651-62 (2002) (Pubitemid 34987786)
9. Wen, Z. & J. E. Darnell, Jr.: Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res, 25, 2062-7 (1997) (Pubitemid 27303439)
10. Wen, Z., Z. Zhong & J. E. Darnell, Jr.: Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell, 82, 241-50 (1995)
11. Zhang, X., J. Blenis, H. C. Li, C. Schindler & S. Chen-Kiang: Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science, 267, 1990-4 (1995)
12. Friedbichler K, M. A. Kerenyi, E. Müllner & R. Moriggl: Stat5 as Hematopoietic Gatekeeper and Oncogene Upon Tyrosine Kinase-Induced Transformation. In: JAK STAT Pathway in Disease. Ed: A. Stephanou. Landes Biosciences, (June 11; 2009)
13. Decker, T. & P. Kovarik: Serine phosphorylation of STATs. Oncogene, 19, 2628-37 (2000) (Pubitemid 30339219)
14. Friedbichler, K., M. A. Kerenyi, B. Kovacic, G. Li, A. Hoelbl, S. Yahiaoui, V. Sexl, E. W. Mullner, S. Fajmann, S. Cerny-Reiterer, P. Valent, H. Beug, F. Gouilleux, K. D. Bunting & R. Moriggl: Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation. Blood, 116, 1548-58 (2010)
15. Gough, D. J., A. Corlett, K. Schlessinger, J. Wegrzyn, A. C. Larner & D. E. Levy: Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science, 324, 1713-6 (2009)
16. Pilz, A., W. Kratky, S. Stockinger, O. Simma, U. Kalinke, K. Lingnau, A. von Gabain, D. Stoiber, V. Sexl, T. Kolbe, T. Rulicke, M. Muller & T. Decker: Dendritic cells require STAT-1 phosphorylated at its transactivating domain for the induction of peptide-specific CTL. J Immunol, 183, 2286-93 (2009)
17. Weaver, A. M. & C. M. Silva: S731 in the transactivation domain modulates STAT5b activity. Biochem Biophys Res Commun, 362, 1026-30 (2007) (Pubitemid 47390677)
18. McCubrey, J. A., W. S. May, V. Duronio & A. Mufson: Serine/threonine phosphorylation in cytokine signal transduction. Leukemia, 14, 9-21 (2000)
19. Beuvink, I., D. Hess, H. Flotow, J. Hofsteenge, B. Groner & N. E. Hynes: Stat5a serine phosphorylation. Serine 779 is constitutively phosphorylated in the mammary gland, and serine 725 phosphorylation influences prolactin-stimulated in vitro DNA binding activity. J Biol Chem, 275, 10247-55 (2000) (Pubitemid 30202081)
20. Zakharova, N., E. S. Lymar, E. Yang, S. Malik, J. J. Zhang, R. G. Roeder & J. E. Darnell, Jr.: Distinct transcriptional activation functions of STAT1alpha and STAT1beta on DNA and chromatin templates. J Biol Chem, 278, 43067-73 (2003) (Pubitemid 37345922)
21. Varinou, L., K. Ramsauer, M. Karaghiosoff, T. Kolbe, K. Pfeffer, M. Muller & T. Decker: Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. Immunity, 19, 793-802 (2003) (Pubitemid 37542300)
22. Kim, J. H., M. S. Yoon & J. Chen: Signal transducer and activator of transcription 3 (STAT3) mediates amino acid inhibition of insulin signaling through serine 727 phosphorylation. J Biol Chem, 284, 35425-32 (2009)
23. Wegrzyn, J., R. Potla, Y. J. Chwae, N. B. Sepuri, Q. Zhang, T. Koeck, M. Derecka, K. Szczepanek, M. Szelag, A. Gornicka, A. Moh, S. Moghaddas, Q. Chen, S. Bobbili, J. Cichy, J. Dulak, D. P. Baker, A. Wolfman, D. Stuehr, M. O. Hassan, X. Y. Fu, N. Avadhani, J. I. Drake, P. Fawcett, E. J. Lesnefsky & A. C. Larner: Function of mitochondrial Stat3 in cellular respiration. Science, 323, 793-7 (2009)
