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Gene Review

PRKD1  -  protein kinase D1

Homo sapiens

Synonyms: PKC-MU, PKC-mu, PKCM, PKD, PKD1, ...
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Disease relevance of PRKD1


High impact information on PRKD1

  • Protein kinase D regulates the fission of cell surface destined transport carriers from the trans-Golgi network [6].
  • When a kinase inactive form of Protein Kinase D (PKD-K618N) was expressed in HeLa cells, it localized to the trans-Golgi network (TGN) and caused extensive tubulation [6].
  • In this report, evidence is presented that the downstream target of Gbetagamma is protein kinase D (PKD), an isoform of protein kinase C. PKD, unlike other members of this class of serine/threonine kinases, contains a pleckstrin homology (PH) domain [7].
  • Our findings suggest a possible mechanism by which the direct interaction of Gbetagamma with PKD regulates the dynamics of Golgi membranes and protein secretion [7].
  • Recently, the serine/threonine kinase protein kinase D1 (PKD1) was identified as a mitochondrial sensor for oxidative stress. mROS-activated PKD regulates a radical-sensing signaling pathway, which relays mROS production to the induction of nuclear genes that mediate cellular detoxification and survival [8].

Chemical compound and disease context of PRKD1

  • Co-transfection of Clostridium botulinum C3 toxin blocked activation of PKD by RhoQ63L, Lbc, or aluminum fluoride-stimulated Galpha(13) [9].
  • Consistent with these expression results, EKI-785 or EKB-569 administration had no effect or worsened PKD, and had no effect on the development of fibrocystic liver disease [10].
  • In the Cy/+ females, testosterone treatment caused azotemia and an increase in the severity of the PKD [11].
  • We measured the changes of forearm flexor H reflexes produced by conditioning radial nerve stimulation at delays of -2, 0, 2, 4, 7.5, 10, 25 and 75 ms in 10 patients with PKD and six with generalized seizure disorder [12].
  • Based on our finding that caffeine exacerbates hypertension in rats with PKD, it may be prudent for patients with ADPKD to limit coffee consumption to four or fewer cups of caffeinated coffee per day, pending studies of humans [13].

Biological context of PRKD1


Anatomical context of PRKD1


Associations of PRKD1 with chemical compounds


Physical interactions of PRKD1

  • CK2 binds to DeltaCSN3(111-403) and CSN7, whereas PKD interacts with full-length CSN3 [26].
  • Although p32 binds to the kinase domain of PKC mu, it does not serve as a substrate [27].
  • Moreover, PKD interacted with PLCgamma even in unstimulated cells, and PKD tyrosine 463 phosphorylation was not required for this interaction [28].
  • Second, TLR5 interacted with PKD in coimmunoprecipitation experiments, and this association was rapidly enhanced by flagellin treatment [29].

Enzymatic interactions of PRKD1

  • Kinetic studies revealed that the three PKD isozymes phosphorylate HDAC5 through a random sequential mechanism, and that ATP has no effect on association of kinase with peptide substrate [16].
  • PKC mu can down-regulate the ability of Syk to phosphorylate PLC gamma 1 in vitro [18].
  • Both CK2 and PKD phosphorylate c-Jun as well as p53 [26].
  • Furthermore, PKD localizes to the area of particle intake in the cell and phosphorylates two of the three cytosolic components of the NADPH oxidase, p40(phox) and p47(phox) [30].

