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PMID: 8524316 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor.

Molecular and cellular biology ·Vol. 16 ·No. 1 ·1996-01-00 ·Pages 369-75

Leaman DW, Pisharody S, Flickinger TW, Commane MA, Schlessinger J, Kerr IM, Levy DE, Stark GR

Abstract

The tyrosine kinase JAK1 and the transcription factors STAT1 and STAT3 are phosphorylated in response to epidermal growth factor (EGF) and other growth factors. We have used EGF receptor-transfected cell lines defective in individual JAKs to assess the roles of these kinases in STAT activation and signal transduction in response to EGF. Although JAK1 is phosphorylated in response to EGF, it is not required for STAT activation or for induction of the c-fos gene. STAT activation in JAK2- and TYK2-defective cells is also normal, and the tyrosine phosphorylation of these two kinases does not increase upon EGF stimulation in wild-type or JAK1-negative cells. In cells transfected with a kinase-negative mutant EGF receptor, there is no STAT activation in response to EGF and c-fos is not induced, showing that the kinase activity of the receptor is required, directly or indirectly, for these two responses. The data do not support a role for any of the three JAK family members tested in STAT activation and are consistent with a JAK-independent pathway in which the intrinsic kinase domain of the EGF receptor is crucial. Furthermore, data from transient transfection experiments in HeLa cells, using c-fos promoters lacking the STAT regulatory element c-sis-inducible element, indicate that this element may play only a minor role in the induction of c-fos by EGF in these cells.