24. Frank, D. A., S. Mahajan & J. Ritz: B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Invest, 100, 3140-8 (1997) (Pubitemid 28022852)
25. Aziz, M. H., H. T. Manoharan, D. R. Church, N. E. Dreckschmidt, W. Zhong, T. D. Oberley, G. Wilding & A. K. Verma: Protein kinase Cepsilon interacts with signal transducers and activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and regulates its constitutive activation in prostate cancer. Cancer Res, 67, 8828-38 (2007) (Pubitemid 47437459)
26. Aziz, M. H., H. T. Manoharan, J. M. Sand & A. K. Verma: Protein kinase Cepsilon interacts with Stat3 and regulates its activation that is essential for the development of skin cancer. Mol Carcinog, 46, 646-53 (2007) (Pubitemid 47255182)
27. Qin, H. R., H. J. Kim, J. Y. Kim, E. M. Hurt, G. J. Klarmann, B. T. Kawasaki, M. A. Duhagon Serrat & W. L. Farrar: Activation of signal transducer and activator of transcription 3 through a phosphomimetic serine 727 promotes prostate tumorigenesis independent of tyrosine 705 phosphorylation. Cancer Res, 68, 7736-41 (2008)
28. Pesu, M., K. Takaluoma, S. Aittomaki, A. Lagerstedt, K. Saksela, P. E. Kovanen & O. Silvennoinen: Interleukin-4-induced transcriptional activation by stat6 involves multiple serine/threonine kinase pathways and serine phosphorylation of stat6. Blood, 95, 494-502 (2000) (Pubitemid 30041661)
29. Wick, K. R. & M. T. Berton: IL-4 induces serine phosphorylation of the STAT6 transactivation domain in B lymphocytes. Mol Immunol, 37, 641-52 (2000) (Pubitemid 32112652)
30. Wang, D., R. Moriggl, D. Stravopodis, N. Carpino, J. C. Marine, S. Teglund, J. Feng & J. N. Ihle: A small amphipathic alpha-helical region is required for transcriptional activities and proteasome-dependent turnover of the tyrosine-phosphorylated Stat5. Embo J, 19, 392-9 (2000) (Pubitemid 30072609)
31. Clark, D. E., C. C. Williams, T. T. Duplessis, K. L. Moring, A. R. Notwick, W. Long, W. S. Lane, I. Beuvink, N. E. Hynes & F. E. Jones: ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events. J Biol Chem, 280, 24175-80 (2005) (Pubitemid 40884906)
32. Sun, W., M. Snyder, D. E. Levy & J. J. Zhang: Regulation of Stat3 transcriptional activity by the conserved LPMSP motif for OSM and IL-6 signaling. FEBS Lett, 580, 5880-4 (2006) (Pubitemid 44584288)
33. Visconti, R., M. Gadina, M. Chiariello, E. H. Chen, L. F. Stancato, J. S. Gutkind & J. J. O'Shea: Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood, 96, 1844-52 (2000) (Pubitemid 30662111)
34. Yamashita, H., J. Xu, R. A. Erwin, W. L. Farrar, R. A. Kirken & H. Rui: Differential control of the phosphorylation state of proline-juxtaposed serine residues Ser725 of Stat5a and Ser730 of Stat5b in prolactin-sensitive cells. J Biol Chem, 273, 30218-24 (1998) (Pubitemid 28545486)
35. Chung, J., E. Uchida, T. C. Grammer & J. Blenis: STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol, 17, 6508-16 (1997) (Pubitemid 27451197)
36. Schuringa, J. J., A. T. Wierenga, W. Kruijer & E. Vellenga: Constitutive Stat3, Tyr705, and Ser727 phosphorylation in acute myeloid leukemia cells caused by the autocrine secretion of interleukin-6. Blood, 95, 3765-70 (2000) (Pubitemid 30412848)
37. Decker, T., M. Müller & P. Kovarik: In: Signal Transducers and Activators of Transcription (Stats): Activation and Biology. Ed: P. B. Seghal, Levy, D. E., and Hirano, T., Kluwer Academic, Dordrecht (2003)
38. Morinobu, A., M. Gadina, W. Strober, R. Visconti, A. Fornace, C. Montagna, G. M. Feldman, R. Nishikomori & J. J. O'Shea: STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A, 99, 12281-6 (2002)
39. Moriggl, R., S. Berchtold, K. Friedrich, G. J. Standke, W. Kammer, M. Heim, M. Wissler, E. Stocklin, F. Gouilleux & B. Groner: Comparison of the transactivation domains of Stat5 and Stat6 in lymphoid cells and mammary epithelial cells. Mol Cell Biol, 17, 3663-78 (1997) (Pubitemid 27281841)
40. Pesu, M., S. Aittomaki, K. Takaluoma, A. Lagerstedt & O. Silvennoinen: p38 Mitogen-activated protein kinase regulates interleukin-4-induced gene expression by stimulating STAT6-mediated transcription. J Biol Chem, 277, 38254-61 (2002) (Pubitemid 35154680)
41. Maiti, N. R., P. Sharma, P. C. Harbor & S. J. Haque: Serine phosphorylation of Stat6 negatively controls its DNA-binding function. J Interferon Cytokine Res, 25, 553-63 (2005) (Pubitemid 41395843)
42. Xue, H. H., D. W. Fink, Jr., X. Zhang, J. Qin, C. W. Turck & W. J. Leonard: Serine phosphorylation of Stat5 proteins in lymphocytes stimulated with IL-2. Int Immunol, 14, 1263-71 (2002) (Pubitemid 35331423)
43. Park, S. H., H. Yamashita, H. Rui & D. J. Waxman: Serine phosphorylation of GH-activated signal transducer and activator of transcription 5a (STAT5a) and STAT5b: impact on STAT5 transcriptional activity. Mol Endocrinol, 15, 2157-71 (2001) (Pubitemid 33141135)
44. Kim, S., T. Koga, M. Isobe, B. E. Kern, T. Yokochi, Y. E. Chin, G. Karsenty, T. Taniguchi & H. Takayanagi: Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev, 17, 1979-91 (2003) (Pubitemid 36999325)
45. Yang, J., M. Chatterjee-Kishore, S. M. Staugaitis, H. Nguyen, K. Schlessinger, D. E. Levy & G. R. Stark: Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. Cancer Res, 65, 939-47 (2005) (Pubitemid 40216455)
46. Durant, L., W. T. Watford, H. L. Ramos, A. Laurence, G. Vahedi, L. Wei, H. Takahashi, H. W. Sun, Y. Kanno, F. Powrie & J. J. O'Shea: Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity, 32, 605-15 (2010)
47. Wei, L., G. Vahedi, H. W. Sun, W. T. Watford, H. Takatori, H. L. Ramos, H. Takahashi, J. Liang, G. Gutierrez-Cruz, C. Zang, W. Peng, J. J. O'Shea & Y. Kanno: Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity, 32, 840-51 (2010)
48. Tanaka, T., M. A. Soriano & M. J. Grusby: SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity, 22, 729-36 (2005) (Pubitemid 40814503)
49. Ramsauer, K., M. Farlik, G. Zupkovitz, C. Seiser, A. Kroger, H. Hauser & T. Decker: Distinct modes of action applied by transcription factors STAT1 and IRF1 to initiate transcription of the IFN-gamma-inducible gbp2 gene. Proc Natl Acad Sci U S A, 104, 2849-54 (2007) (Pubitemid 46327968)
50. Litterst, C. M., S. Kliem, D. Marilley & E. Pfitzner: NCoA-1/SRC-1 is an essential coactivator of STAT5 that binds to the FDL motif in the alpha-helical region of the STAT5 transactivation domain. J Biol Chem, 278, 45340-51 (2003) (Pubitemid 37432670)
