Home LiteratureArticle Details
PMID: 1328860 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Jun is phosphorylated by several protein kinases at the same sites that are modified in serum-stimulated fibroblasts.

Molecular and cellular biology ·Vol. 12 ·No. 10 ·1992-10-00 ·Pages 4694-705

Baker SJ, Kerppola TK, Luk D, Vandenberg MT, Marshak DR, Curran T, Abate C

Abstract

c-jun is a member of the family of immediate-early genes whose expression is induced by factors such as serum stimulation, phorbol ester, and differentiation signals. Here we show that increased Jun synthesis after serum stimulation is accompanied by a concomitant increase in phosphorylation. Several serine-threonine kinases were evaluated for their ability to phosphorylate Jun in vitro. p34cdc2, protein kinase C, casein kinase II, and pp44mapk phosphorylated Jun efficiently, whereas cyclic AMP-dependent protein kinase and glycogen synthase kinase III did not. The sites phosphorylated by p34cdc2 were similar to those phosphorylated in vivo after serum induction. The major sites of phosphorylation were mapped to serines 63, 73, and 246. Phosphorylation of full-length Jun with several kinases did not affect the DNA-binding activity of Jun homodimers or Fos-Jun heterodimers. Comparison of the DNA binding and in vitro transcription properties of wild-type and mutated proteins containing either alanine or aspartic acid residues in place of Ser-63, -73, and -246 revealed only minor differences among homodimeric complexes and no differences among Fos-Jun heterodimers. Thus, phosphorylation of Jun did not produce a significant change in dimerization, DNA-binding, or in vitro transcription activity. The regulatory role of phosphorylation in the modulation of Jun function is likely to be considerably more complex than previously suggested.

Related Genes
MeSH Terms
Blood CDC2 Protein Kinase/metabolism Calcium-Calmodulin-Dependent Protein Kinases Casein Kinases DNA/metabolism DNA Mutational Analysis Fibroblasts/metabolism Glycogen Synthase Kinases HeLa Cells Humans Phosphorylation Protein Binding Protein Kinase C/metabolism Protein Kinases/metabolism Proto-Oncogene Proteins c-jun/biosynthesis,metabolism Serine/metabolism Transcription, Genetic
Chemicals
Proto-Oncogene Proteins c-jun Serine DNA Protein Kinases Glycogen Synthase Kinases Casein Kinases Protein Kinase C Calcium-Calmodulin-Dependent Protein Kinases CDC2 Protein Kinase
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Baker S J
Department of Molecular Oncology and Virology, Roche Institute of Molecular Biology, Nutley, New Jersey 07110.
Kerppola T K
Luk D
Vandenberg M T
Marshak D R
Curran T
Abate C
References (93)
93 references, click to expand
  1. The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes.
    Genes Dev. 1989 Feb;3(2):173-84 PMID: 2497053
  2. Preferential heterodimer formation by isolated leucine zippers from fos and jun.
    Science. 1989 Aug 11;245(4918):646-8 PMID: 2503872
  3. Leucine zippers of fos, jun and GCN4 dictate dimerization specificity and thereby control DNA binding.
    Nature. 1989 Aug 17;340(6234):568-71 PMID: 2505081
  4. Purification and characterization of an insulin-like growth factor II variant from human plasma.
    J Biol Chem. 1989 Nov 15;264(32):19155-60 PMID: 2553732
  5. The avian cellular homolog of the oncogene jun.
    Oncogene. 1988 Dec;3(6):659-63 PMID: 2577867
  6. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB.
    Nature. 1988 Aug 11;334(6182):494-8 PMID: 2900470
  7. The Fos complex and Fos-related antigens recognize sequence elements that contain AP-1 binding sites.
    Science. 1988 Mar 4;239(4844):1150-3 PMID: 2964084
  8. 12-o-Tetradecanoyl-phorbol-13-acetate-differentiated U937 cells express a macrophage-like profile of neutral proteinases. High levels of secreted collagenase and collagenase inhibitor accompany low levels of intracellular elastase and cathepsin G.
    J Clin Invest. 1986 May;77(5):1675-81 PMID: 3009552
  9. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor.
    Cell. 1987 Jun 19;49(6):729-39 PMID: 3034432
  10. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements.