MeSH Terms
Base Sequence Cell Line DNA Primers/genetics DNA-Binding Proteins/metabolism Epidermal Growth Factor/pharmacology ErbB Receptors/metabolism Gene Expression/drug effects Genes, fos HeLa Cells Humans Janus Kinase 1 Molecular Sequence Data Protein-Tyrosine Kinases/metabolism STAT1 Transcription Factor STAT3 Transcription Factor Trans-Activators/metabolism
Chemicals
DNA Primers DNA-Binding Proteins STAT1 Transcription Factor STAT1 protein, human STAT3 Transcription Factor STAT3 protein, human Trans-Activators Epidermal Growth Factor ErbB Receptors Protein-Tyrosine Kinases JAK1 protein, human Janus Kinase 1
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Leaman D W
Department of Molecular Biology, Cleveland Clinic Foundation, Ohio 44195, USA.
Pisharody S
Flickinger T W
Commane M A
Schlessinger J
Kerr I M
Levy D E
Stark G R
References (76)
76 references, click to expand
  1. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing.
    Cell. 1987 Oct 23;51(2):199-209 PMID: 3499230
  2. c-fos sequence necessary for basal expression and induction by epidermal growth factor, 12-O-tetradecanoyl phorbol-13-acetate and the calcium ionophore.
    Mol Cell Biol. 1987 Oct;7(10):3490-502 PMID: 3119989
  3. Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene.
    Science. 1987 Dec 4;238(4832):1408-10 PMID: 3500513
  4. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization.
    Cell. 1988 Apr 8;53(1):37-43 PMID: 3127059
  5. The c-fos serum response element responds to protein kinase C-dependent and -independent signals but not to cyclic AMP.
    Genes Dev. 1988 Apr;2(4):394-402 PMID: 2453393
  6. Transcriptional autoregulation of the proto-oncogene fos.
    Nature. 1988 Jul 28;334(6180):314-9 PMID: 2839774
  7. Growth factor receptor tyrosine kinases.
    Annu Rev Biochem. 1988;57:443-78 PMID: 3052279
  8. Fos and Jun: the AP-1 connection.
    Cell. 1988 Nov 4;55(3):395-7 PMID: 3141060
  9. Biological activities of EGF-receptor mutants with individually altered autophosphorylation sites.
    EMBO J. 1988 Oct;7(10):3045-52 PMID: 3263271
  10. Transcription activation by serum, PDGF, and TPA through the c-fos DSE: cell type specific requirements for induction.
    Oncogene. 1989 Jan;4(1):3-11 PMID: 2915902
  11. Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction.
    Proc Natl Acad Sci U S A. 1989 Mar;86(5):1603-7 PMID: 2466296
  12. Multiple sequence elements in the c-fos promoter mediate induction by cAMP.
    Genes Dev. 1989 Feb;3(2):198-211 PMID: 2541049
  13. Occupation of the c-fos serum response element in vivo by a multi-protein complex is unaltered by growth factor induction.
    Nature. 1989 Jul 6;340(6228):68-70 PMID: 2786995
  14. trans-repression of the mouse c-fos promoter: a novel mechanism of Fos-mediated trans-regulation.
    Cell. 1989 Dec 22;59(6):999-1007 PMID: 2513130
  15. Use of a selectable marker regulated by alpha interferon to obtain mutations in the signaling pathway.
    Mol Cell Biol. 1989 Nov;9(11):4605-12 PMID: 2513475
  16. Signal transduction by receptors with tyrosine kinase activity.
    Cell. 1990 Apr 20;61(2):203-12 PMID: 2158859
  17. Structural design and molecular evolution of a cytokine receptor superfamily.
    Proc Natl Acad Sci U S A. 1990 Sep;87(18):6934-8 PMID: 2169613
  18. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes.
    Oncogene. 1990 Sep;5(9):1329-36 PMID: 2216457
  19. ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains.
    Proc Natl Acad Sci U S A. 1990 Nov;87(21):8555-9 PMID: 2236065
  20. Putative tyrosine kinases expressed in K-562 human leukemia cells.
    Proc Natl Acad Sci U S A. 1990 Nov;87(22):8913-7 PMID: 2247464
  21. Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator.
    Genes Dev. 1990 Oct;4(10):1753-65 PMID: 2249773
  22. The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma.
    EMBO J. 1990 Dec;9(13):4375-80 PMID: 2176151
  23. The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter.
    EMBO J. 1990 Dec;9(13):4477-84 PMID: 2176154
  24. Distinct protein targets for signals acting at the c-fos serum response element.
    Science. 1991 Jan 11;251(4990):189-92 PMID: 1898992
  25. Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase.
    Mol Cell Biol. 1991 Apr;11(4):2057-65 PMID: 1848670
  26. Isolation and characterization of a new mutant human cell line unresponsive to alpha and beta interferons.
    Mol Cell Biol. 1991 Aug;11(8):4189-95 PMID: 1906577
  27. High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both alpha and gamma interferons.
    Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11455-9 PMID: 1837150
  28. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130.
    Science. 1994 Jan 7;263(5143):89-92 PMID: 8272872
  29. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components.
    Science. 1994 Jan 7;263(5143):92-5 PMID: 8272873
  30. Cytokine signal transduction.
    Cell. 1994 Jan 28;76(2):253-62 PMID: 8293462
  31. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.
    Science. 1994 Apr 1;264(5155):95-8 PMID: 8140422
  32. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway.
    Cell. 1994 Apr 8;77(1):63-71 PMID: 7512451
  33. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response.
    EMBO J. 1994 May 1;13(9):2182-91 PMID: 7514531
  34. Stat3 and Stat4: members of the family of signal transducers and activators of transcription.
    Proc Natl Acad Sci U S A. 1994 May 24;91(11):4806-10 PMID: 7545930
  35. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.
    Science. 1994 Jun 3;264(5164):1415-21 PMID: 8197455
  36. Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation.
    Mol Cell Biol. 1994 Jul;14(7):4342-9 PMID: 8007943
  37. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2.
    Nature. 1994 Jul 14;370(6485):151-3 PMID: 8022485
