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The mechanism of protein kinase C regulation

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Frontiers in Biology

Abstract

Protein kinase C (PKC) is a family of serine/threonine protein kinases that plays a central role in transducing extracellular signals into a variety of intracellular responses ranging from cell proliferation to apoptosis. Nine PKC genes have been identified in the human genome, which encode 10 proteins. Each member of this protein kinase family displays distinct biochemical characteristics and is enriched in different cellular and subcellular locations. Activation of PKC has been implicated in the regulation of cell growth and differentiation. This review summarizes works of the past years in the field of PKC biochemistry that covers regulation and activation mechanism of different PKC isoforms.

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References

  • Balendran A, Hare G R, Kieloch A, Williams M R, Alessi D R (2000). Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett, 484(3): 217–223

    Article  PubMed  CAS  Google Scholar 

  • Benes C H, Wu N, Elia A E, Dharia T, Cantley L C, Soltoff S P (2005). The C2 domain of PKCdelta is a phosphotyrosine binding domain. Cell, 121(2): 271–280

    Article  PubMed  CAS  Google Scholar 

  • Berridge M J, Irvine R F (1984). Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature, 312(5992): 315–321

    Article  PubMed  CAS  Google Scholar 

  • Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y (1982). Direct activation of calcium-activated, phospholipids-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem, 257(13): 7847–7851

    PubMed  CAS  Google Scholar 

  • Cenni V, Döppler H, Sonnenburg E D, Maraldi N, Newton A C, Toker A (2002). Regulation of novel protein kinase C epsilon by phosphorylation. Biochem J, 363(Pt 3): 537–545

    Article  PubMed  CAS  Google Scholar 

  • Chou M M, Hou W, Johnson J, Graham L K, Lee M H, Chen C S, Newton A C, Schaffhausen B S, Toker A (1998). Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Curr Biol, 8(19): 1069–1077

    Article  PubMed  CAS  Google Scholar 

  • Corbalán-García S, Rodríguez-Alfaro J A, Gómez-Fernández J C (1999). Determination of the calcium-binding sites of the C2 domain of protein kinase Calpha that are critical for its translocation to the plasma membrane. Biochem J, 337(Pt 3): 513–521

    Article  PubMed  Google Scholar 

  • Corbalán-Garcia S, Sánchez-Carrillo S, García-García J, Gómez-Fernández J C (2003). Characterization of the membrane binding mode of the C2 domain of PKC epsilon. Biochemistry, 42(40): 11661–11668

    Article  PubMed  Google Scholar 

  • Denning M F, Dlugosz A A, Threadgill D W, Magnuson T, Yuspa S H (1996). Activation of the epidermal growth factor receptor signal transduction pathway stimulates tyrosine phosphorylation of protein kinase C delta. J Biol Chem, 271(10): 5325–5331

    Article  PubMed  CAS  Google Scholar 

  • Döppler H, Storz P (2007). A novel tyrosine phosphorylation site in protein kinase D contributes to oxidative stress-mediated activation. J Biol Chem, 282(44): 31873–31881

    Article  PubMed  Google Scholar 

  • Dutil E M, Keranen L M, DePaoli-Roach A A, Newton A C (1994). In vivo regulation of protein kinase C by trans-phosphorylation followed by autophosphorylation. J Biol Chem, 269(47): 29359–29362

    PubMed  CAS  Google Scholar 

  • Dutil E M, Toker A, Newton A C (1998). Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Curr Biol, 8(25): 1366–1375

    Article  PubMed  CAS  Google Scholar 

  • Edwards A S, Faux M C, Scott J D, Newton A C (1999). Carboxylterminal phosphorylation regulates the function and subcellular localization of protein kinase C betaII. J Biol Chem, 274(10): 6461–6468

    Article  PubMed  CAS  Google Scholar 

  • England K, Watson J, Beale G, Warner M, Cross J, Rumsby M (2001). Signalling pathways regulating the dephosphorylation of Ser729 in the hydrophobic domain of protein kinase Cepsilon upon cell passage. J Biol Chem, 276(13): 10437–10442

    Article  PubMed  CAS  Google Scholar 

  • Gatti A, Robinson P J (1997). Okadaic acid interferes with phorbol-estermediated down-regulation of protein kinase C-alpha, C-delta and Cepsilon. Eur J Biochem, 249: 92–97

    Article  PubMed  CAS  Google Scholar 

  • Grodsky N, Li Y, Bouzida D, Love R, Jensen J, Nodes B, Nonomiya J, Grant S (2006). Structure of the catalytic domain of human protein kinase C beta II complexed with a bisindolylmaleimide inhibitor. Biochemistry, 45(47): 13970–13981