51. Magne, S., S. Caron, M. Charon, M. C. Rouyez & I. Dusanter-Fourt: STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression. Mol Cell Biol, 23, 8934-45 (2003) (Pubitemid 37499784)
52. Letimier, F. A., N. Passini, S. Gasparian, E. Bianchi & L. Rogge: Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation. Embo J, 26, 1292-302 (2007) (Pubitemid 46398709)
53. Pattenden, S. G., R. Klose, E. Karaskov & R. Bremner: Interferon-gamma-induced chromatin remodeling at the CIITA locus is BRG1 dependent. Embo J, 21, 1978-86 (2002) (Pubitemid 34437195)
54. Liu, H., H. Kang, R. Liu, X. Chen & K. Zhao: Maximal induction of a subset of interferon target genes requires the chromatin-remodeling activity of the BAF complex. Mol Cell Biol, 22, 6471-9 (2002)
55. Huang, M., F. Qian, Y. Hu, C. Ang, Z. Li & Z. Wen: Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-alpha-inducible genes. Nat Cell Biol, 4, 774-81 (2002) (Pubitemid 35214771)
56. Litterst, C. M. & E. Pfitzner: Transcriptional activation by STAT6 requires the direct interaction with NCoA-1. J Biol Chem, 276, 45713-21 (2001)
57. Litterst, C. M. & E. Pfitzner: An LXXLL motif in the transactivation domain of STAT6 mediates recruitment of NCoA-1/SRC-1. J Biol Chem, 277, 36052-60 (2002)
58. Kovarik, P., M. Mangold, K. Ramsauer, H. Heidari, R. Steinborn, A. Zotter, D. E. Levy, M. Muller & T. Decker: Specificity of signaling by STAT1 depends on SH2 and Cterminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression. Embo J, 20, 91-100 (2001) (Pubitemid 32099105)
59. Kovarik, P., D. Stoiber, P. A. Eyers, R. Menghini, A. Neininger, M. Gaestel, P. Cohen & T. Decker: Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogenactivated protein kinase whereas IFN-gamma uses a different signaling pathway. Proc Natl Acad Sci U S A, 96, 13956-61 (1999)
60. Su, L., R. C. Rickert & M. David: Rapid STAT phosphorylation via the B cell receptor. Modulatory role of CD19. J Biol Chem, 274, 31770-4 (1999)
61. Ng, J. & D. Cantrell: STAT3 is a serine kinase target in T lymphocytes. Interleukin 2 and T cell antigen receptor signals converge upon serine 727. J Biol Chem, 272, 24542-9 (1997) (Pubitemid 27418667)
62. Stephens, J. M., S. J. Lumpkin & J. B. Fishman: Activation of signal transducers and activators of transcription 1 and 3 by leukemia inhibitory factor, oncostatin-M, and interferon-gamma in adipocytes. J Biol Chem, 273, 31408-16 (1998) (Pubitemid 28533160)
63. Lim, C. P. & X. Cao: Regulation of Stat3 activation by MEK kinase 1. J Biol Chem, 276, 21004-11 (2001)
64. Imada, K., E. T. Bloom, H. Nakajima, J. A. Horvath-Arcidiacono, G. B. Udy, H. W. Davey & W. J. Leonard: Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J Exp Med, 188, 2067-74 (1998) (Pubitemid 28562523)
65. Udy, G. B., R. P. Towers, R. G. Snell, R. J. Wilkins, S. H. Park, P. A. Ram, D. J. Waxman & H. W. Davey: Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A, 94, 7239-44 (1997) (Pubitemid 27345299)
66. Boucheron, C., S. Dumon, S. C. Santos, R. Moriggl, L. Hennighausen, S. Gisselbrecht & F. Gouilleux: A single amino acid in the DNA binding regions of STAT5A and STAT5B confers distinct DNA binding specificities. J Biol Chem, 273, 33936-41 (1998) (Pubitemid 29008857)
67. Ehret, G. B., P. Reichenbach, U. Schindler, C. M. Horvath, S. Fritz, M. Nabholz & P. Bucher: DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites. J Biol Chem, 276, 6675-88 (2001)
68. Moriggl, R., V. Gouilleux-Gruart, R. Jahne, S. Berchtold, C. Gartmann, X. Liu, L. Hennighausen, A. Sotiropoulos, B. Groner & F. Gouilleux: Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Mol Cell Biol, 16, 5691-700 (1996) (Pubitemid 26315089)
69. Soldaini, E., S. John, S. Moro, J. Bollenbacher, U. Schindler & W. J. Leonard: DNA binding site selection of dimeric and tetrameric Stat5 proteins reveals a large repertoire of divergent tetrameric Stat5a binding sites. Mol Cell Biol, 20, 389-401 (2000) (Pubitemid 30002580)
70. Verdier, F., R. Rabionet, F. Gouilleux, C. Beisenherz-Huss, P. Varlet, O. Muller, P. Mayeux, C. Lacombe, S. Gisselbrecht & S. Chretien: A sequence of the CIS gene promoter interacts preferentially with two associated STAT5A dimers: a distinct biochemical difference between STAT5A and STAT5B. Mol Cell Biol, 18, 5852-60 (1998) (Pubitemid 28450536)
71. Gebert, C. A., S. H. Park & D. J. Waxman: Regulation of signal transducer and activator of transcription (STAT) 5b activation by the temporal pattern of growth hormone stimulation. Mol Endocrinol, 11, 400-14 (1997) (Pubitemid 27147007)
72. Kirken, R. A., M. G. Malabarba, J. Xu, X. Liu, W. L. Farrar, L. Hennighausen, A. C. Larner, P. M. Grimley & H. Rui: Prolactin stimulates serine/tyrosine phosphorylation and formation of heterocomplexes of multiple Stat5 isoforms in Nb2 lymphocytes. J Biol Chem, 272, 14098-103 (1997) (Pubitemid 27232814)
73. Wartmann, M., N. Cella, P. Hofer, B. Groner, X. Liu, L. Hennighausen & N. E. Hynes: Lactogenic hormone activation of Stat5 and transcription of the beta-casein gene in mammary epithelial cells is independent of p42 ERK2 mitogen-activated protein kinase activity. J Biol Chem, 271, 31863-8 (1996) (Pubitemid 26422207)
74. Beadling, C., J. Ng, J. W. Babbage & D. A. Cantrell: Interleukin-2 activation of STAT5 requires the convergent action of tyrosine kinases and a serine/threonine kinase pathway distinct from the Raf1/ERK2 MAP kinase pathway. Embo J, 15, 1902-13 (1996) (Pubitemid 26119693)
75. Pfitzner, E., R. Jahne, M. Wissler, E. Stoecklin & B. Groner: p300/CREB-binding protein enhances the prolactin-mediated transcriptional induction through direct interaction with the transactivation domain of Stat5, but does not participate in the Stat5-mediated suppression of the glucocorticoid response. Mol Endocrinol, 12, 1582-93 (1998) (Pubitemid 30663440)
76. Zhu, M., S. John, M. Berg & W. J. Leonard: Functional association of Nmi with Stat5 and Stat1 in IL-2-and IFNgamma-mediated signaling. Cell, 96, 121-30 (1999)
77. Stocklin, E., M. Wissler, F. Gouilleux & B. Groner: Functional interactions between Stat5 and the glucocorticoid receptor. Nature, 383, 726-8 (1996) (Pubitemid 26360650)
78. Gewinner, C., G. Hart, N. Zachara, R. Cole, C. Beisenherz-Huss & B. Groner: The coactivator of transcription CREB-binding protein interacts preferentially with the glycosylated form of Stat5. J Biol Chem, 279, 3563-72 (2004) (Pubitemid 38140596)
79. Wang, D., D. Stravopodis, S. Teglund, J. Kitazawa & J. N. Ihle: Naturally occurring dominant negative variants of Stat5. Mol Cell Biol, 16, 6141-8 (1996) (Pubitemid 26360974)
80. Kazansky, A. V., B. Raught, S. M. Lindsey, Y. F. Wang & J. M. Rosen: Regulation of mammary gland factor/Stat5a during mammary gland development. Mol Endocrinol, 9, 1598-609 (1995)
81. Li, G., Z. Wang, Y. Zhang, Z. Kang, E. Haviernikova, Y. Cui, L. Hennighausen, R. Moriggl, D. Wang, W. Tse & K. D. Bunting: STAT5 requires the N-domain to maintain hematopoietic stem cell repopulating function and appropriate lymphoid-myeloid lineage output. Exp Hematol, 35, 1684-94 (2007) (Pubitemid 47633780)
82. Kamemura, K., B. K. Hayes, F. I. Comer & G. W. Hart: Dynamic interplay between O-glycosylation and Ophosphorylation of nucleocytoplasmic proteins: alternative glycosylation/phosphorylation of THR-58, a known mutational hot spot of c-Myc in lymphomas, is regulated by mitogens. J Biol Chem, 277, 19229-35 (2002) (Pubitemid 34952491)
83. Wang, Z., M. Gucek & G. W. Hart: Cross-talk between GlcNAcylation and phosphorylation: site-specific phosphorylation dynamics in response to globally elevated O-GlcNAc. Proc Natl Acad Sci U S A, 105, 13793-8 (2008)
84. Jackson, S. P. & R. Tjian: O-glycosylation of eukaryotic transcription factors: implications for mechanisms of transcriptional regulation. Cell, 55, 125-33 (1988)
85. Garcia, R., C. L. Yu, A. Hudnall, R. Catlett, K. L. Nelson, T. Smithgall, D. J. Fujita, S. P. Ethier & R. Jove: Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ, 8, 1267-76 (1997) (Pubitemid 28008723)
86. Plaza-Menacho, I., T. van der Sluis, H. Hollema, O. Gimm, C. H. Buys, A. I. Magee, C. M. Isacke, R. M. Hofstra & B. J. Eggen: Ras/ERK1/2-mediated STAT3 Ser727 phosphorylation by familial medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity, and transformation. J Biol Chem, 282, 6415-24 (2007) (Pubitemid 47100884)
87. Bunting, K. D.: STAT5 signaling in normal and pathologic hematopoiesis. Front Biosci, 12, 2807-20 (2007)
88. Harir, N., C. Boudot, K. Friedbichler, K. Sonneck, R. Kondo, S. Martin-Lanneree, L. Kenner, M. Kerenyi, S. Yahiaoui, V. Gouilleux-Gruart, J. Gondry, L. Benit, I. Dusanter-Fourt, K. Lassoued, P. Valent, R. Moriggl & F. Gouilleux: Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade. Blood, 112, 2463-73 (2008)
89. Harir, N., C. Pecquet, M. Kerenyi, K. Sonneck, B. Kovacic, R. Nyga, M. Brevet, I. Dhennin, V. Gouilleux-Gruart, H. Beug, P. Valent, K. Lassoued, R. Moriggl & F. Gouilleux: Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias. Blood, 109, 1678-86 (2007) (Pubitemid 46239602)
90. Nyga, R., C. Pecquet, N. Harir, H. Gu, I. Dhennin-Duthille, A. Regnier, V. Gouilleux-Gruart, K. Lassoued & F. Gouilleux: Activated STAT5 proteins induce activation of the PI 3-kinase/Akt and Ras/MAPK pathways via the Gab2 scaffolding adapter. Biochem J, 390, 359-66 (2005) (Pubitemid 41192263)
91. Li, G., Z. Wang, K. L. Miskimen, Y. Zhang, W. Tse & K. D. Bunting: Gab2 promotes hematopoietic stem cell maintenance and self-renewal synergistically with STAT5. PLoS One, 5, e9152 (2010)
