Protein Kinase D Induces Transcription through Direct Phosphorylation of the cAMP-response Element-binding Protein*

Protein kinase D (PKD), a family of serine/threonine kinases, can be activated by a multitude of stimuli in a protein kinase C-dependent or -independent manner. PKD is involved in signal transduction pathways controlling cell proliferation, apoptosis, motility, and protein trafficking. Despite its versatile functions, few genuine in vivo substrates for PKD have been identified. In this study we demonstrate that the transcription factor cAMP-response element-binding protein (CREB) is a direct substrate for PKD. PKD1 and CREB interact in cells, and activated PKD1 provokes CREB phosphorylation at Ser-133 both in vitro and in vivo. A constitutive active mutant of PKD1 stimulates GAL4-CREB-mediated transcription in a Ser-133-dependent manner, activates CRE-responsive promoters, and increases the expression of CREB target genes. PKD1 also enhances transcription mediated by two other members of the CREB family, ATF-1 and CREM. Our results describe a novel mechanism for PKD-induced signaling through activation of the transcription factor CREB and suggest that stimulus-induced phosphorylation of CREB, reported to be mediated by protein kinase C, may involve downstream activated PKD.

[1]  A. Toker,et al.  Tyrosine Phosphorylation of Protein Kinase D in the Pleckstrin Homology Domain Leads to Activation* , 2003, The Journal of Biological Chemistry.

[2]  B. Webb,et al.  Protein kinase C isoenzymes: a review of their structure, regulation and role in regulating airways smooth muscle tone and mitogenesis , 2000, British journal of pharmacology.

[3]  S. Keyse,et al.  Both Binding and Activation of p38 Mitogen-Activated Protein Kinase (MAPK) Play Essential Roles in Regulation of the Nucleocytoplasmic Distribution of MAPK-Activated Protein Kinase 5 by Cellular Stress , 2002, Molecular and Cellular Biology.

[4]  T. Iglesias,et al.  Protein Kinase D Activation by Mutations within Its Pleckstrin Homology Domain* , 1998, The Journal of Biological Chemistry.

[5]  E. Rozengurt,et al.  Oxidative Stress Induces Protein Kinase C-mediated Activation Loop Phosphorylation and Nuclear Redistribution of Protein Kinase D* , 2004, Journal of Biological Chemistry.

[6]  E. Rozengurt,et al.  Protein Kinase D Potentiates DNA Synthesis and Cell Proliferation Induced by Bombesin, Vasopressin, or Phorbol Esters in Swiss 3T3 Cells* , 2001, The Journal of Biological Chemistry.

[7]  E. Rozengurt,et al.  Protein Kinase C Phosphorylates Protein Kinase D Activation Loop Ser744 and Ser748 and Releases Autoinhibition by the Pleckstrin Homology Domain* , 2003, The Journal of Biological Chemistry.

[8]  E. Rozengurt,et al.  Uncoupling of protein kinase D from suppression of EGF-dependent c-Jun phosphorylation in cancer cells. , 2003, Biochemical and biophysical research communications.

[9]  E. Rozengurt,et al.  Oxidative Stress Induces Protein Kinase D Activation in Intact Cells , 2000, The Journal of Biological Chemistry.

[10]  E. Olson,et al.  Protein Kinase D1 Phosphorylates HDAC7 and Induces Its Nuclear Export after T-cell Receptor Activation* , 2005, Journal of Biological Chemistry.

[11]  E. Jellum,et al.  Characterization of in-vitro-translated human regulatory and catalytic subunits of cAMP-dependent protein kinases. , 1994, European journal of biochemistry.

[12]  J. Prestle,et al.  PKCu is a novel, atypical member of the protein kinase C family. , 1994, The Journal of biological chemistry.

[13]  V. Malhotra,et al.  Gβγ-Mediated Regulation of Golgi Organization Is through the Direct Activation of Protein Kinase D , 1999, Cell.

[14]  Rick B. Vega,et al.  Regulation of Cardiac Stress Signaling by Protein Kinase D1 , 2006, Molecular and Cellular Biology.

[15]  F. Dequiedt,et al.  Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor–induced Nur77 expression and apoptosis , 2005, The Journal of experimental medicine.

[16]  Richard G. Jenner,et al.  Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[17]  W. Merlevede,et al.  Platelet-derived Growth Factor Stimulates Protein Kinase D through the Activation of Phospholipase Cγ and Protein Kinase C* , 1998, The Journal of Biological Chemistry.

[18]  D. Kufe,et al.  Proteolytic Cleavage and Activation of Protein Kinase C μ by Caspase-3 in the Apoptotic Response of Cells to 1-β-d-Arabinofuranosylcytosine and Other Genotoxic Agents* , 2000, The Journal of Biological Chemistry.

[19]  E. Rozengurt,et al.  Neurotensin induces protein kinase C-dependent protein kinase D activation and DNA synthesis in human pancreatic carcinoma cell line PANC-1. , 2002, Cancer research.

[20]  J. Lemonnier,et al.  Protein Kinase C-independent Activation of Protein Kinase D Is Involved in BMP-2-induced Activation of Stress Mitogen-activated Protein Kinases JNK and p38 and Osteoblastic Cell Differentiation* , 2004, Journal of Biological Chemistry.

[21]  U. Moens,et al.  The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells. , 2005, Cellular signalling.

[22]  T. Iglesias,et al.  Phosphorylation‐dependent protein kinase Dactivation , 1999, Electrophoresis.

[23]  E. Rozengurt,et al.  Protein kinase D (PKD) activation in intact cells through a protein kinase C‐dependent signal transduction pathway. , 1996, The EMBO journal.

[24]  P. Vandenabeele,et al.  Doxorubicin-induced activation of protein kinase D1 through caspase-mediated proteolytic cleavage: identification of two cleavage sites by microsequencing. , 2004, Cellular signalling.

[25]  Lewis C Cantley,et al.  A rapid method for determining protein kinase phosphorylation specificity , 2004, Nature Methods.

[26]  U. Moens,et al.  What turns CREB on? , 2004, Cellular signalling.

[27]  E. Rozengurt,et al.  Protein Kinase D Signaling* , 2005, Journal of Biological Chemistry.

[28]  Sadia Vancauwenbergh,et al.  Activation of Hematopoietic Progenitor Kinase 1 Involves Relocation, Autophosphorylation, and Transphosphorylation by Protein Kinase D1 , 2005, Molecular and Cellular Biology.

[29]  Zhou Songyang,et al.  Determination of the Specific Substrate Sequence Motifs of Protein Kinase C Isozymes* , 1997, The Journal of Biological Chemistry.

[30]  C. Gomez-Sanchez,et al.  Angiotensin II-mediated protein kinase D activation stimulates aldosterone and cortisol secretion in H295R human adrenocortical cells. , 2006, Endocrinology.

[31]  M. Montminy,et al.  Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133 , 1989, Cell.

[32]  A. Toker,et al.  A Phosphorylation State-specific Antibody Recognizes Hsp27, a Novel Substrate of Protein Kinase D* , 2005, Journal of Biological Chemistry.

[33]  Apoor Patel,et al.  The RAS Effector RIN1 Directly Competes with RAF and Is Regulated by 14-3-3 Proteins , 2002, Molecular and Cellular Biology.

[34]  J. Arthur,et al.  MSKs are required for the transcription of the nuclear orphan receptors Nur77, Nurr1 and Nor1 downstream of MAPK signalling. , 2005, The Biochemical journal.

[35]  J. Gordon.  Use of vanadate as protein-phosphotyrosine phosphatase inhibitor. , 1991, Methods in enzymology.

[36]  U. Moens,et al.  Multisite phosphorylation of the cAMP response element-binding protein (CREB) by a diversity of protein kinases. , 2007, Frontiers in bioscience : a journal and virtual library.

[37]  Y. Ghanekar,et al.  Protein kinase D: activation for Golgi carrier formation. , 2005, Trends in cell biology.

[38]  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.

[39]  T. Seufferlein,et al.  Protein kinase D: a family affair , 2003, FEBS letters.

[40]  P. Rehberger,et al.  Protein‐kinase‐Cμ expression correlates with enhanced keratinocyte proliferation in normal and neoplastic mouse epidermis and in cell culture , 1999 .

[41]  A. Ullrich,et al.  Cell‐type specific phosphorylation of threonines T654 and T669 by PKD defines the signal capacity of the EGF receptor , 1999, The EMBO journal.

[42]  Peter Storz,et al.  Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIβ at the Golgi complex , 2005, Nature Cell Biology.

[43]  T. Iglesias,et al.  Identification and Cloning of Kidins220, a Novel Neuronal Substrate of Protein Kinase D* , 2000, The Journal of Biological Chemistry.

[44]  R. Goodman,et al.  Deacetylase Activity Is Required for cAMP Activation of a Subset of CREB Target Genes* , 2003, Journal of Biological Chemistry.

[45]  M. Gautel,et al.  Protein Kinase D Is a Novel Mediator of Cardiac Troponin I Phosphorylation and Regulates Myofilament Function , 2004, Circulation research.

[46]  E. Rozengurt,et al.  Expression and Characterization of PKD, a Phorbol Ester and Diacylglycerol-stimulated Serine Protein Kinase (*) , 1995, The Journal of Biological Chemistry.