    Article  PubMed  CAS  Google Scholar 

  • Gschwendt M, Kielbassa K, Kittstein W, Marks F (1994). Tyrosine phosphorylation and stimulation of protein kinase C delta from porcine spleen by src in vitro. Dependence on the activated state of protein kinase C delta. FEBS Lett, 347(1): 85–89

    Article  PubMed  CAS  Google Scholar 

  • Guerrero-Valero M, Ferrer-Orta C, Querol-Audí J, Marin-Vicente C, Fita I, Gómez-Fernández J C, Verdaguer N, Corbalán-García S (2009). Structural and mechanistic insights into the association of PKCalpha-C2 domain to PtdIns(4,5)P2. Proc Natl Acad Sci U S A, 106(16): 6603–6607

    Article  PubMed  CAS  Google Scholar 

  • Hansra G, Bornancin F, Whelan R, Hemmings B A, Parker P J (1996). 12-O-Tetradecanoylphorbol-13-acetate-induced dephosphorylation of protein kinase Calpha correlates with the presence of a membrane-associated protein phosphatase 2A heterotrimer. J Biol Chem, 271(51): 32785–32788

    Article  PubMed  CAS  Google Scholar 

  • Hirano Y, Yoshinaga S, Ogura K, Yokochi M, Noda Y, Sumimoto H, Inagaki F (2004). Solution structure of atypical protein kinase C PB1 domain and its mode of interaction with ZIP/p62 and MEK5. J Biol Chem, 279(30): 31883–31890

    Article  PubMed  CAS  Google Scholar 

  • Hirano Y, Yoshinaga S, Takeya R, Suzuki N N, Horiuchi M, Kohjima M, Sumimoto H, Inagaki F (2005). Structure of a cell polarity regulator, a complex between atypical PKC and Par6 PB1 domains. J Biol Chem, 280(10): 9653–9661

    Article  PubMed  CAS  Google Scholar 

  • House C, Kemp B E (1987). Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. Science, 238: 1726–1728

    Article  PubMed  CAS  Google Scholar 

  • House C, Kemp B E (1990). Protein kinase C pseudosubstrate prototope: structure-function relationships. Cell Signal, 2(2): 187–190

    Article  PubMed  CAS  Google Scholar 

  • Joy S V, Scates A C, Bearelly S, Dar M, Taulien C A, Goebel J A, Cooney M J (2005). Ruboxistaurin, a protein kinase C beta inhibitor, as an emerging treatment for diabetes microvascular complications. Ann Pharmacother, 39(10): 1693–1699

    Article  PubMed  CAS  Google Scholar 

  • Kawakami Y, Kitaura J, Yao L, McHenry RW, Kawakami Y, Newton A C, Kang S, Kato RM, Leitges M, Rawlings D J, Kawakami T (2003). A Ras activation pathway dependent on Syk phosphorylation of protein kinase C. Proc Natl Acad Sci U S A, 100(16): 9470–9475

    Article  PubMed  CAS  Google Scholar 

  • Kazi J U, Kabir N N, Soh J W (2008). Bioinformatic prediction and analysis of eukaryotic protein kinases in the rat genome. Gene, 410(1): 147–153

    Article  PubMed  CAS  Google Scholar 

  • Keranen L M, Dutil E M, Newton A C (1995). Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. Curr Biol, 5(12): 1394–1403

    Article  PubMed  CAS  Google Scholar 

  • Kikkawa U, Takai Y, Tanaka Y, Miyake R, Nishizuka Y (1983). Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters. J Biol Chem, 258(19): 11442–11445

    PubMed  CAS  Google Scholar 

  • Kitatani K, Idkowiak-Baldys J, Hannun Y A (2007). Mechanism of inhibition of sequestration of protein kinase C alpha/betaII by ceramide. Roles of ceramide-activated protein phosphatases and phosphorylation/dephosphorylation of protein kinase C alpha/betaII on threonine 638/641. J Biol Chem, 282(28): 20647–20656

    Article  PubMed  CAS  Google Scholar 

  • Koide H, Ogita K, Kikkawa U, Nishizuka Y (1992). Isolation and characterization of the epsilon subspecies of protein kinase C from rat brain. Proc Natl Acad Sci U S A, 89(4): 1149–1153

