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PMID: 10698949 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation.

The EMBO journal ·Vol. 19 ·No. 5 ·2000-03-01 ·Pages 1087-97

Kumar V, Pandey P, Sabatini D, Kumar M, Majumder PK, Bharti A, Carmichael G, Kufe D, Kharbanda S

Abstract

Hormones and growth factors induce protein translation in part by phosphorylation of the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). The rapamycin and FK506-binding protein (FKBP)-target 1 (RAFT1, also known as FRAP) is a mammalian homolog of the Saccharomyces cerevisiae target of rapamycin proteins (mTOR) that regulates 4E-BP1. However, the molecular mechanisms involved in growth factor-initiated phosphorylation of 4E-BP1 are not well understood. Here we demonstrate that protein kinase Cdelta (PKCdelta) associates with RAFT1 and that PKCdelta is required for the phosphorylation and inactivation of 4E-BP1. PKCdelta-mediated phosphorylation of 4E-BP1 is wortmannin resistant but rapamycin sensitive. As shown for serum, phosphorylation of 4E-BP1 by PKCdelta inhibits the interaction between 4E-BP1 and eIF4E and stimulates cap-dependent translation. Moreover, a dominant-negative mutant of PKCdelta inhibits serum-induced phosphorylation of 4E-BP1. These findings demonstrate that PKCdelta associates with RAFT1 and thereby regulates phosphorylation of 4E-BP1 and cap-dependent initiation of protein translation.

MeSH Terms
Androstadienes/pharmacology Animals Anti-Bacterial Agents/pharmacology Carrier Proteins/genetics,metabolism Cell Line Isoenzymes/genetics,metabolism Peptide Initiation Factors/genetics,metabolism Phosphoproteins/genetics,metabolism Phosphorylation Phosphotransferases (Alcohol Group Acceptor) Protein Biosynthesis Protein Kinase C/genetics,metabolism Protein Kinase C-delta RNA, Messenger/genetics Sirolimus/metabolism,pharmacology TOR Serine-Threonine Kinases Wortmannin
Chemicals
Androstadienes Anti-Bacterial Agents Carrier Proteins Isoenzymes Peptide Initiation Factors Phosphoproteins RNA, Messenger Phosphotransferases (Alcohol Group Acceptor) TOR Serine-Threonine Kinases Protein Kinase C Protein Kinase C-delta Sirolimus Wortmannin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Kumar V
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Pandey P
Sabatini D
Kumar M
Majumder P K
Bharti A
Carmichael G
Kufe D
Kharbanda S
References (73)
73 references, click to expand
  1. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression.
    Cell. 1993 May 7;73(3):585-96 PMID: 8387896
  2. Cytoplasmic regulation of mRNA function: the importance of the 3' untranslated region.
    Cell. 1993 Jul 16;74(1):9-14 PMID: 7687524
  3. Cyclosporin A, FK506 and rapamycin: more than just immunosuppression.
    Trends Biochem Sci. 1993 Sep;18(9):334-8 PMID: 7694398
  4. Expression of an oncogenic rasHa gene in murine keratinocytes induces tyrosine phosphorylation and reduced activity of protein kinase C delta.
    J Biol Chem. 1993 Dec 15;268(35):26079-81 PMID: 8253722
  5. Rottlerin, a novel protein kinase inhibitor.
    Biochem Biophys Res Commun. 1994 Feb 28;199(1):93-8 PMID: 8123051
  6. Nuclear localization of p85s6k: functional requirement for entry into S phase.
    EMBO J. 1994 Apr 1;13(7):1557-65 PMID: 8156994
  7. Protein kinase C--a question of specificity.
    Trends Biochem Sci. 1994 Feb;19(2):73-7 PMID: 8160269
  8. Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors.
    Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3730-4 PMID: 8170978
  9. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family.
    Proc Natl Acad Sci U S A. 1994 May 10;91(10):4441-5 PMID: 8183928
  10. 4E-BP1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase.
    Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4076-80 PMID: 8633019
  11. Translocation of PKC delta by insulin in a rat hepatoma cell line.
    Endocrine. 1998 Apr;8(2):161-7 PMID: 9704573
  12. Regulation of DNA-dependent protein kinase by the Lyn tyrosine kinase.
    J Biol Chem. 1998 Oct 2;273(40):25654-8 PMID: 9748231
  13. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1.
    Science. 1998 Sep 25;281(5385):2042-5 PMID: 9748166
  14. Inactivation of DNA-dependent protein kinase by protein kinase Cdelta: implications for apoptosis.
    Mol Cell Biol. 1998 Nov;18(11):6719-28 PMID: 9774685
  15. Functional role for protein kinase Cbeta as a regulator of stress-activated protein kinase activation and monocytic differentiation of myeloid leukemia cells.
    Mol Cell Biol. 1999 Jan;19(1):461-70 PMID: 9858570
  16. Intracellular signalling: PDK1--a kinase at the hub of things.
    Curr Biol. 1999 Feb 11;9(3):R93-6 PMID: 10021376
  17. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism.
    Genes Dev. 1999 Jun 1;13(11):1422-37 PMID: 10364159
  18. Dissociation of the eukaryotic initiation factor-4E/4E-BP1 complex involves phosphorylation of 4E-BP1 by an mTOR-associated kinase.
    FEBS Lett. 1999 Sep 3;457(3):489-93 PMID: 10471835
  19. Mammalian TOR controls one of two kinase pathways acting upon nPKCdelta and nPKCepsilon.
    J Biol Chem. 1999 Dec 3;274(49):34758-64 PMID: 10574945
  20. Activation of the epidermal growth factor receptor signal transduction pathway stimulates tyrosine phosphorylation of protein kinase C delta.
    J Biol Chem. 1996 Mar 8;271(10):5325-31 PMID: 8621384
  21. Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus.
    Proc Natl Acad Sci U S A. 1996 May 28;93(11):5578-83 PMID: 8643618
  22. Protein kinase C delta specifically associates with phosphatidylinositol 3-kinase following cytokine stimulation.
    J Biol Chem. 1996 Jun 14;271(24):14514-8 PMID: 8663229
  23. Cloning and expression of cDNA encoding protein synthesis elongation factor-2 kinase.
    J Biol Chem. 1996 Jul 19;271(29):17547-54 PMID: 8663182
  24. The stress response to ionizing radiation involoves c-Abl-dependent phosphorylation of SHPTP1.
    Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):6898-901 PMID: 8692915
  25. A signaling pathway to translational control.
    Cell. 1996 Aug 23;86(4):517-20 PMID: 8752206
  26. TOR controls translation initiation and early G1 progression in yeast.
    Mol Biol Cell. 1996 Jan;7(1):25-42 PMID: 8741837
  27. Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf.
    J Biol Chem. 1996 Sep 20;271(38):23512-9 PMID: 8798560
  28. Phosphatidylinositol 3-kinase related kinases.
    Curr Opin Immunol. 1996 Jun;8(3):412-8 PMID: 8793996
  29. Control of the translational regulators PHAS-I and PHAS-II by insulin and cAMP in 3T3-L1 adipocytes.
    J Biol Chem. 1996 Nov 22;271(47):30199-204 PMID: 8939971
  30. Proteolytic activation of protein kinase C delta by an ICE/CED 3-like protease induces characteristics of apoptosis.
    J Exp Med. 1996 Dec 1;184(6):2399-404 PMID: 8976194
  31. Functional interaction between DNA-PK and c-Abl in response to DNA damage.
    Nature. 1997 Apr 17;386(6626):732-5 PMID: 9109492
  32. Nuclear antisense RNA induces extensive adenosine modifications and nuclear retention of target transcripts.
    Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3542-7 PMID: 9108012
  33. Association between v-Src and protein kinase C delta in v-Src-transformed fibroblasts.
    J Biol Chem. 1997 May 16;272(20):13275-80 PMID: 9148947
  34. Tumor promotion by depleting cells of protein kinase C delta.
    Mol Cell Biol. 1997 Jun;17(6):3418-28 PMID: 9154841
  35. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin.
    Science. 1997 Jul 4;277(5322):99-101 PMID: 9204908
  36. Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k.
    EMBO J. 1997 Jun 16;16(12):3693-704 PMID: 9218810
  37. Regulation of eIF-4E BP1 phosphorylation by mTOR.
    J Biol Chem. 1997 Oct 17;272(42):26457-63 PMID: 9334222
  38. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase.
    Curr Biol. 1997 Oct 1;7(10):776-89 PMID: 9368760
  39. TOR signalling and control of cell growth.
    Curr Opin Cell Biol. 1997 Dec;9(6):782-7 PMID: 9425342
  40. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1.
    Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1432-7 PMID: 9465032
  41. Interaction of polyadenylate-binding protein with the eIF4G homologue PAIP enhances translation.
    Nature. 1998 Apr 2;392(6675):520-3 PMID: 9548260
  42. The mRNA 5' cap-binding protein eIF4E and control of cell growth.
    Curr Opin Cell Biol. 1998 Apr;10(2):268-75 PMID: 9561852
  43. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway.
    Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7772-7 PMID: 9636226
  44. The heterogeneity and differential expression of multiple species of the protein kinase C family.
    Biofactors. 1988 Jan;1(1):17-20 PMID: 3076428
  45. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast.
    Science. 1991 Aug 23;253(5022):905-9 PMID: 1715094
  46. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase.
    Nature. 1992 Jul 2;358(6381):70-3 PMID: 1614535
  47. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases.
    Cell. 1992 Jun 26;69(7):1227-36 PMID: 1377606
  48. Ras-dependent signal transduction is indispensable but not sufficient for the activation of AP1/Jun by PKC delta.
    EMBO J. 1994 May 15;13(10):2331-40 PMID: 8194525
  49. A mammalian protein targeted by G1-arresting rapamycin-receptor complex.
    Nature. 1994 Jun 30;369(6483):756-8 PMID: 8008069
  50. mRNA translation: influence of the 5' and 3' untranslated regions.
    Curr Opin Genet Dev. 1994 Apr;4(2):310-5 PMID: 8032210
  51. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs.
    Cell. 1994 Jul 15;78(1):35-43 PMID: 7518356
  52. Stimulation of the platelet-derived growth factor beta receptor signaling pathway activates protein kinase C-delta.
    Mol Cell Biol. 1994 Oct;14(10):6727-35 PMID: 7935392
  53. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function.
    Nature. 1994 Oct 27;371(6500):762-7 PMID: 7935836
  54. PHAS-I as a link between mitogen-activated protein kinase and translation initiation.
    Science. 1994 Oct 28;266(5185):653-6 PMID: 7939721
  55. Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins.
    Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11477-81 PMID: 7972087
  56. Interaction between FKBP12-rapamycin and TOR involves a conserved serine residue.
    J Biol Chem. 1994 Dec 23;269(51):32027-30 PMID: 7528205
  57. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells.
    J Biol Chem. 1995 Jan 13;270(2):815-22 PMID: 7822316
  58. The first and third uORFs in RSV leader RNA are efficiently translated: implications for translational regulation and viral RNA packaging.
    Nucleic Acids Res. 1995 Mar 11;23(5):861-8 PMID: 7708504
  59. Protein kinase C and lipid signaling for sustained cellular responses.
    FASEB J. 1995 Apr;9(7):484-96 PMID: 7737456
  60. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents.
    Nature. 1995 Aug 31;376(6543):785-8 PMID: 7651539
  61. Control of p70 s6 kinase by kinase activity of FRAP in vivo.
    Nature. 1995 Oct 5;377(6548):441-6 PMID: 7566123
  62. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints.
    Science. 1995 Oct 6;270(5233):50-1 PMID: 7569949
  63. Growth-dependent translation of IGF-II mRNA by a rapamycin-sensitive pathway.
    Nature. 1995 Sep 28;377(6547):358-62 PMID: 7566093
  64. The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain.
    EMBO J. 1995 Nov 1;14(21):5279-87 PMID: 7489717
  65. The protein kinase C and protein kinase C related gene families.
    Curr Opin Struct Biol. 1995 Jun;5(3):396-402 PMID: 7583639
  66. c-Abl activation regulates induction of the SEK1/stress-activated protein kinase pathway in the cellular response to 1-beta-D-arabinofuranosylcytosine.
    J Biol Chem. 1995 Dec 22;270(51):30278-81 PMID: 8530447
  67. Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells.
    EMBO J. 1995 Dec 15;14(24):6148-56 PMID: 8557034
  68. Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E.
    Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1065-70 PMID: 8577715
  69. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation.
    EMBO J. 1996 Feb 1;15(3):658-64 PMID: 8599949
  70. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase.
    Science. 1992 Aug 14;257(5072):973-7 PMID: 1380182
  71. A new member of the protein kinase C family, nPKC theta, predominantly expressed in skeletal muscle.
    Mol Cell Biol. 1992 Sep;12(9):3930-8 PMID: 1508194
  72. Cell division arrest induced by phorbol ester in CHO cells overexpressing protein kinase C-delta subspecies.
    Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10159-63 PMID: 1438205
  73. p70s6k function is essential for G1 progression.
    Nature. 1993 May 13;363(6425):170-2 PMID: 8483501
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.5.1087
Published
2000-03-01
Pages
1087-97
Language
English
Region
England
NLM ID
8208664
PMCID
PMC305647
Subset
IM
Grants
NCI NIH HHS · CA75216 · United States
External Links
PubMed source DOI: 10.1093/emboj/19.5.1087 PMC Full Text View journal details
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