Functional interaction between RAFT1/FRAP/mTOR and protein kinase Cδ in the regulation of cap‐dependent initiation of translation

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 Cδ (PKCδ) associates with RAFT1 and that PKCδ is required for the phosphorylation and inactivation of 4E‐BP1. PKCδ‐mediated phosphorylation of 4E‐BP1 is wortmannin resistant but rapamycin sensitive. As shown for serum, phosphorylation of 4E‐BP1 by PKCδ inhibits the interaction between 4E‐BP1 and eIF4E and stimulates cap‐dependent translation. Moreover, a dominant‐negative mutant of PKCδ inhibits serum‐induced phosphorylation of 4E‐BP1. These findings demonstrate that PKCδ associates with RAFT1 and thereby regulates phosphorylation of 4E–BP1 and cap‐dependent initiation of protein translation.

[1]  P. Parker,et al.  Mammalian TOR Controls One of Two Kinase Pathways Acting upon nPKCδ and nPKCε* , 1999, The Journal of Biological Chemistry.

[2]  R. Denton,et al.  Dissociation of the eukaryotic initiation factor‐4E/4E‐BP1 complex involves phosphorylation of 4E‐BP1 by an mTOR‐associated kinase , 1999, FEBS letters.

[3]  S. Gygi,et al.  Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. , 1999, Genes & development.

[4]  J. Avruch,et al.  Intracellular signalling: PDK1 – a kinase at the hub of things , 1999, Current Biology.

[5]  Functional Role for Protein Kinase Cβ as a Regulator of Stress-Activated Protein Kinase Activation and Monocytic Differentiation of Myeloid Leukemia Cells , 1999, Molecular and Cellular Biology.

[6]  Shengfang Jin,et al.  Inactivation of DNA-Dependent Protein Kinase by Protein Kinase Cδ: Implications for Apoptosis , 1998, Molecular and Cellular Biology.

[7]  Shengfang Jin,et al.  Regulation of DNA-dependent Protein Kinase by the Lyn Tyrosine Kinase* , 1998, The Journal of Biological Chemistry.

[8]  Philip R. Cohen,et al.  Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. , 1998, Science.

[9]  R. Roth,et al.  Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  N. Sonenberg,et al.  Interaction of polyadenylate-binding protein with the eIF4G homologue PAIP enhances translation , 1998, Nature.

[11]  A. Gingras,et al.  The mRNA 5' cap-binding protein eIF4E and control of cell growth. , 1998, Current opinion in cell biology.

[12]  S. Snyder,et al.  RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Pagano,et al.  Activation of Protein Kinase C Triggers Its Ubiquitination and Degradation , 1998, Molecular and Cellular Biology.

[14]  G. Thomas,et al.  TOR signalling and control of cell growth. , 1997, Current opinion in cell biology.

[15]  M. Kasuga,et al.  Regulation of eIF-4E BP1 Phosphorylation by mTOR* , 1997, The Journal of Biological Chemistry.

[16]  Colin B. Reese,et al.  3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase , 1997, Current Biology.

[17]  Christine C. Hudson,et al.  Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. , 1997, Science.

[18]  R. Pearson,et al.  Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k , 1997, The EMBO journal.

[19]  A. Hornia,et al.  Tumor promotion by depleting cells of protein kinase C delta , 1997, Molecular and cellular biology.

[20]  D. Shalloway,et al.  Association between v-Src and Protein Kinase C δ in v-Src-transformed Fibroblasts* , 1997, The Journal of Biological Chemistry.

[21]  S. Inoue,et al.  Functional interaction between DNA-PK and c-Abl in response to DNA damage , 1997, Nature.

[22]  Madhur Kumar,et al.  Nuclear antisense RNA induces extensive adenosine modifications and nuclear retention of target transcripts. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Ratnofsky,et al.  Proteolytic Activation of Protein Kinase C ␦ by an Ice/ced 3-like Protease Induces Characteristics of Apoptosis Materials and Methods , 1996 .

[24]  J. Lawrence,et al.  Control of the Translational Regulators PHAS-I and PHAS-II by Insulin and cAMP in 3T3-L1 Adipocytes* , 1996, The Journal of Biological Chemistry.

[25]  Shigeo Ohno,et al.  Protein Kinase C δ Activates the MEK-ERK Pathway in a Manner Independent of Ras and Dependent on Raf* , 1996, The Journal of Biological Chemistry.

[26]  S. Schreiber,et al.  A Signaling Pathway to Translational Control , 1996, Cell.

[27]  Christopher G. Proud,et al.  Cloning and Expression of cDNA Encoding Protein Synthesis Elongation Factor-2 Kinase* , 1996, The Journal of Biological Chemistry.

[28]  R. Weichselbaum,et al.  The stress response to ionizing radiation involoves c-Abl-dependent phosphorylation of SHPTP1. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[29]  S. Lowe,et al.  Transcriptional activation by p53, but not induction of the p21 gene, is essential for oncogene‐mediated apoptosis. , 1996, The EMBO journal.

[30]  V. Duronio,et al.  Protein Kinase C δ Specifically Associates with Phosphatidylinositol 3-Kinase Following Cytokine Stimulation* , 1996, The Journal of Biological Chemistry.

[31]  R. Abraham.  Phosphatidylinositol 3-kinase related kinases. , 1996, Current opinion in immunology.

[32]  A. Gingras,et al.  Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A. Gingras,et al.  4E-BP1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[34]  T. Magnuson,et al.  Activation of the Epidermal Growth Factor Receptor Signal Transduction Pathway Stimulates Tyrosine Phosphorylation of Protein Kinase C (*) , 1996, The Journal of Biological Chemistry.

[35]  N. Sonenberg,et al.  Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Gingras,et al.  Rapamycin blocks the phosphorylation of 4E‐BP1 and inhibits cap‐dependent initiation of translation. , 1996, The EMBO journal.

