Protein kinase C zeta type

PRKCZ
Identifiers
Aliases PRKCZ, PKC-ZETA, PKC2, protein kinase C zeta
External IDs MGI: 97602 HomoloGene: 55681 GeneCards: PRKCZ
Targeted by Drug
arachidonic acid, balanol[1]
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez

5590

18762

Ensembl

ENSG00000067606

ENSMUSG00000029053

UniProt

Q05513

Q02956

RefSeq (mRNA)

NM_001033581
NM_001033582
NM_001242874
NM_002744

NM_001039079
NM_008860

RefSeq (protein)

NP_001028753.1
NP_001028754.1
NP_001229803.1
NP_002735.3

NP_032886.2

Location (UCSC) Chr 1: 2.05 – 2.19 Mb Chr 4: 155.26 – 155.36 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

Protein kinase C, zeta (PKCζ), also known as PRKCZ, is an protein that in humans is encoded by the PRKCZ gene. The PRKCZ gene encodes at least two alternative transcripts, the full-length PKCζ and an N-terminal truncated form PKMζ. PKMζ is thought to be responsible for maintaining long-term memories in the brain. The importance of PKCζ in the creation and maintenance of long-term potentiation was first described by Todd Sacktor and his colleagues at the State University of New York at Brooklyn in 1993.[4]

Structure

PKC-zeta has an N-terminal regulatory domain, followed by a hinge region and a C-terminal catalytic domain. Second messengers stimulate PKCs by binding to the regulatory domain, translocating the enzyme from cytosol to membrane, and producing a conformational change that removes auto-inhibition of the PKC catalytic protein kinase activity. PKM-zeta, a brain-specific isoform of PKC-zeta generated from an alternative transcript, lacks the regulatory region of full-length PKC-zeta and is therefore constitutively active.[5]

PKMζ is the independent catalytic domain of PKCζ and, lacking an autoinhibitory regulatory domain of the full-length PKCζ, is constitutively and persistently active, without the need of a second messenger. It was originally thought of as being a cleavage product of full-length PKCζ, an atypical isoform of protein kinase C (PKC). Like other PKC isoforms, PKCζ is a serine/threonine kinase that adds phosphate groups to target proteins. It is atypical in that unlike other PKC isoforms, PKCζ does not require calcium or diacylglycerol (DAG) to become active, but rather relies on a different second messenger, presumably generated through a phosphoinositide 3-kinase (PI3-kinase) pathway. It is now known that PKMζ is not the result of cleavage of full-length PKCζ, but rather, in the mammalian brain, is translated from its own brain-specific mRNA, that is transcribed by an internal promoter within the PKCζ gene.[5] The promoter for full-length PKCζ is largely inactive in the forebrain and so PKMζ is the dominant form of ζ in the forebrain and the only PKM that is translated from its own mRNA.

Function

PKCζ

Atypical PKC (aPKC) isoforms [zeta (this enzyme) and lambda/iota] play important roles in insulin-stimulated glucose transport. Human adipocytes contain PKC-zeta, rather than PKC-lambda/iota, as their major aPKC. Inhibition of the PKCζ enzyme inhibits insulin-stimulated glucose transport while activation of PKCζ increases glucose transport.[6]

PKMζ

PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP).[7][8][9] LTP is one of the major cellular mechanisms that are widely considered to underlie learning and memory.[10] This theory arose from the observation that PKMζ perfused post synaptically into neurons causes synaptic potentiation, and selective inhibitors of PKMζ like zeta inhibitory peptide (ZIP), when bath applied one hour after tetanization, inhibit the late phase or maintenance of LTP. Thus PKMζ is both necessary and sufficient for maintaining LTP. Subsequent work showed that inhibiting PKMζ reversed LTP maintenance when applied up to 5 hours after LTP was induced in hippocampal slices, and after 22 hours in vivo. Inhibiting PKMζ in behaving animals erased spatial long-term memories in the hippocampus that were up to one month old, without affecting spatial short-term memories,[9] and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.[11] When ZIP was injected into rats' sensorimotor cortices, it erased muscle memories for a task, even after several weeks of training.[12] In the neocortex, thought to be the site of storage for most long-term memories, PKMζ inhibition erased associative memories for conditioned taste aversion in the insular cortex, up to 3 months after training.[13][14] The protein also seems to be involved, through the nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction.[15] PKMζ is thus the first molecule shown to be a component of the storage mechanism of long-term memory. Although results from PKCζ/PKMζ-null mice demonstrate LTP and memory appear largely the same as wild-type mice,[16][17] the normal function of PKMζ in LTP and long-term memory storage was shown to be compensated by the other atypical PKC isoform, PKCι/λ in the knock-out.[18][19][20]

Alteration in PKMζ may be involved in neurodegeneration Alzheimer's disease.[21]

Model organisms

Model organisms have been used in the study of PRKCZ function. A conditional knockout mouse line, called Prkcztm1a(EUCOMM)Wtsi[28][29] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[30][31][32]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[26][33] Twenty five tests were carried out on mutant mice and three significant abnormalities were observed.[26] Homozygous mutant males had Bergmeister's papilla, while both sexes had atypical plasma chemistry and abnormal melanocyte morphology.[26]

Inhibitors

Interactions

PRKCZ has been shown to interact with:

References

  1. "Drugs that physically interact with Protein kinase C zeta type view/edit references on wikidata".
  2. "Human PubMed Reference:".
  3. "Mouse PubMed Reference:".
  4. Sacktor TC, Osten P, Valsamis H, Jiang X, Naik MU, Sublette E (1993). "Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation". Proceedings of the National Academy of Sciences of the United States of America. 90 (18): 8342–8346. doi:10.1073/pnas.90.18.8342. PMC 47352Freely accessible. PMID 8378304.
  5. 1 2 Hernandez AI, Blace N, Crary JF, Serrano PA, Leitges M, Libien JM, Weinstein G, Tcherapanov A, Sacktor TC (October 2003). "Protein kinase M zeta synthesis from a brain mRNA encoding an independent protein kinase C zeta catalytic domain. Implications for the molecular mechanism of memory". J. Biol. Chem. 278 (41): 40305–16. doi:10.1074/jbc.M307065200. PMID 12857744.
  6. Bandyopadhyay G, Sajan MP, Kanoh Y, Standaert ML, Quon MJ, Lea-Currie R, Sen A, Farese RV (February 2002). "PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human adipocytes". J. Clin. Endocrinol. Metab. 87 (2): 716–23. doi:10.1210/jc.87.2.716. PMID 11836310.
  7. Ling DS, Benardo LS, Serrano PA, Blace N, Kelly MT, Crary JF, Sacktor TC (2002). "Protein kinase Mzeta is necessary and sufficient for LTP maintenance". Nat. Neurosci. 5 (4): 295–6. doi:10.1038/nn829. PMID 11914719.
  8. Serrano P, Yao Y, Sacktor TC (2005). "Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation". J Neurosci. 25 (8): 1979–84. doi:10.1523/JNEUROSCI.5132-04.2005. PMID 15728837.
  9. 1 2 Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC (2006). "Storage of spatial information by the maintenance mechanism of LTP". Science. 313 (5790): 1141–4. doi:10.1126/science.1128657. PMID 16931766.
  10. Cooke SF, Bliss TV (2006). "Plasticity in the human central nervous system". Brain. 129 (Pt 7): 1659–73. doi:10.1093/brain/awl082. PMID 16672292.
  11. Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J, Alberini C, Kelley AE, Maren S, Rudy JW, Yin JC, Sacktor TC, Fenton AA (2008). Lu B, ed. "PKMζ maintains spatial, instrumental, and classically conditioned long-term memories". PLoS Biology. 6 (12): 2698–706. doi:10.1371/journal.pbio.0060318. PMC 2605920Freely accessible. PMID 19108606.
  12. von Kraus LM, Sacktor TC, Francis JT (2010). Brezina V, ed. "Erasing Sensorimotor Memories via PKMζ Inhibition". PLoS ONE. 5 (6): e11125. doi:10.1371/journal.pone.0011125. PMC 2886075Freely accessible. PMID 20559553.
  13. Shema R, Sacktor TC, Dudai Y (2007). "Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMζ". Science. 317 (5840): 951–3. doi:10.1126/science.1144334. PMID 17702943.
  14. Shema R, Hazvi S, Sacktor TC, Dudai Y (2009). "Boundary conditions for the maintenance of memory by PKMζ in neocortex". Learn. Mem. 16 (2): 122–8. doi:10.1101/lm.1183309. PMC 2661244Freely accessible. PMID 19181618.
  15. Crespo JA, Stöckl P, Ueberall F, Jenny M, Saria A, Zernig G (February 2012). "Activation of PKCzeta and PKMzeta in the nucleus accumbens core is necessary for the retrieval, consolidation and reconsolidation of the drug memory". PLoS ONE. 7 (2): e30502. doi:10.1371/journal.pone.0030502. PMC 3277594Freely accessible. PMID 22348011.
  16. Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL (January 2013). "PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory". Nature. 493 (7432): 420–3. doi:10.1038/nature11802. PMC 3830948Freely accessible. PMID 23283174.
  17. Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C, McMahon T, Dadgar J, Fischbach-Weiss SC, Messing RO (January 2013). "Prkcz null mice show normal learning and memory". Nature. 493 (7432): 416–9. doi:10.1038/nature11803. PMC 3548047Freely accessible. PMID 23283171.
  18. Tsokas P, Hsieh C, Yao Y, Lesburguères E, Wallace EJ, Tcherepanov A, Jothianandan D, Hartley BR, Pan L, Rivard B, Farese RV, Sajan MP, Bergold PJ, Hernández AI, Cottrell JE, Shouval HZ, Fenton AA, Sacktor TC. "Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice". eLife. 5: e14846. doi:10.7554/eLife.14846.
  19. Morris RG (2016-05-17). "Forget me not". eLife. 5: e16597. doi:10.7554/eLife.16597.
  20. Frankland PW, Josselyn SA (July 2016). "Neuroscience: In search of the memory molecule". Nature. 535 (7610): 41–2. doi:10.1038/nature18903. PMID 27362229.
  21. Crary JF, Shao CY, Mirra SS, Hernandez AI, Sacktor TC (April 2006). "Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease". J. Neuropathol. Exp. Neurol. 65 (4): 319–26. doi:10.1097/01.jnen.0000218442.07664.04. PMID 16691113.
  22. "Eye morphology data for Prkcz". Wellcome Trust Sanger Institute.
  23. "Clinical chemistry data for Prkcz". Wellcome Trust Sanger Institute.
  24. "Salmonella infection data for Prkcz". Wellcome Trust Sanger Institute.
  25. "Citrobacter infection data for Prkcz". Wellcome Trust Sanger Institute.
  26. 1 2 3 4 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  27. Mouse Resources Portal, Wellcome Trust Sanger Institute.
  28. "International Knockout Mouse Consortium".
  29. "Mouse Genome Informatics".
  30. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (June 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410Freely accessible. PMID 21677750.
  31. Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  32. Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  33. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837Freely accessible. PMID 21722353.
  34. Abdel-Halim M, Diesel B, Kiemer AK, Abadi AH, Hartmann RW, Engel M (Aug 2014). "Discovery and optimization of 1,3,5-trisubstituted pyrazolines as potent and highly selective allosteric inhibitors of protein kinase C-ζ". Journal of Medicinal Chemistry. 57 (15): 6513–30. doi:10.1021/jm500521n. PMID 25058929.
  35. Hodgkinson CP, Sale EM, Sale GJ (2002). "Characterization of PDK2 activity against protein kinase B gamma". Biochemistry. 41 (32): 10351–9. doi:10.1021/bi026065r. PMID 12162751.
  36. 1 2 3 4 Van Der Hoeven PC, Van Der Wal JC, Ruurs P, Van Dijk MC, Van Blitterswijk J (2000). "14-3-3 isotypes facilitate coupling of protein kinase C-zeta to Raf-1: negative regulation by 14-3-3 phosphorylation". Biochem. J. 345 (2): 297–306. doi:10.1042/0264-6021:3450297. PMC 1220759Freely accessible. PMID 10620507.
  37. Storz P, Hausser A, Link G, Dedio J, Ghebrehiwet B, Pfizenmaier K, Johannes FJ (2000). "Protein kinase C [micro] is regulated by the multifunctional chaperon protein p32". J. Biol. Chem. 275 (32): 24601–7. doi:10.1074/jbc.M002964200. PMID 10831594.
  38. 1 2 Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, Johannes FJ, Aitken A (2003). "Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C". Biochem. Biophys. Res. Commun. 307 (3): 459–65. doi:10.1016/S0006-291X(03)01187-2. PMID 12893243.
  39. Kuroda S, Nakagawa N, Tokunaga C, Tatematsu K, Tanizawa K (1999). "Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein". J. Cell Biol. 144 (3): 403–11. doi:10.1083/jcb.144.3.403. PMC 2132904Freely accessible. PMID 9971736.
  40. Fujita T, Ikuta J, Hamada J, Okajima T, Tatematsu K, Tanizawa K, Kuroda S (2004). "Identification of a tissue-non-specific homologue of axonal fasciculation and elongation protein zeta-1". Biochem. Biophys. Res. Commun. 313 (3): 738–44. doi:10.1016/j.bbrc.2003.12.006. PMID 14697253.
  41. Diaz-Meco MT, Moscat J (2001). "MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling". Mol. Cell. