Neuroscience Bulletin

, Volume 30, Issue 3, pp 497–504 | Cite as

Protein kinase D: a new player among the signaling proteins that regulate functions in the nervous system

  • Gang Li
  • Yun Wang


Protein kinase D (PKD) is an evolutionarily-conserved family of protein kinases. It has structural, regulatory, and enzymatic properties quite different from the PKC family. Many stimuli induce PKD signaling, including G-protein-coupled receptor agonists and growth factors. PKD1 is the most studied member of the family. It functions during cell proliferation, differentiation, secretion, cardiac hypertrophy, immune regulation, angiogenesis, and cancer. Previously, we found that PKD1 is also critically involved in pain modulation. Since then, a series of studies performed in our lab and by other groups have shown that PKDs also participate in other processes in the nervous system including neuronal polarity establishment, neuroprotection, and learning. Here, we discuss the connections between PKD structure, enzyme function, and localization, and summarize the recent findings on the roles of PKD-mediated signaling in the nervous system.


PKD neuronal polarity pain modulation neuroprotection learning 


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  1. [1]
    Rozengurt E, Rey O, Waldron RT. Protein kinase D signaling. J Biol Chem 2005, 280: 13205–13208.PubMedCrossRefGoogle Scholar
  2. [2]
    Hayashi A, Seki N, Hattori A, Kozuma S, Saito T. PKC, a new member of the protein kinase C family, composes a fourth subfamily with PKCμ. Biochim Biophys Acta 1999, 1450: 99–106.PubMedCrossRefGoogle Scholar
  3. [3]
    Nishikawa K, Toker A, Johannes FJ, Songyang Z, Cantley LC. Determination of the specific substrate sequence motifs of protein kinase C isozymes. J Biol Chem 1997, 272: 952–960.PubMedCrossRefGoogle Scholar
  4. [4]
    Valverde AM, Sinnett-Smith J, Van Lint J, Rozengurt E. Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain. Proc Natl Acad Sci U S A 1994, 91: 8572–8576.PubMedCentralPubMedCrossRefGoogle Scholar
  5. [5]
    Liljedahl M, Maeda Y, Colanzi A, Ayala I, Van Lint J, Malhotra V. Protein kinase D regulates the fission of cell surface destined transport carriers from the trans-Golgi network. Cell 2001, 104: 409–420.PubMedCrossRefGoogle Scholar
  6. [6]
    Yeaman C, Ayala MI, Wright JR, Bard F, Bossard C, Ang A, et al. Protein kinase D regulates basolateral membrane protein exit from trans-Golgi network. Nat Cell Biol 2004, 6: 106–112.PubMedCentralPubMedCrossRefGoogle Scholar
  7. [7]
    Johannes FJ, Prestle J, Eis S, Oberhagemann P, Pfizenmaier K. PKCμ is a novel, atypical member of the protein kinase C family. J Biol Chem 1994, 269: 6140–6148.PubMedGoogle Scholar
  8. [8]
    Newton AC. Regulation of protein kinase C. Curr Opin Cell Biol 1997, 9: 161–167.PubMedCrossRefGoogle Scholar
  9. [9]
    Mellor H, Parker PJ. The extended protein kinase C superfamily. Biochem J 1998, 332: 281.PubMedCentralPubMedGoogle Scholar
  10. [10]
    Sturany S, Van Lint J, Müller F, Wilda M, Hameister H, Höcker M, et al. Molecular cloning and characterization of the human protein kinase D2 a novel member of the protein kinase D family of serine threonine kinases. J Biol Chem 2001, 276: 3310–3318.PubMedCrossRefGoogle Scholar
  11. [11]
    Hanks SK. Genomic analysis of the eukaryotic protein kinase superfamily: a perspective. Genome Biol 2003, 4: 111.PubMedCentralPubMedCrossRefGoogle Scholar
  12. [12]