[37]  I. Stansfield,et al.  An MBoC Favorite: TOR controls translation initiation and early G1 progression in yeast , 2012, Molecular biology of the cell.

[38]  N. Sonenberg.  8 mRNA 5′ Cap-binding Protein elF4E and Control of Cell Growth , 1996 .

[39]  G. Thomas,et al.  14 Ribosomal Protein S6 Phosphorylation and Signal Transduction , 1996 .

[40]  L. Zon,et al.  c-Abl Activation Regulates Induction of the SEK1/Stress-activated Protein Kinase Pathway in the Cellular Response to 1-β-D-Arabinofuranosylcytosine (*) , 1995, The Journal of Biological Chemistry.

[41]  R. Weichselbaum,et al.  Proteolytic activation of protein kinase C delta by an ICE‐like protease in apoptotic cells. , 1995, The EMBO journal.

[42]  R. Pearson,et al.  The principal target of rapamycin‐induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. , 1995, The EMBO journal.

[43]  S. Schreiber,et al.  PIK-Related Kinases: DNA Repair, Recombination, and Cell Cycle Checkpoints , 1995, Science.

[44]  S. Schreiber,et al.  Control of p70 S6 kinase by kinase activity of FRAP in vivo , 1995, Nature.

[45]  F. Nielsen,et al.  Growth-dependent translation of IGF-II mRNA by a rapamycin-sensitive pathway , 1995, Nature.

[46]  R. Weichselbaum,et al.  Activation of the c-Abl tyrosine kinase in the stress response to DMA-damaging agents , 1995, Nature.

[47]  L. Dekker,et al.  The protein kinase C and protein kinase C related gene families. , 1995, Current opinion in structural biology.

[48]  S. Kharbanda,et al.  Monocyte Colony-stimulating Factor Stimulates Binding of Phosphatidylinositol 3-Kinase to Grb2Sos Complexes in Human Monocytes (*) , 1995, The Journal of Biological Chemistry.

[49]  Y. Nishizuka.  Protein kinase C and lipid signaling for sustained cellular responses , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  O. Donzé,et al.  The first and third uORFs in RSV leader RNA are efficiently translated: implications for translational regulation and viral RNA packaging. , 1995, Nucleic acids research.

[51]  R. Abraham,et al.  Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells (*) , 1995, The Journal of Biological Chemistry.

[52]  M. Mclaughlin,et al.  Interaction between FKBP12-rapamycin and TOR involves a conserved serine residue. , 1994, The Journal of biological chemistry.

[53]  A. Nairn,et al.  Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[54]  N. Sonenberg,et al.  PHAS-I as a link between mitogen-activated protein kinase and translation initiation. , 1994, Science.

[55]  A. Gingras,et al.  Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function , 1994, Nature.

[56]  J. Pierce,et al.  Stimulation of the platelet-derived growth factor beta receptor signaling pathway activates protein kinase C-delta , 1994, Molecular and cellular biology.

[57]  Paul Tempst,et al.  RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs , 1994, Cell.

[58]  Stuart L. Schreiber,et al.  A mammalian protein targeted by G1-arresting rapamycin–receptor complex , 1994, Nature.

[59]  G. Thomas,et al.  Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[60]  K. Suzuki,et al.  Ras‐dependent signal transduction is indispensable but not sufficient for the activation of AP1/Jun by PKC delta. , 1994, The EMBO journal.

[61]  J. Lawrence,et al.  Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[62]  A. Fernández,et al.  Nuclear localization of p85s6k: functional requirement for entry into S phase. , 1994, The EMBO journal.

[63]  N. Sonenberg.  mRNA translation: influence of the 5' and 3' untranslated regions. , 1994, Current opinion in genetics & development.

[64]  F. Marks,et al.  Rottlerin, a novel protein kinase inhibitor. , 1994, Biochemical and biophysical research communications.

[65]  L. Dekker,et al.  Protein kinase C--a question of specificity. , 1994, Trends in biochemical sciences.

[66]  S. Yuspa,et al.  Expression of an oncogenic rasHa gene in murine keratinocytes induces tyrosine phosphorylation and reduced activity of protein kinase C delta. , 1993, The Journal of biological chemistry.

[67]  J. Kunz,et al.  Cyclosporin A, FK506 and rapamycin: more than just immunosuppression. , 1993, Trends in biochemical sciences.

[68]  R. Jackson,et al.  Cytoplasmic regulation of mRNA function: The importance of the 3′ untranslated region , 1993, Cell.

[69]  H. Lane,et al.  p70s6k function is essential for G1 progression , 1993, Nature.

[70]  J. Kunz,et al.  Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression , 1993, Cell.

[71]  Y. Nishizuka,et al.  Cell division arrest induced by phorbol ester in CHO cells overexpressing protein kinase C-delta subspecies. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[72]  K. Suzuki,et al.  A new member of the protein kinase C family, nPKC theta, predominantly expressed in skeletal muscle , 1992, Molecular and cellular biology.

[73]  J. Avruch,et al.  Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. , 1992, Science.

[74]  G. Crabtree,et al.  Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase , 1992, Nature.

[75]  G. Crabtree,et al.  Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases , 1992, Cell.

[76]  J. Miller.  Myoblast diversity in skeletal myogenesis: How much and to what end? , 1992, Cell.

[77]  J. Heitman,et al.  Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast , 1991, Science.

[78]  R. Davis,et al.  Activation of the epidermal growth factor receptor tyrosine protein kinase in the absence of receptor oligomerization. , 1988, The Journal of biological chemistry.

[79]  Y. Nishizuka.  The heterogeneity and differential expression of multiple species of the protein kinase C family. , 1988, BioFactors.