[47]  M. Montminy,et al.  Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB , 1988, Nature.

[48]  E. Rozengurt,et al.  Bombesin, Vasopressin, Endothelin, Bradykinin, and Platelet-derived Growth Factor Rapidly Activate Protein Kinase D through a Protein Kinase C-dependent Signal Transduction Pathway* , 1997, The Journal of Biological Chemistry.

[49]  Yun Wang,et al.  Interaction between protein kinase Cmu and the vanilloid receptor type 1. , 2004, The Journal of biological chemistry.

[50]  A. Toker,et al.  Protein Kinase C Selectively Regulates Protein Kinase D-Dependent Activation of NF- B in Oxidative Stress Signaling , 2004 .

[51]  F. Lezoualc’h,et al.  cAMP-Binding Protein Epac Induces Cardiomyocyte Hypertrophy , 2005, Circulation research.

[52]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors , 2000 .

[53]  C. Vinson,et al.  NO activation of fos promoter elements requires nuclear translocation of G-kinase I and CREB phosphorylation but is independent of MAP kinase activation , 2000, Oncogene.

[54]  V. Malhotra,et al.  Protein kinase D: an intracellular traffic regulator on the move. , 2002, Trends in cell biology.

[55]  Y. Yamane,et al.  Differentiation of immature oligodendrocytes is regulated by phosphorylation of cyclic AMP‐response element binding protein by a protein kinase C signaling cascade , 2005, Journal of neuroscience research.

[56]  O. Seternes,et al.  Synergistic activation of CREB-mediated transcription by forskolin and phorbol ester requires PKC and depends on the glutamine-rich Q2 transactivation domain. , 2004, Cellular signalling.

[57]  T. Osborne,et al.  NF-I proteins from brain interact with the proenkephalin cAMP inducible enhancer. , 1991, Nucleic acids research.

[58]  Q. Wang.  PKD at the crossroads of DAG and PKC signaling. , 2006, Trends in pharmacological sciences.

[59]  E. Rozengurt,et al.  Protein kinase D complexes with C-Jun N-terminal kinase via activation loop phosphorylation and phosphorylates the C-Jun N-terminus , 2002, Oncogene.

[60]  E. Kandel,et al.  cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[61]  V. Malhotra,et al.  PKCη is required for β1γ2/β3γ2- and PKD-mediated transport to the cell surface and the organization of the Golgi apparatus , 2005, The Journal of cell biology.

[62]  Rick B. Vega,et al.  Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5 , 2004, Molecular and Cellular Biology.

[63]  G. Mosialos,et al.  A protein kinase-A recognition sequence is structurally linked to transformation by p59v-rel and cytoplasmic retention of p68c-rel , 1991, Molecular and cellular biology.

[64]  P. Rao,et al.  E-cadherin phosphorylation by protein kinase D1/protein kinase C{mu} is associated with altered cellular aggregation and motility in prostate cancer. , 2005, Cancer research.

[65]  R. Halaban,et al.  Identification of p90RSK as the probable CREB-Ser133 kinase in human melanocytes. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[66]  Timothy J. Nelson,et al.  SRF-dependent gene expression in isolated cardiomyocytes: regulation of genes involved in cardiac hypertrophy. , 2005, Journal of molecular and cellular cardiology.

[67]  M. Montminy,et al.  Regulation of somatostatin gene transcription by cyclic adenosine monophosphate. , 1996, Metabolism: clinical and experimental.

[68]  C. Waterman-Storer,et al.  Protein Kinase D-Mediated Anterograde Membrane Trafficking Is Required for Fibroblast Motility , 2004, Current Biology.

[69]  J. Vandenheede,et al.  Getting to know protein kinase D. , 2002, The international journal of biochemistry & cell biology.

[70]  A. Shaywitz,et al.  CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. , 1999, Annual review of biochemistry.

[71]  Marc Montminy,et al.  Transcriptional regulation by the phosphorylation-dependent factor CREB , 2001, Nature Reviews Molecular Cell Biology.

[72]  S. Hanks,et al.  Genomic analysis of the eukaryotic protein kinase superfamily: a perspective , 2003, Genome Biology.

[73]  Michael R. Elliott,et al.  Protein Kinase A Regulatory Subunit Type IIβ Directly Interacts with and Suppresses CREB Transcriptional Activity in Activated T Cells1 , 2003, The Journal of Immunology.

[74]  E. Olson,et al.  Essential Role for Protein Kinase D Family Kinases in the Regulation of Class II Histone Deacetylases in B Lymphocytes , 2006, Molecular and Cellular Biology.