  38. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells.
    Nature. 1994 Jul 14;370(6485):153-7 PMID: 8022486
  39. Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor.
    Mol Cell Biol. 1994 Aug;14(8):5192-201 PMID: 7518560
  40. Signaling by the cytokine receptor superfamily: JAKs and STATs.
    Trends Biochem Sci. 1994 May;19(5):222-7 PMID: 8048164
  41. Two pathways for serum regulation of the c-fos serum response element require specific sequence elements and a minimal domain of serum response factor.
    Mol Cell Biol. 1994 Sep;14(9):5920-8 PMID: 8065325
  42. An interleukin-4-induced transcription factor: IL-4 Stat.
    Science. 1994 Sep 16;265(5179):1701-6 PMID: 8085155
  43. Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors.
    J Biol Chem. 1994 Sep 30;269(39):24391-5 PMID: 7523373
  44. Transcriptional regulation by extracellular signals: mechanisms and specificity.
    Cell. 1995 Jan 27;80(2):199-211 PMID: 7834740
  45. Heterotrimeric G proteins: organizers of transmembrane signals.
    Cell. 1995 Jan 27;80(2):249-57 PMID: 7834744
  46. Regulation of c-fos expression in transgenic mice requires multiple interdependent transcription control elements.
    Neuron. 1995 Feb;14(2):241-52 PMID: 7857636
  47. Role of STAT2 in the alpha interferon signaling pathway.
    Mol Cell Biol. 1995 Mar;15(3):1312-7 PMID: 7532278
  48. Jaks and Stats in signaling by the cytokine receptor superfamily.
    Trends Genet. 1995 Feb;11(2):69-74 PMID: 7716810
  49. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.
    EMBO J. 1995 Apr 3;14(7):1421-9 PMID: 7537214
  50. An incomplete program of cellular tyrosine phosphorylations induced by kinase-defective epidermal growth factor receptors.
    J Biol Chem. 1995 May 19;270(20):12085-93 PMID: 7538132
  51. Alpha and beta interferons and their receptor and their friends and relations.
    J Interferon Cytokine Res. 1995 Jan;15(1):3-26 PMID: 7648431
  52. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway.
    Annu Rev Biochem. 1995;64:621-51 PMID: 7574495
  53. The SRE: a growth factor responsive transcriptional regulator.
    Semin Cancer Biol. 1990 Feb;1(1):47-58 PMID: 2133110
  54. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor.
    Science. 1992 Aug 7;257(5071):809-13 PMID: 1496401
  55. Activation of transcription factors by interferon-alpha in a cell-free system.
    Science. 1992 Aug 7;257(5071):813-5 PMID: 1496402
  56. Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha.
    Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7836-9 PMID: 1502203
  57. The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction.
    Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7840-3 PMID: 1502204
  58. Cell-free activation of a DNA-binding protein by epidermal growth factor.
    Nature. 1993 Mar 4;362(6415):79-83 PMID: 7680434
  59. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain.
    Cell. 1993 Apr 23;73(2):381-93 PMID: 8386592
  60. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation.
    Nature. 1993 May 6;363(6424):45-51 PMID: 8479536
  61. The mitogen-activated protein kinase signal transduction pathway.
    J Biol Chem. 1993 Jul 15;268(20):14553-6 PMID: 8325833
  62. Induction by EGF and interferon-gamma of tyrosine phosphorylated DNA binding proteins in mouse liver nuclei.
    Science. 1993 Sep 24;261(5129):1733-6 PMID: 8378774
  63. Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation.
    Science. 1993 Sep 24;261(5129):1736-9 PMID: 8378775
  64. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors.
    Science. 1993 Sep 24;261(5129):1739-44 PMID: 8397445
  65. Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter.
    Cell. 1993 Sep 24;74(6):1135-45 PMID: 8402883
  66. Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-alpha and -gamma signal transduction pathways.
    EMBO J. 1993 Nov;12(11):4221-8 PMID: 7693454
  67. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction.
    Nature. 1993 Nov 11;366(6451):129-35 PMID: 8232552
  68. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway.
    Nature. 1993 Nov 11;366(6451):166-70 PMID: 7901766
  69. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins.
    Nature. 1993 Dec 9;366(6455):580-3 PMID: 7504784
  70. Epidermal growth factor-induced down-regulation of receptor does not occur in HeLa cells grown in defined medium.
    Proc Natl Acad Sci U S A. 1980 May;77(5):2735-9 PMID: 6248863
  71. Amplification and enhanced expression of the epidermal growth factor receptor gene in A431 human carcinoma cells.
    Science. 1984 Apr 27;224(4647):417-9 PMID: 6200934
  72. Epidermal growth factor and oncogenes induce transcription of the same cellular mRNA in rat fibroblasts.
    EMBO J. 1985 Jun;4(6):1435-40 PMID: 3875482
  73. Transient accumulation of c-fos RNA following serum stimulation requires a conserved 5' element and c-fos 3' sequences.
    Cell. 1985 Oct;42(3):889-902 PMID: 2414012
  74. Interferon-stimulated transcription: isolation of an inducible gene and identification of its regulatory region.
    Proc Natl Acad Sci U S A. 1986 Dec;83(23):8929-33 PMID: 3466167
  75. Multiple protein-binding sites in the 5'-flanking region regulate c-fos expression.
    Mol Cell Biol. 1986 Dec;6(12):4305-16 PMID: 3025651
  76. Inducible binding of a factor to the c-fos regulatory region.
    Proc Natl Acad Sci U S A. 1987 Mar;84(5):1272-6 PMID: 3029776
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.16.1.369
Published
1996-01-00
Pages
369-75
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231011
Subset
IM
Grants
NIAID NIH HHS · F32-AI08956 · United States
NIAID NIH HHS · R01 AI28900 · United States
NCI NIH HHS · T32-CA09161 · United States
External Links
PubMed source DOI: 10.1128/MCB.16.1.369 PMC Full Text View journal details
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