    Article  PubMed  CAS  Google Scholar 

  • Konishi H, Yamauchi E, Taniguchi H, Yamamoto T, Matsuzaki H, Takemura Y, Ohmae K, Kikkawa U, Nishizuka Y (2001). Phosphorylation sites of protein kinase C delta in H2O2-treated cells and its activation by tyrosine kinase in vitro. Proc Natl Acad Sci U S A, 98(12): 6587–6592

    Article  PubMed  CAS  Google Scholar 

  • Le Good J.A., Ziegler W.H., Parekh D.B., Alessi D.R., Cohen P., and Parker P.J., (1998). Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science, 281: 2042–2045

    Article  PubMed  Google Scholar 

  • Leach K L, James M L, Blumberg P M (1983). Characterization of a specific phorbol ester aporeceptor in mouse brain cytosol. Proc Natl Acad Sci U S A, 80(14): 4208–4212

    Article  PubMed  CAS  Google Scholar 

  • Lee I H, Lim H J, Yoon S, Seong J K, Bae D S, Rhee S G, Bae Y S (2008). Ahnak protein activates PKC through dissociation of PKCPP2A complex. J Biol Chem, 283: 6312–6320

    Article  PubMed  CAS  Google Scholar 

  • Lee K Y, D’Acquist F., Hayden M S, Shim J H, Ghosh S (2005). PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation. Science, 308: 114–118

    Article  PubMed  CAS  Google Scholar 

  • Littler D R, Walker J R, She Y M, Finerty P J Jr, Newman E M, Dhe-Paganon S (2006). Structure of human protein kinase C eta (PKCeta) C2 domain and identification of phosphorylation sites. Biochem Biophys Res Commun, 349(4): 1182–1189

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Witte S, Liu Y C, Doyle M, Elly C, Altman A (2000). Regulation of protein kinase Ctheta function during T cell activation by Lck-mediated tyrosine phosphorylation. J Biol Chem, 275(5): 3603–3609

    Article  PubMed  CAS  Google Scholar 

  • Lo H H, Bartek G A, Fischer S M (1994). In vitro activation of mouse skin protein kinase C by fatty acids and their hydroxylated metabolites. Lipids, 29(8): 547–553

    Article  PubMed  CAS  Google Scholar 

  • Mackay H J, Twelves C J (2007). Targeting the protein kinase C family: are we there yet? Nat Rev Cancer, 7: 554–562

    Article  PubMed  CAS  Google Scholar 

  • Makowske M, Rosen O M(1989). Complete activation of protein kinase C by an antipeptide antibody directed against the pseudosubstrate prototope. J Biol Chem, 264(27): 16155–16159

    PubMed  CAS  Google Scholar 

  • Medkova M, Cho W (1998). Mutagenesis of the C2 domain of protein kinase C-alpha. Differential roles of Ca2+ ligands and membrane binding residues. J Biol Chem, 273(28): 17544–17552

    Article  PubMed  CAS  Google Scholar 

  • Mellor H, Parker P J (1998). The extended protein kinase C superfamily. Biochem J, 332(Pt 2): 281–292

    PubMed  CAS  Google Scholar 

  • Messerschmidt A, Macieira S, Velarde M, Bädeker M, Benda C, Jestel A, Brandstetter H, Neuefeind T, Blaesse M (2005). Crystal structure of the catalytic domain of human atypical protein kinase C-iota reveals interaction mode of phosphorylation site in turn motif. J Mol Biol, 352(4): 918–931

    Article  PubMed  CAS  Google Scholar 

  • Moscat J, Diaz-Meco M T, Albert A, Campuzano S (2006). Cell signaling and function organized by PB1 domain interactions. Mol Cell, 23(5): 631–640

    Article  PubMed  CAS  Google Scholar 

  • Müller G, Ayoub M, Storz P, Rennecke J, Fabbro D, Pfizenmaier K (1995). PKC zeta is a molecular switch in signal transduction of TNF-alpha, bifunctionally regulated by ceramide and arachidonic acid. EMBO J, 14(9): 1961–1969

    PubMed  Google Scholar 

  • Murakami K, Chan S Y, Routtenberg A (1986). Protein kinase C activation by cis-fatty acid in the absence of Ca2+ and phospholipids. J Biol Chem, 261(33): 15424–15429

    PubMed  CAS  Google Scholar 

  • Murakami K, Routtenberg A (1985). Direct activation of purified protein kinase C by unsaturated fatty acids (oleate and arachidonate) in the absence of phospholipids and Ca2+. FEBS Lett, 192(2): 189–193

    Article  PubMed  CAS  Google Scholar 

  • Newton A C (2001). Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev, 101(8): 2353–2364

    Article  PubMed  CAS  Google Scholar 

  • Newton A C (2003). Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J, 370(Pt 2): 361–371

    Article  PubMed  CAS  Google Scholar 

  • Newton A C, Koshland D E Jr (1987). Protein kinase C autophosphorylates by an intrapeptide reaction. J Biol Chem, 262(21): 10185–10188

    PubMed  CAS  Google Scholar 

  • Ochoa W F, Garcia-Garcia J, Fita I, Corbalan-Garcia S, Verdaguer N, Gomez-Fernandez J C (2001). Structure of the C2 domain from novel protein kinase Cepsilon. A membrane binding model for Ca(2+)-independent C2 domains. J Mol Biol, 311(4): 837–849

    Article  PubMed  CAS  Google Scholar 

  • Ogita K, Miyamoto S, Yamaguchi K, Koide H, Fujisawa N, Kikkawa U, Sahara S, Fukami Y, Nishizuka Y (1992). Isolation and characterization of delta-subspecies of protein kinase C from rat brain. Proc Natl Acad Sci U S A, 89(5): 1592–1596

    Article  PubMed  CAS  Google Scholar 

  • Orr J W, Newton A C (1994). Intrapeptide regulation of protein kinase C. J Biol Chem, 269(11): 8383–8387

    PubMed  CAS  Google Scholar 

  • Pappa H, Murray-Rust J, Dekker L V, Parker P J, McDonald N Q (1998). Crystal structure of the C2 domain from protein kinase C-delta. Structure, 6(7): 885–894

    Article  PubMed  CAS  Google Scholar 

  • Parekh D, Ziegler W, Yonezawa K, Hara K, Parker P J (1999). Mammalian TOR controls one of two kinase pathways acting upon nPKCdelta and nPKCepsilon. J Biol Chem, 274(49): 34758–34764

    Article  PubMed  CAS  Google Scholar 

  • Pike A C W, Amos A, Johansson C, Sobott F, Savitsky P, Berridge G, Fedorov O, Umeano C, Gorrec F, Bunkoczi G, et al. (2007). Crystal structure of C2 domain of protein kinase C gamma. Cited from Protein data bank

  • Rybin V O, Guo J, Gertsberg Z, Elouardighi H, Steinberg S F (2007). Protein kinase Cepsilon (PKCepsilon) and Src control PKCdelta activation loop phosphorylation in cardiomyocytes. J Biol Chem, 282(32): 23631–23638

    Article  PubMed  CAS  Google Scholar 

  • Rybin V O, Sabri A, Short J, Braz J C, Molkentin J D, Steinberg S F (2003). Cross-regulation of novel protein kinase C (PKC) isoform function in cardiomyocytes. Role of PKC epsilon in activation loop phosphorylations and PKC delta in hydrophobic motif phosphorylations. J Biol Chem, 278(16): 14555–14564

    Article  PubMed  CAS  Google Scholar 

  • Seibenhener M L, Roehm J, White WO, Neidigh K B, Vandenplas M L, Wooten M W (1999). Identification of Src as a novel atypical protein kinase C-interacting protein. Mol Cell Biol Res Commun, 2(1): 28–31

    Article  PubMed  CAS  Google Scholar 

  • Shen G X (2003). Selective protein kinase C inhibitors and their applications. Curr Drug Targets Cardiovasc Haematol Disord, 3(4): 301–307

    Article  PubMed  CAS  Google Scholar 

  • Shinomura T, Asaoka Y, Oka M, Yoshida K, Nishizuka Y (1991). Synergistic action of diacylglycerol and unsaturated fatty acid for protein kinase C activation: its possible implications. Proc Natl Acad Sci USA, 88(12): 5149–5153

    Article  PubMed  CAS  Google Scholar 

  • Sonnenburg E D, Gao T, Newton A C (2001). The phosphoinositi-dedependent kinase, PDK-1, phosphorylates conventional protein kinase C isozymes by a mechanism that is independent of phosphoinositide 3-kinase. J Biol Chem, 276(48): 45289–45297

    Article  PubMed  CAS  Google Scholar 

  • Srivastava J, Goris J, Dilworth S M, Parker P J (2002). Dephosphorylation of PKCdelta by protein phosphatase 2Ac and its inhibition by nucleotides. FEBS Lett, 516(1–3): 265–269

    Article  PubMed  CAS  Google Scholar 

  • Sumimoto H, Kamakura S, Ito T (2007). Structure and function of the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants. Sci STKE, 2007(401): re6