    Cell. 1987 Jun 19;49(6):741-52 PMID: 3034433
  11. Memories of fos.
    Bioessays. 1987 Dec;7(6):255-8 PMID: 3124834
  12. Fos and Jun: the AP-1 connection.
    Cell. 1988 Nov 4;55(3):395-7 PMID: 3141060
  13. c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities.
    Cell. 1988 Dec 2;55(5):917-24 PMID: 3142692
  14. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins.
    Science. 1988 Jun 24;240(4860):1759-64 PMID: 3289117
  15. Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc.
    Proc Natl Acad Sci U S A. 1987 Mar;84(5):1182-6 PMID: 3469660
  16. Candidate product of the FBJ murine osteosarcoma virus oncogene: characterization of a 55,000-dalton phosphoprotein.
    J Virol. 1982 Apr;42(1):114-22 PMID: 6283132
  17. Molecular weight determinations of proteins by californium plasma desorption mass spectrometry.
    Science. 1984 Nov 9;226(4675):696-8 PMID: 6387912
  18. MAP kinase by any other name smells just as sweet.
    Cell. 1992 Jan 10;68(1):3-6 PMID: 1310074
  19. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK.
    Cell. 1992 Mar 20;68(6):1041-50 PMID: 1312393
  20. Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity.
    EMBO J. 1992 Feb;11(2):653-65 PMID: 1537340
  21. Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669.
    J Biol Chem. 1991 Aug 15;266(23):15266-76 PMID: 1651322
  22. Growth-regulated signal transduction by the MAP kinases and RSKs.
    Cancer Cells. 1991 Nov;3(11):445-9 PMID: 1662059
  23. Transfer of proteins to membranes facilitates both cyanogen bromide cleavage and two-dimensional proteolytic mapping.
    Oncogene. 1990 Jun;5(6):921-3 PMID: 1688326
  24. Casein kinase II phosphorylation increases the rate of serum response factor-binding site exchange.
    EMBO J. 1992 Jan;11(1):97-105 PMID: 1740119
  25. The retinoblastoma protein is phosphorylated on multiple sites by human cdc2.
    EMBO J. 1991 Dec;10(13):4279-90 PMID: 1756735
  26. c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins.
    Oncogene. 1991 Apr;6(4):533-42 PMID: 1827665
  27. Synthetic peptide substrates for casein kinase II.
    Methods Enzymol. 1991;200:134-56 PMID: 1835512
  28. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity.
    Cell. 1991 Feb 8;64(3):573-84 PMID: 1846781
  29. A potential role for c-jun in cell cycle progression through late G1 and S.
    Oncogene. 1991 Feb;6(2):229-35 PMID: 1900357
  30. Primary response genes induced by growth factors and tumor promoters.
    Annu Rev Biochem. 1991;60:281-319 PMID: 1883198
  31. A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity.
    Cell. 1991 Feb 22;64(4):751-9 PMID: 1900040
  32. Interleukin-1 or phorbol induction of the stromelysin promoter requires an element that cooperates with AP-1.
    Nucleic Acids Res. 1991 Jan 25;19(2):335-41 PMID: 1901643
  33. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun.
    Annu Rev Neurosci. 1991;14:421-51 PMID: 1903243
  34. Transcriptional regulation by Fos and Jun in vitro: interaction among multiple activator and regulatory domains.
    Mol Cell Biol. 1991 Jul;11(7):3624-32 PMID: 1904542
  35. Long-term increase in the levels of c-jun mRNA and jun protein-like immunoreactivity in motor and sensory neurons following axon damage.
    Neurosci Lett. 1991 Aug 5;129(1):107-10 PMID: 1922958
  36. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.
    Cell. 1991 May 17;65(4):663-75 PMID: 2032290
  37. Redox regulation of fos and jun DNA-binding activity in vitro.
    Science. 1990 Sep 7;249(4973):1157-61 PMID: 2118682
  38. Fos and jun cooperate in transcriptional regulation via heterologous activation domains.
    Mol Cell Biol. 1990 Oct;10(10):5532-5 PMID: 2119000
  39. Altered protein conformation on DNA binding by Fos and Jun.
    Nature. 1990 Oct 11;347(6293):572-5 PMID: 2120592
  40. A ubiquitous nuclear protein stimulates the DNA-binding activity of fos and jun indirectly.
    Cell Growth Differ. 1990 Oct;1(10):455-62 PMID: 2126189
  41. mXBP/CRE-BP2 and c-Jun form a complex which binds to the cyclic AMP, but not to the 12-O-tetradecanoylphorbol-13-acetate, response element.