92. Zhang, Y., E. Diaz-Flores, G. Li, Z. Wang, Z. Kang, E. Haviernikova, S. Rowe, C. K. Qu, W. Tse, K. M. Shannon & K. D. Bunting: Abnormal hematopoiesis in Gab2 mutant mice. Blood, 110, 116-24 (2007) (Pubitemid 47026826)
93. Baumgartner, C., S. Cerny-Reiterer, K. Sonneck, M. Mayerhofer, K. V. Gleixner, R. Fritz, M. Kerenyi, C. Boudot, F. Gouilleux, J. W. Kornfeld, C. Sillaber, R. Moriggl & P. Valent: Expression of activated STAT5 in neoplastic mast cells in systemic mastocytosis: subcellular distribution and role of the transforming oncoprotein KIT D816V. Am J Pathol, 175, 2416-29 (2009)
94. Bunting, K. D., X. Y. Xie, I. Warshawsky & E. D. Hsi: Cytoplasmic localization of phosphorylated STAT5 in human acute myeloid leukemia is inversely correlated with Flt3-ITD. Blood, 110, 2775-6 (2007) (Pubitemid 47523213)
95. Li, G., K. L. Miskimen, Z. Wang, X. Y. Xie, W. Tse, F. Gouilleux, R. Moriggl & K. D. Bunting: Effective targeting of STAT5-mediated survival in myeloproliferative neoplasms using ABT-737 combined with rapamycin. Leukemia, 24, 1397-405 (2010)
96. Creamer, B. A., K. Sakamoto, J. W. Schmidt, A. A. Triplett, R. Moriggl & K. U. Wagner: Stat5 promotes survival of mammary epithelial cells through transcriptional activation of a distinct promoter in Akt1. Mol Cell Biol, 30, 2957-70 (2010)
97. Li, G., K. L. Miskimen, Z. Wang, X. Y. Xie, J. Brenzovich, J. J. Ryan, W. Tse, R. Moriggl & K. D. Bunting: STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease. Blood, 115, 1416-24 (2010)
98. Onishi, M., T. Nosaka, K. Misawa, A. L. Mui, D. Gorman, M. McMahon, A. Miyajima & T. Kitamura: Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol Cell Biol, 18, 3871-9 (1998) (Pubitemid 28287910)
99. Grebien, F., M. A. Kerenyi, B. Kovacic, T. Kolbe, V. Becker, H. Dolznig, K. Pfeffer, U. Klingmuller, M. Muller, H. Beug, E. W. Mullner & R. Moriggl: Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2. Blood, 111, 4511-22 (2008)
100. Moriggl, R., V. Sexl, L. Kenner, C. Duntsch, K. Stangl, S. Gingras, A. Hoffmeyer, A. Bauer, R. Piekorz, D. Wang, K. D. Bunting, E. F. Wagner, K. Sonneck, P. Valent, J. N. Ihle & H. Beug: Stat5 tetramer formation is associated with leukemogenesis. Cancer Cell, 7, 87-99 (2005) (Pubitemid 40126385)
101. Aoki, N. & T. Matsuda: A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus. Mol Endocrinol, 16, 58-69 (2002) (Pubitemid 34044498)
102. Chen, Y., R. Wen, S. Yang, J. Schuman, E. E. Zhang, T. Yi, G. S. Feng & D. Wang: Identification of Shp-2 as a Stat5A phosphatase. J Biol Chem, 278, 16520-7 (2003) (Pubitemid 36799512)
103. Johnson, K. J., A. R. Peck, C. Liu, T. H. Tran, F. E. Utama, A. B. Sjolund, J. D. Schaber, A. K. Witkiewicz & H. Rui: PTP1B Suppresses Prolactin Activation of Stat5 in Breast Cancer Cells. Am J Pathol (2010)
104. Rigacci, S., V. Guidotti, M. Parri & A. Berti: Modulation of STAT5 interaction with LMW-PTP during early megakaryocyte differentiation. Biochemistry, 47, 1482-9 (2008) (Pubitemid 351231199)
105. Xu, D. & C. K. Qu: Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci, 13, 4925-32 (2008) (Pubitemid 351599646)
106. Buettner, R., L. B. Mora & R. Jove: Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res, 8, 945-54 (2002) (Pubitemid 35177340)