    Article  PubMed  Google Scholar 

  • Sun X, Wu F, Datta R, Kharbanda S, Kufe D (2000). Interaction between protein kinase C delta and the c-Abl tyrosine kinase in the cellular response to oxidative stress. J Biol Chem, 275(11): 7470–7473

    Article  PubMed  CAS  Google Scholar 

  • Sutton R B, Sprang S R (1998). Structure of the protein kinase Cbeta phospholipid-binding C2 domain complexed with Ca2+. Structure, 6(11): 1395–1405

    Article  PubMed  CAS  Google Scholar 

  • Szallasi Z, Bogi K, Gohari S, Biro T, Acs P, Blumberg PM (1996). Nonequivalent roles for the first and second zinc fingers of protein kinase Cdelta. Effect of their mutation on phorbol ester-induced translocation in NIH 3T3 cells. J Biol Chem, 271(31): 18299–18301

    Article  PubMed  CAS  Google Scholar 

  • Szallasi Z, Denning M F, Chang E Y, Rivera J, Yuspa S H, Lehel C, Olah Z, Anderson W B, Blumberg P M (1995). Development of a rapid approach to identification of tyrosine phosphorylation sites: application to PKC delta phosphorylated upon activation of the high affinity receptor for IgE in rat basophilic leukemia cells. Biochem Biophys Res Commun, 214(3): 888–894

    Article  PubMed  CAS  Google Scholar 

  • Toker A, Meyer M, Reddy K K, Falck J R, Aneja R, Aneja S, Parra A, Burns D J, Ballas L M, Cantley L C (1994). Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. J Biol Chem, 269(51): 32358–32367

    PubMed  CAS  Google Scholar 

  • Tominaga M, Kitagawa Y, Tanaka S, Kishimoto A (1991). Phosphorylation of type II (beta) protein kinase C by casein kinase II. J Biochem, 110(4): 655–660

    PubMed  CAS  Google Scholar 

  • Verdaguer N, Corbalan-Garcia S, Ochoa WF, Fita I, Gómez-Fernández J C (1999). Ca2+ bridges the C2 membrane-binding domain of protein kinase Calpha directly to phosphatidylserine. EMBO J, 18(22): 6329–6338

    Article  PubMed  CAS  Google Scholar 

  • Vila J, Walker J M, Itarte E, Weber M J, Sando J J (1989). Phosphorylation of protein kinase C by casein kinase-1. FEBS Lett, 255(1): 205–208

    Article  PubMed  CAS  Google Scholar 

  • Wooten M W, Vandenplas M L, Seibenhener ML, Geetha T, Diaz-Meco M T (2001). Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase C’s via a src kinase pathway. Mol Cell Biol, 21(24): 8414–8427

    Article  PubMed  CAS  Google Scholar 

  • Xu R X, Pawelczyk T, Xia T H, Brown S C (1997). NMR structure of a protein kinase C-gamma phorbol-binding domain and study of protein-lipid micelle interactions. Biochemistry, 36(35): 10709–10717

    Article  PubMed  CAS  Google Scholar 

  • Xu Z B, Chaudhary D, Olland S, Wolfrom S, Czerwinski R, Malakian K, Lin L, Stahl M L, Joseph-McCarthy D, Benander C, Fitz L, Greco R, Somers W S, Mosyak L (2004). Catalytic domain crystal structure of protein kinase C-theta (PKCtheta). J Biol Chem, 279(48): 50401–50409

    Article  PubMed  CAS  Google Scholar 

  • Zhang G, Kazanietz M G, Blumberg P M, Hurley J H (1995). Crystal structure of the cys2 activator-binding domain of protein kinase C delta in complex with phorbol ester. Cell, 81(6): 917–924

    Article  PubMed  CAS  Google Scholar 

  • Ziegler WH, Parekh D B, Le Good J A, Whelan R D, Kelly J J, Frech M, Hemmings B A, Parker P J (1999). Rapamycin-sensitive phosphorylation of PKC on a carboxy-terminal site by an atypical PKC complex. Curr Biol, 9(10): 522–529

    Article  PubMed  CAS  Google Scholar 

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  1. Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Bagura Road, Barisal, Bangladesh

    Julhash U. Kazi

  2. Quality Control Section, Opsonin Pharma Ltd, Bagura Road, Barisal, Bangladesh

    Julhash U. Kazi

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Kazi, J.U. The mechanism of protein kinase C regulation. Front. Biol. 6, 328–336 (2011). https://doi.org/10.1007/s11515-011-1070-5

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