    Mol Cell Biol. 1990 Apr;10(4):1609-21 PMID: 2138707
  42. Direct cloning of leucine zipper proteins: Jun binds cooperatively to the CRE with CRE-BP1.
    Oncogene. 1990 Apr;5(4):451-8 PMID: 2139203
  43. Domain swapping reveals the modular nature of Fos, Jun, and CREB proteins.
    Mol Cell Biol. 1990 Sep;10(9):4565-73 PMID: 2143806
  44. Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene.
    Cell. 1990 May 4;61(3):497-504 PMID: 2159384
  45. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone.
    Cell. 1990 Sep 21;62(6):1189-204 PMID: 2169351
  46. Identification of Xenopus S6 protein kinase homologs (pp90rsk) in somatic cells: phosphorylation and activation during initiation of cell proliferation.
    Mol Cell Biol. 1990 Jun;10(6):3204-15 PMID: 2342472
  47. Fos and Jun bind cooperatively to the AP-1 site: reconstitution in vitro.
    Genes Dev. 1988 Dec;2(12B):1687-99 PMID: 2467839
  48. jun-D: a third member of the jun gene family.
    Proc Natl Acad Sci U S A. 1989 Mar;86(5):1500-3 PMID: 2493644
  49. Leucine repeats and an adjacent DNA binding domain mediate the formation of functional cFos-cJun heterodimers.
    Science. 1989 Mar 31;243(4899):1689-94 PMID: 2494701
  50. Expression of different Jun and Fos proteins during the G0-to-G1 transition in mouse fibroblasts: in vitro and in vivo associations.
    Mol Cell Biol. 1991 May;11(5):2451-9 PMID: 1901942
  51. Phosphorylation of c-jun mediated by MAP kinases.
    Nature. 1991 Oct 17;353(6345):670-4 PMID: 1922387
  52. The nonphosphorylated form of RNA polymerase II preferentially associates with the preinitiation complex.
    Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10004-8 PMID: 1946417
  53. Characterization of synthetic peptide substrates for p34cdc2 protein kinase.
    J Cell Biochem. 1991 Apr;45(4):391-400 PMID: 2045431
  54. Isolation of human fos-related genes and their expression during monocyte-macrophage differentiation.
    Oncogene. 1990 Mar;5(3):249-55 PMID: 2107490
  55. Analysis of dimerization and DNA binding functions in Fos and Jun by domain-swapping: involvement of residues outside the leucine zipper/basic region.
    Oncogene. 1990 Jun;5(6):929-39 PMID: 2113670
  56. Transcription factor interactions: selectors of positive or negative regulation from a single DNA element.
    Science. 1990 Sep 14;249(4974):1266-72 PMID: 2119054
  57. Control of c-Jun activity by interaction of a cell-specific inhibitor with regulatory domain delta: differences between v- and c-Jun.
    Cell. 1990 Nov 16;63(4):815-25 PMID: 2121368
  58. Heterodimer formation between CREB and JUN proteins.
    Oncogene. 1990 Mar;5(3):295-302 PMID: 2138276
  59. Negative and positive regulation by transcription factor cAMP response element-binding protein is modulated by phosphorylation.
    Proc Natl Acad Sci U S A. 1990 Jun;87(11):4320-4 PMID: 2140898
  60. Signal transduction by receptors with tyrosine kinase activity.
    Cell. 1990 Apr 20;61(2):203-12 PMID: 2158859
  61. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction.
    Cell. 1990 Sep 21;62(6):1205-15 PMID: 2169352
  62. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa.
    Anal Biochem. 1987 Nov 1;166(2):368-79 PMID: 2449095
  63. The leucine repeat motif in Fos protein mediates complex formation with Jun/AP-1 and is required for transformation.
    Cell. 1989 Feb 10;56(3):507-16 PMID: 2492453
  64. Parallel association of Fos and Jun leucine zippers juxtaposes DNA binding domains.
    Science. 1989 Mar 31;243(4899):1695-9 PMID: 2494702
  65. The product of a novel growth factor activated gene, fos B, interacts with JUN proteins enhancing their DNA binding activity.
    EMBO J. 1989 Mar;8(3):805-13 PMID: 2498083
  66. Biochemical analysis of transcriptional activation by Jun: differential activity of c- and v-Jun.
    Cell. 1989 Nov 17;59(4):709-17 PMID: 2510934
  67. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133.
    Cell. 1989 Nov 17;59(4):675-80 PMID: 2573431
  68. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene.
    Nature. 1987 Jul 9-15;328(6126):175-8 PMID: 2885756
  69. fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen.
    Mol Cell Biol. 1988 May;8(5):2063-9 PMID: 3133553
  70. DNA binding activities of three murine Jun proteins: stimulation by Fos.
    Cell. 1988 Dec 2;55(5):907-15 PMID: 3142691
  71. A gene activated by growth factors is related to the oncogene v-jun.
    Proc Natl Acad Sci U S A. 1988 Mar;85(5):1487-91 PMID: 3422745
  72. Aligning amino acid sequences: comparison of commonly used methods.
    J Mol Evol. 1984-1985;21(2):112-25 PMID: 6100188
  73. Yeast as a model system for understanding the control of DNA replication in Eukaryotes.
    Bioessays. 1990 Oct;12(10):457-63 PMID: 2082935
  74. Structural analysis of bovine pancreatic thread protein.
    J Protein Chem. 1990 Oct;9(5):623-32 PMID: 2085387
  75. Isolation and characterization of fra-2, an additional member of the fos gene family.
    Proc Natl Acad Sci U S A. 1990 May;87(9):3619-23 PMID: 2110368
  76. Prooxidant states and tumor promotion.
    Science. 1985 Jan 25;227(4685):375-81 PMID: 2981433
  77. Activation of transcription by two factors that bind promoter and enhancer sequences of the human metallothionein gene and SV40.
    Nature. 1987 Jan 22-28;325(6102):368-72 PMID: 3027570
  78. A thousand and one protein kinases.
    Cell. 1987 Sep 11;50(6):823-9 PMID: 3113737
  79. Functional antagonism between c-Jun and MyoD proteins: a direct physical association.
    Cell. 1992 Feb 7;68(3):507-19 PMID: 1310896
  80. Tyrosyl phosphorylation and activation of MAP kinases by p56lck.
    Science. 1992 Feb 14;255(5046):853-5 PMID: 1311128
  81. Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases.
    Cell. 1992 Mar 20;68(6):1031-40 PMID: 1312392
  82. Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme.
    EMBO J. 1992 Sep;11(9):3323-35 PMID: 1380454
  83. Nuclear localization and regulation of erk- and rsk-encoded protein kinases.
    Mol Cell Biol. 1992 Mar;12(3):915-27 PMID: 1545823
  84. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases.
    Science. 1991 Jun 7;252(5011):1427-30 PMID: 1646483
  85. Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation. Characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase.
    J Biol Chem. 1991 Aug 15;266(23):15277-85 PMID: 1651323
  86. Mitotic phosphorylation of the Oct-1 homeodomain and regulation of Oct-1 DNA binding activity.
    Science. 1991 Dec 20;254(5039):1814-6 PMID: 1684878
  87. A 42-kD tyrosine kinase substrate linked to chromaffin cell secretion exhibits an associated MAP kinase activity and is highly related to a 42-kD mitogen-stimulated protein in fibroblasts.
    J Cell Biol. 1990 Mar;110(3):731-42 PMID: 1689732
  88. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation.
    Science. 1991 Aug 23;253(5022):912-4 PMID: 1715095
  89. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73.
    Nature. 1991 Dec 12;354(6353):494-6 PMID: 1749429
  90. Fos is phosphorylated by p34cdc2, cAMP-dependent protein kinase and protein kinase C at multiple sites clustered within regulatory regions.
    Oncogene. 1991 Dec;6(12):2179-85 PMID: 1766667
  91. Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity.
    Proc Natl Acad Sci U S A. 1991 May 1;88(9):3720-4 PMID: 1827203
  92. NF-I proteins from brain interact with the proenkephalin cAMP inducible enhancer.
    Nucleic Acids Res. 1991 May 25;19(10):2721-8 PMID: 1828294
  93. Oncogenes and signal transduction.
    Cell. 1991 Jan 25;64(2):281-302 PMID: 1846320
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
Published
1992-10-00
Pages
4694-705
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC360396
Subset
IM
Grants
NCI NIH HHS · CA 13106 · United States
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]