Regulatory relationships of PRKD1

  • Secretion of NT is regulated by phorbol ester-sensitive protein kinase C (PKC) isoforms-alpha and -delta and may involve protein kinase D (PKD) [19].
  • Protein kinase D (PKD) binds to diacylglycerol (DAG) in the trans-Golgi network (TGN) and is activated by trimeric G-protein subunits beta gamma [14].
  • Analysis of mutants of the chicken B cell line DT40 deficient in either Syk, Lyn, Btk, or PLC gamma 2 revealed that BCR-induced activation of PKC mu, like activation of PLC gamma 2, requires Syk and is partially regulated by Btk, but is Lyn independent [18].
  • Protein kinase D is sufficient to suppress EGF-induced c-Jun Ser 63 phosphorylation [31].
  • Moreover transfection of PKD(Y463F), PKD(S738A/S742A), or PKD-small interfering RNA blocked VEGF-induced angiogenesis in vivo [28].
  • 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 [32].
  • As a consequence of this trimeric complex, the existing interaction between PKCdelta and PKD1 was increased, and the transfer of phosphate groups from PKCdelta to PKD1 was at least partly blocked by Spry2 [33].
  • DAG to which PKD1 is recruited in this pathway is formed downstream of phospholipase D1 (PLD1) and a lipase-inactive PLD1 or inhibition of PLD1 by pharmacological inhibitors blocked PKD1 activation under oxidative stress [34].

Other interactions of PRKD1

  • The purpose of our present study was: (i) to define the role of PKD in NT release from BON endocrine cells and (ii) to delineate the upstream signaling mechanisms mediating this effect [19].
  • Because catalytically active PKD associates with JNK we determined whether it could phosphorylate the c-Jun N-terminus as a potential mechanism by which it suppresses c-Jun Ser 63 phosphorylation when it complexes with JNK [15].
  • The association is mediated through the pleckstrin homology domain of PKD and the C-terminal domain of ASK1 [35].
  • Uncoupling of protein kinase D from suppression of EGF-dependent c-Jun phosphorylation in cancer cells [36].
  • In vitro phosphorylation of fusion proteins showed that both Syk and PLC gamma 1 are potential substrates of PKC mu in vivo [18].

Analytical, diagnostic and therapeutic context of PRKD1


  1. Neurotensin induces protein kinase C-dependent protein kinase D activation and DNA synthesis in human pancreatic carcinoma cell line PANC-1. Guha, S., Rey, O., Rozengurt, E. Cancer Res. (2002) [Pubmed]
  2. Protein kinase D: a family affair. Rykx, A., De Kimpe, L., Mikhalap, S., Vantus, T., Seufferlein, T., Vandenheede, J.R., Van Lint, J. FEBS Lett. (2003) [Pubmed]
  3. Metallothionein 2A interacts with the kinase domain of PKCmu in prostate cancer. Rao, P.S., Jaggi, M., Smith, D.J., Hemstreet, G.P., Balaji, K.C. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  4. Autosomal dominant polycystic kidney disease: modification of disease progression. Peters, D.J., Breuning, M.H. Lancet (2001) [Pubmed]
  5. Protein kinase D2 mediates activation of nuclear factor kappaB by Bcr-Abl in Bcr-Abl+ human myeloid leukemia cells. Mihailovic, T., Marx, M., Auer, A., Van Lint, J., Schmid, M., Weber, C., Seufferlein, T. Cancer Res. (2004) [Pubmed]
  6. Protein kinase D regulates the fission of cell surface destined transport carriers from the trans-Golgi network. Liljedahl, M., Maeda, Y., Colanzi, A., Ayala, I., Van Lint, J., Malhotra, V. Cell (2001) [Pubmed]
  7. Gbetagamma-mediated regulation of Golgi organization is through the direct activation of protein kinase D. Jamora, C., Yamanouye, N., Van Lint, J., Laudenslager, J., Vandenheede, J.R., Faulkner, D.J., Malhotra, V. Cell (1999) [Pubmed]
  8. Mitochondrial ROS--radical detoxification, mediated by protein kinase D. Storz, P. Trends Cell Biol. (2007) [Pubmed]
  9. Activation of protein kinase D by signaling through Rho and the alpha subunit of the heterotrimeric G protein G13. Yuan, J., Slice, L.W., Rozengurt, E. J. Biol. Chem. (2001) [Pubmed]
  10. Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats. Torres, V.E., Sweeney, W.E., Wang, X., Qian, Q., Harris, P.C., Frost, P., Avner, E.D. Kidney Int. (2004) [Pubmed]
  11. Gender and the effect of gonadal hormones on the progression of inherited polycystic kidney disease in rats. Cowley, B.D., Rupp, J.C., Muessel, M.J., Gattone, V.H. Am. J. Kidney Dis. (1997) [Pubmed]
  12. Reciprocal inhibition between the forearm muscles in patients with paroxysmal kinesigenic dyskinesia. Lee, M.S., Kim, W.C., Lyoo, C.H., Lee, H.J. J. Neurol. Sci. (1999) [Pubmed]
  13. Chronic caffeine consumption exacerbates hypertension in rats with polycystic kidney disease. Tanner, G.A., Tanner, J.A. Am. J. Kidney Dis. (2001) [Pubmed]
  14. Protein kinase D regulates basolateral membrane protein exit from trans-Golgi network. Yeaman, C., Ayala, M.I., Wright, J.R., Bard, F., Bossard, C., Ang, A., Maeda, Y., Seufferlein, T., Mellman, I., Nelson, W.J., Malhotra, V. Nat. Cell Biol. (2004) [Pubmed]
  15. Protein kinase D complexes with C-Jun N-terminal kinase via activation loop phosphorylation and phosphorylates the C-Jun N-terminus. Hurd, C., Waldron, R.T., Rozengurt, E. Oncogene (2002) [Pubmed]
  16. Protein kinase D directly phosphorylates histone deacetylase 5 via a random sequential kinetic mechanism. Huynh, Q.K., McKinsey, T.A. Arch. Biochem. Biophys. (2006) [Pubmed]
  17. Protein kinase C-dependent protein kinase D activation modulates ERK signal pathway and endothelial cell proliferation by vascular endothelial growth factor. Wong, C., Jin, Z.G. J. Biol. Chem. (2005) [Pubmed]
  18. Protein kinase C mu (PKC mu) associates with the B cell antigen receptor complex and regulates lymphocyte signaling. Sidorenko, S.P., Law, C.L., Klaus, S.J., Chandran, K.A., Takata, M., Kurosaki, T., Clark, E.A. Immunity (1996) [Pubmed]
  19. The role of protein kinase D in neurotensin secretion mediated by protein kinase C-alpha/-delta and Rho/Rho kinase. Li, J., O'Connor, K.L., Hellmich, M.R., Greeley, G.H., Townsend, C.M., Evers, B.M. J. Biol. Chem. (2004) [Pubmed]
  20. Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase D1. Arnold, R., Patzak, I.M., Neuhaus, B., Vancauwenbergh, S., Veillette, A., Van Lint, J., Kiefer, F. Mol. Cell. Biol. (2005) [Pubmed]
  21. Protein kinase D mediates mitochondrion-to-nucleus signaling and detoxification from mitochondrial reactive oxygen species. Storz, P., Döppler, H., Toker, A. Mol. Cell. Biol. (2005) [Pubmed]