    Johnson LN, Lowe ED, Noble ME, Owen DJ. The structural basis for substrate recognition and control by protein kinases. FEBS Lett 1998, 430: 1–11.PubMedCrossRefGoogle Scholar
  13. [13]
    Vertommen D, Rider M, Ni Y, Waelkens E, Merlevede W, Vandenheede JR, et al. Regulation of protein kinase D by multisite phosphorylation identification of phosphorylation sites by mass spectrometry and characterization by sitedirected mutagenesis. J Biol Chem 2000, 275: 19567–19576.PubMedCrossRefGoogle Scholar
  14. [14]
    Iglesias T, Waldron RT, Rozengurt E. Identification of in vivo phosphorylation sites required for protein kinase D activation. J Biol Chem 1998, 273: 27662–27667.PubMedCrossRefGoogle Scholar
  15. [15]
    Matthews SA, Rozengurt E, Cantrell D. Characterization of serine 916 as an in vivo autophosphorylation site for protein kinase D/protein kinase Cμ. J Biol Chem 1999, 274: 26543–26549.PubMedCrossRefGoogle Scholar
  16. [16]
    Waldron RT, Rey O, Iglesias T, Tugal T, Cantrell D, Rozengurt E. Activation loop Ser744 and Ser748 in protein kinase D are transphosphorylated in vivo. J Biol Chem 2001, 276: 32606–32615.PubMedCrossRefGoogle Scholar
  17. [17]
    Waldron RT, Rozengurt E. Protein kinase C phosphorylates protein kinase D activation loop Ser744 and Ser748 and releases autoinhibition by the pleckstrin homology domain. J Biol Chem 2003, 278: 154–163.PubMedCrossRefGoogle Scholar
  18. [18]
    Brändlin I, Hübner S, Eiseler T, Martinez-Moya M, Horschinek A, Hausser A, et al. Protein kinase C (PKC) η-mediated PKCμ activation modulates ERK and JNK signal pathways. J Biol Chem 2002, 277: 6490–6496.PubMedCrossRefGoogle Scholar
  19. [19]
    Waldron RT, Iglesias T, Rozengurt E. The pleckstrin homology domain of protein kinase D interacts preferentially with the η isoform of protein kinase C. J Biol Chem 1999, 274: 9224–9230.PubMedCrossRefGoogle Scholar
  20. [20]
    Jamora C, Yamanouye N, Van Lint J, Laudenslager J, Vandenheede JR, Faulkner DJ, et al. Gβγ-mediated regulation of Golgi organization is through the direct activation of protein kinase D. Cell 1999, 98: 59–68.PubMedCrossRefGoogle Scholar
  21. [21]
    Añel AMD, Malhotra V. PKCη is required for β1γ2/β3γ2- and PKD-mediated transport to the cell surface and the organization of the Golgi apparatus. J Cell Biol 2005, 169: 83–91.PubMedCentralCrossRefGoogle Scholar
  22. [22]
    Rey O, Sinnett-Smith J, Zhukova E, Rozengurt E. Regulated nucleocytoplasmic transport of protein kinase D in response to G protein-coupled receptor activation. J Biol Chem 2001, 276: 49228–49235.PubMedCrossRefGoogle Scholar
  23. [23]
    Endo K, Oki E, Biedermann V, Kojima H, Yoshida K, Johannes FJ, 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. J Biol Chem 2000, 275: 18476–18481.PubMedCrossRefGoogle Scholar
  24. [24]
    Iglesias T, Rozengurt E. Protein kinase D activation by mutations within its pleckstrin homology domain. J Biol Chem 1998, 273: 410–416.PubMedCrossRefGoogle Scholar
  25. [25]
    Storz P, Döppler H, Johannes FJ, Toker A. Tyrosine phosphorylation of protein kinase D in the pleckstrin homology domain leads to activation. J Biol Chem 2003, 278: 17969–17976.PubMedCrossRefGoogle Scholar
  26. [26]
    Iglesias T, Rozengurt E. Protein kinase D activation by deletion of its cysteine-rich motifs. FEBS Lett 1999, 454: 53–56.PubMedCrossRefGoogle Scholar
  27. [27]
    Iglesias T, Matthews S, Rozengurt E. Dissimilar phorbol ester binding properties of the individual cysteine-rich motifs of protein kinase D. FEBS Lett 1998, 437: 19–23.PubMedCrossRefGoogle Scholar
  28. [28]
    Storz P, Hausser A, Link G, Dedio J, Ghebrehiwet B, Pfizenmaier K, et al. Protein kinase C μ is regulated by the multifunctional chaperon protein p32. J Biol Chem 2000, 275: 24601–24607.PubMedCrossRefGoogle Scholar
  29. [29]
    Matthews SA, Iglesias T, Rozengurt E, Cantrell D. Spatial and temporal regulation of protein kinase D (PKD). EMBO J 2000, 19: 2935–2945.PubMedCentralPubMedCrossRefGoogle Scholar
  30. [30]
    Hausser A, Link G, Bamberg L, Burzlaff A, Lutz S, Pfizenmaier K, et al. Structural requirements for localization and activation of protein kinase C μ (PKCμ) at the Golgi compartment. J Cell Biol 2002, 156: 65–74.PubMedCentralPubMedCrossRefGoogle Scholar
  31. [31]
    Rey O, Young SH, Cantrell D, Rozengurt E. Rapid protein kinase D translocation in response to G protein-coupled receptor activation dependence on protein kinase C. J Biol Chem 2001, 276: 32616–32626.PubMedCrossRefGoogle Scholar
  32. [32]
    Matthews S, Iglesias T, Cantrell D, Rozengurt E. Dynamic redistribution of protein kinase D (PKD) as revealed by a GFPPKD fusion protein: dissociation from PKD activation. FEBS Lett 1999, 457: 515–521.PubMedCrossRefGoogle Scholar
  33. [33]
    Maeda Y, Beznoussenko GV, Van Lint J, Mironov AA, Malhotra V. Recruitment of protein kinase D to the trans-Golgi network via the first cysteine-rich domain. EMBO J 2001, 20: 5982–5990.PubMedCentralPubMedCrossRefGoogle Scholar
  34. [34]
    Ghanekar Y, Lowe M. Protein kinase D: activation for Golgi carrier formation. Trends Cell Biol 2005, 15: 511–514.PubMedCrossRefGoogle Scholar
  35. [35]
    Baron CL, Malhotra V. Role of diacylglycerol in PKD recruitment to the TGN and protein transport to the plasma membrane. Science 2002, 295: 325–328.PubMedCrossRefGoogle Scholar
  36. [36]
    Pfeffer S. Membrane domains in the secretory and endocytic pathways. Cell 2003, 112: 507–517.PubMedCrossRefGoogle Scholar
  37. [37]
    Wang QJ. PKD at the crossroads of DAG and PKC signaling. Trends Pharmacol Sci 2006, 27: 317.PubMedCrossRefGoogle Scholar
  38. [38]
    Bossard C, Bresson D, Polishchuk RS, Malhotra V. Dimeric PKD regulates membrane fission to form transport carriers at the TGN. J Cell Biol 2007, 179: 1123–1131.PubMedCentralPubMedCrossRefGoogle Scholar
  39. [39]
    Oancea E, Bezzerides VJ, Greka A, Clapham DE. Mechanism of persistent protein kinase D1 translocation and activation. Dev Cell 2003, 4: 561–574.PubMedCrossRefGoogle Scholar
  40. [40]
    Auer A, von Blume J, Sturany S, von Wichert G, Van Lint J, Vandenheede J, et al. Role of the regulatory domain of protein kinase D2 in phorbol ester binding, catalytic activity, and nucleocytoplasmic shuttling. Mol Biol Cell 2005, 16: 4375–4385.PubMedCentralPubMedCrossRefGoogle Scholar
  41. [41]
    Irie K, Nakahara A, Ohigashi H, Fukuda H, Wender PA, Konishi H, et al. Synthesis and phorbol ester-binding studies of the individual cysteine-rich motifs of protein kinase D. Bioorg Med Chem Lett 1999, 9: 2487–2490.PubMedCrossRefGoogle Scholar
  42. [42]
    Van Lint J, Rykx A, Maeda Y, Vantus T, Sturany S, Malhotra V, et al. Protein kinase D: an intracellular traffic regulator on the move. Trends Cell Biol 2002, 12: 193–200.PubMedCrossRefGoogle Scholar
  43. [43]
    Rey O, Rozengurt E. Protein kinase D interacts with Golgi via its cysteine-rich domain. Biochem Biophys Res Commun 2001, 287: 21–26.PubMedCrossRefGoogle Scholar
  44. [44]
    Szallasi A, Cortright DN, Blum CA, Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 2007, 6: 357–372.PubMedCrossRefGoogle Scholar
  45. [45]
    Immke DC, Gavva NR. The TRPV1 receptor and nociception. Semin Cell Dev Biol 2006, 17: 582.PubMedCrossRefGoogle Scholar
  46. [46]
    Cortright DN, Szallasi A. Biochemical pharmacology of the vanilloid receptor TRPV1. Eur J Biochem 2004, 271: 1814–1819.PubMedCrossRefGoogle Scholar
  47. [47]
    Wang Y, Kedei N, Wang M, Wang QJ, Huppler AR, Toth A, et al. Interaction between protein kinase Cμ and the vanilloid receptor type 1. J Biol Chem 2004, 279: 53674–53682.PubMedCrossRefGoogle Scholar
  48. [48]
    Zhu H, Yang Y, Zhang H, Han Y, Li Y, Zhang Y, et al. Interaction between protein kinase D1 and transient receptor potential V1 in primary sensory neurons is involved in heat hypersensitivity. Pain 2008, 137: 574–588.PubMedCrossRefGoogle Scholar
  49. [49]
    Wang Y. The functional regulation of TRPV1 and its role in pain sensitization. Neurochem Res 2008, 33: 2008–2012.PubMedCrossRefGoogle Scholar
  50. [50]
    Craig AM, Banker G. Neuronal polarity. Annu Rev Neurosci 1994, 17: 267–310.PubMedCrossRefGoogle Scholar
  51. [51]
    Dotti CG, Sullivan CA, Banker GA. The establishment of polarity by hippocampal neurons in culture. J Neurosci 1988, 8: 1454–1468.PubMedGoogle Scholar
  52. [52]
    Yin DM, Huang YH, Zhu YB, Wang Y. Both the establishment and maintenance of neuronal polarity require the activity of protein kinase D in the Golgi apparatus. J Neurosci 2008, 28: 8832–8843.PubMedCrossRefGoogle Scholar
  53. [53]
    Czondor K, Ellwanger K, Fuchs YF, Lutz S, Gulyas M, Mansuy IM, et al. Protein kinase D controls the integrity of Golgi apparatus and the maintenance of dendritic arborization in hippocampal neurons. Mol Biol Cell 2009, 20: 2108–2120.PubMedCentralPubMedCrossRefGoogle Scholar
  54. [54]
    Bisbal M, Conde C, Donoso M, Bollati F, Sesma J, Quiroga S, et al. Protein kinase d regulates trafficking of dendritic membrane proteins in developing neurons. J Neurosci 2008, 28: 9297–9308.PubMedCentralPubMedCrossRefGoogle Scholar
  55. [55]
    Sánchez-Ruiloba L, Cabrera-Poch N, Rodríguez-Martínez M, López-Menéndez C, Jean-Mairet RM, Higuero AM, et al. Protein kinase D intracellular localization and activity control kinase D-interacting substrate of 220-kDa traffic through a postsynaptic density-95/discs large/zonula occludens-1-binding motif. J Biol Chem 2006, 281: 18888–18900.PubMedCrossRefGoogle Scholar
  56. [56]
    Bracale A, Cesca F, Neubrand VE, Newsome TP, Way M, Schiavo G. Kidins220/ARMS is transported by a kinesin-1-based mechanism likely to be involved in neuronal differentiation. Mol Biol Cell 2007, 18: 142–152.PubMedCentralPubMedCrossRefGoogle Scholar
  57. [57]
    Higuero AM, Sánchez-Ruiloba L, Doglio LE, Portillo F, Abad-Rodríguez J, Dotti CG, et al. Kidins220/ARMS modulates the activity of microtubule-regulating proteins and controls neuronal polarity and development. J Biol Chem 2010, 285: 1343–1357.PubMedCentralPubMedCrossRefGoogle Scholar
  58. [58]
    Cabrera-Poch N, Sánchez-Ruiloba L, Rodríguez-Martínez M, Iglesias T. Lipid raft disruption triggers protein kinase C and Src-dependent protein kinase D activation and Kidins220 phosphorylation in neuronal cells. J Biol Chem 2004, 279: 28592–28602.PubMedCrossRefGoogle Scholar
  59. [59]
    Benton R, Johnston DS. Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell 2003, 115: 691–704.PubMedCrossRefGoogle Scholar
  60. [60]
    Chen Y, Wang Q, Hu H, Yu P, Zhu J, Drewes G, et al. Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity. Proc Natl Acad Sci U S A 2006, 103: 8534–8539.PubMedCentralPubMedCrossRefGoogle Scholar
  61. [61]
    Lin D, Edwards AS, Fawcett JP, Mbamalu G, Scott JD, Pawson T. A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nat Cell Biol 2000, 2: 540–547.PubMedCrossRefGoogle Scholar
  62. [62]
    Wu Q, DiBona VL, Bernard LP, Zhang H. The polarity protein partitioning-defective 1 (PAR-1) regulates dendritic spine morphogenesis through phosphorylating postsynaptic density protein 95 (PSD-95). J Biol Chem 2012, 287: 30781–30788.PubMedCentralPubMedCrossRefGoogle Scholar
  63. [63]
    Watkins JL, Lewandowski KT, Meek SE, Storz P, Toker A, Piwnica-Worms H. Phosphorylation of the Par-1 polarity kinase by protein kinase D regulates 14-3-3 binding and membrane association. Proc Natl Acad Sci U S A 2008, 105: 18378–18383.PubMedCentralPubMedCrossRefGoogle Scholar
  64. [64]
    Asaithambi A, Kanthasamy A, Saminathan H, Anantharam V, Kanthasamy AG. Protein kinase D1 (PKD1) activation mediates a compensatory protective response during early stages of oxidative stress-induced neuronal degeneration. Mol Neurodegener 2011, 6: 43.PubMedCentralPubMedCrossRefGoogle Scholar
  65. [65]
    Stetler RA, Cao G, Gao Y, Zhang F, Wang S, Weng Z, et al. Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. J Neurosci 2008, 28: 13038–13055.PubMedCentralPubMedCrossRefGoogle Scholar
  66. [66]
    Doppler H, Storz P, Li J, Comb MJ, Toker A. A phosphorylation state-specific antibody recognizes Hsp27, a novel substrate of protein kinase D. J Biol Chem 2005, 280: 15013–15019.PubMedCrossRefGoogle Scholar
  67. [67]
    Stetler RA, Gao Y, Zhang L, Weng Z, Zhang F, Hu X, et al. Phosphorylation of HSP27 by protein kinase D is essential for mediating neuroprotection against ischemic neuronal injury. J Neurosci 2012, 32: 2667–2682.PubMedCentralPubMedCrossRefGoogle Scholar
  68. [68]
    Feng H, Ren M, Chen L, Rubin CS. Properties, regulation, and in vivo functions of a novel protein kinase D Caenorhabditis elegans DKF-2 links diacylglycerol second messenger to the regulation of stress responses and life span. J Biol Chem 2007, 282: 31273–31288.PubMedCrossRefGoogle Scholar
  69. [69]
    Ren M, Feng H, Fu Y, Land M, Rubin CS. Protein kinase D (DKF-2), a diacylglycerol effector, is an essential regulator of C. elegans innate immunity. Immunity 2009, 30: 521.PubMedCentralPubMedCrossRefGoogle Scholar
  70. [70]
    Hukema RK, Rademakers S, Dekkers MP, Burghoorn J, Jansen G. Antagonistic sensory cues generate gustatory plasticity in Caenorhabditis elegans. EMBO J 2006, 25: 312–322.PubMedCentralPubMedCrossRefGoogle Scholar
  71. [71]
    Jansen G, Weinkove D, Plasterk RH. The G-protein {gamma} subunit gpc-1 of the nematode C. elegans is involved in taste adaptation. Sci Signal 2002, 21: 986.Google Scholar
  72. [72]
    Saeki S, Yamamoto M, Iino Y. Plasticity of chemotaxis revealed by paired presentation of a chemoattractant and starvation in the nematode Caenorhabditis elegans. J Exp Biol 2001, 204: 1757–1764.PubMedGoogle Scholar
  73. [73]
    Fu Y, Ren M, Feng H, Chen L, Altun ZF, Rubin CS. Neuronal and intestinal protein kinase d isoforms mediate Na+ (salt taste)-induced learning. Sci Signal 2009, 2: ra42.Google Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning CommissionPeking UniversityBeijingChina
  2. 2.PKU-IDG/McGovern Institute for Brain ResearchPeking UniversityBeijingChina

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