107. Yu, H. & R. Jove: The STATs of cancer-new molecular targets come of age. Nat Rev Cancer, 4, 97-105 (2004) (Pubitemid 38198738)
108. Darnell, J. E., Jr.: Transcription factors as targets for cancer therapy. Nat Rev Cancer, 2, 740-9 (2002) (Pubitemid 37328909)
109. Uddin, S., F. Lekmine, N. Sharma, B. Majchrzak, I. Mayer, P. R. Young, G. M. Bokoch, E. N. Fish & L. C. Platanias: The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins. J Biol Chem, 275, 27634-40 (2000)
110. Uddin, S., B. Majchrzak, J. Woodson, P. Arunkumar, Y. Alsayed, R. Pine, P. R. Young, E. N. Fish & L. C. Platanias: Activation of the p38 mitogen-activated protein kinase by type I interferons. J Biol Chem, 274, 30127-31 (1999)
111. Zauberman, A., D. Zipori, M. Krupsky & R. Ben-Levy: Stress activated protein kinase p38 is involved in IL-6 induced transcriptional activation of STAT3. Oncogene, 18, 3886-93 (1999) (Pubitemid 29358567)
112. Pircher, T. J., H. Petersen, J. A. Gustafsson & L. A. Haldosen: Extracellular signal-regulated kinase (ERK) interacts with signal transducer and activator of transcription (STAT) 5a. Mol Endocrinol, 13, 555-65 (1999) (Pubitemid 30636423)
113. Kreegipuu, A., N. Blom & S. Brunak: PhosphoBase, a database of phosphorylation sites: release 2.0. Nucleic Acids Res, 27, 237-9 (1999) (Pubitemid 29209448)
114. Lilly, M. & A. Kraft: Enforced expression of the Mr 33,000 Pim-1 kinase enhances factor-independent survival and inhibits apoptosis in murine myeloid cells. Cancer Res, 57, 5348-55 (1997) (Pubitemid 27516373)
115. Mikkers, H., M. Nawijn, J. Allen, C. Brouwers, E. Verhoeven, J. Jonkers & A. Berns: Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors. Mol Cell Biol, 24, 6104-15 (2004) (Pubitemid 38787993)
116. Peng, C., A. Knebel, N. A. Morrice, X. Li, K. Barringer, J. Li, S. Jakes, B. Werneburg & L. Wang: Pim kinase substrate identification and specificity. J Biochem, 141, 353-62 (2007) (Pubitemid 46770388)
117. Gururaj, A. E., S. K. Rayala & R. Kumar: p21-activated kinase signaling in breast cancer. Breast Cancer Res, 7, 5-12 (2005) (Pubitemid 40214530)
118. Wang, R. A., R. K. Vadlamudi, R. Bagheri-Yarmand, I. Beuvink, N. E. Hynes & R. Kumar: Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands. J Cell Biol, 161, 583-92 (2003) (Pubitemid 36578582)
119. Ubersax, J. A. & J. E. Ferrell, Jr.: Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol, 8, 530-41 (2007) (Pubitemid 46985383)
120. Peng, B., K. D. Sutherland, E. Y. Sum, M. Olayioye, S. Wittlin, T. K. Tang, G. J. Lindeman & J. E. Visvader: CPAP is a novel stat5-interacting cofactor that augments stat5-mediated transcriptional activity. Mol Endocrinol, 16, 2019-33 (2002) (Pubitemid 35013452)
121. Paukku, K., J. Yang & O. Silvennoinen: Tudor and nuclease-like domains containing protein p100 function as coactivators for signal transducer and activator of transcription 5. Mol Endocrinol, 17, 1805-14 (2003) (Pubitemid 37072296)
122. Nakajima, H., P. K. Brindle, M. Handa & J. N. Ihle: Functional interaction of STAT5 and nuclear receptor corepressor SMRT: implications in negative regulation of STAT5-dependent transcription. Embo J, 20, 6836-44 (2001) (Pubitemid 33134213)