  22. Bruton's tyrosine kinase (Btk) associates with protein kinase C mu. Johannes, F.J., Hausser, A., Storz, P., Truckenmüller, L., Link, G., Kawakami, T., Pfizenmaier, K. FEBS Lett. (1999) [Pubmed]
  23. Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein. Fugmann, T., Hausser, A., Schöffler, P., Schmid, S., Pfizenmaier, K., Olayioye, M.A. J. Cell Biol. (2007) [Pubmed]
  24. Potent and selective disruption of protein kinase D functionality by a benzoxoloazepinolone. Sharlow, E.R., Giridhar, K.V., LaValle, C.R., Chen, J., Leimgruber, S., Barrett, R., Bravo-Altamirano, K., Wipf, P., Lazo, J.S., Wang, Q.J. J. Biol. Chem. (2008) [Pubmed]
  25. The protein scaffold NHERF-1 controls the amplitude and duration of localized protein kinase D activity. Kunkel, M.T., Garcia, E.L., Kajimoto, T., Hall, R.A., Newton, A.C. J. Biol. Chem. (2009) [Pubmed]
  26. Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome. Uhle, S., Medalia, O., Waldron, R., Dumdey, R., Henklein, P., Bech-Otschir, D., Huang, X., Berse, M., Sperling, J., Schade, R., Dubiel, W. EMBO J. (2003) [Pubmed]
  27. Protein kinase C [micro] is regulated by the multifunctional chaperon protein p32. Storz, P., Hausser, A., Link, G., Dedio, J., Ghebrehiwet, B., Pfizenmaier, K., Johannes, F.J. J. Biol. Chem. (2000) [Pubmed]
  28. Requirement of Protein Kinase D Tyrosine Phosphorylation for VEGF-A165-induced Angiogenesis through Its Interaction and Regulation of Phospholipase C{gamma} Phosphorylation. Qin, L., Zeng, H., Zhao, D. J. Biol. Chem. (2006) [Pubmed]
  29. Protein kinase D interaction with TLR5 is required for inflammatory signaling in response to bacterial flagellin. Ivison, S.M., Graham, N.R., Bernales, C.Q., Kifayet, A., Ng, N., Shobab, L.A., Steiner, T.S. J. Immunol. (2007) [Pubmed]
  30. Involvement of protein kinase D in Fc gamma-receptor activation of the NADPH oxidase in neutrophils. Davidson-Moncada, J.K., Lopez-Lluch, G., Segal, A.W., Dekker, L.V. Biochem. J. (2002) [Pubmed]
  31. Protein kinase D is sufficient to suppress EGF-induced c-Jun Ser 63 phosphorylation. Hurd, C., Rozengurt, E. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  32. Protein kinase D induces transcription through direct phosphorylation of the cAMP-response element-binding protein. Johannessen, M., Delghandi, M.P., Rykx, A., Dragset, M., Vandenheede, J.R., Van Lint, J., Moens, U. J. Biol. Chem. (2007) [Pubmed]
  33. Sprouty2 interacts with protein kinase C delta and disrupts phosphorylation of protein kinase D1. Chow, S.Y., Yu, C.Y., Guy, G.R. J. Biol. Chem. (2009) [Pubmed]
  34. Mitochondrial diacylglycerol initiates protein-kinase D1-mediated ROS signaling. Cowell, C.F., Döppler, H., Yan, I.K., Hausser, A., Umezawa, Y., Storz, P. J. Cell. Sci. (2009) [Pubmed]
  35. Protein kinase D specifically mediates apoptosis signal-regulating kinase 1-JNK signaling induced by H2O2 but not tumor necrosis factor. Zhang, W., Zheng, S., Storz, P., Min, W. J. Biol. Chem. (2005) [Pubmed]
  36. Uncoupling of protein kinase D from suppression of EGF-dependent c-Jun phosphorylation in cancer cells. Hurd, C., Rozengurt, E. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  37. A phosphorylation state-specific antibody recognizes Hsp27, a novel substrate of protein kinase D. Döppler, H., Storz, P., Li, J., Comb, M.J., Toker, A. J. Biol. Chem. (2005) [Pubmed]
  38. Molecular cloning and characterization of the human protein kinase D2. A novel member of the protein kinase D family of serine threonine kinases. Sturany, S., Van Lint, J., Muller, F., Wilda, M., Hameister, H., Hocker, M., Brey, A., Gern, U., Vandenheede, J., Gress, T., Adler, G., Seufferlein, T. J. Biol. Chem. (2001) [Pubmed]
  39. Regulation of protein kinase D by multisite phosphorylation. Identification of phosphorylation sites by mass spectrometry and characterization by site-directed mutagenesis. Vertommen, D., Rider, M., Ni, Y., Waelkens, E., Merlevede, W., Vandenheede, J.R., Van Lint, J. J. Biol. Chem. (2000) [Pubmed]
  40. Regulated nucleocytoplasmic transport of protein kinase D in response to G protein-coupled receptor activation. Rey, O., Sinnett-Smith, J., Zhukova, E., Rozengurt, E. J. Biol. Chem. (2001) [Pubmed]
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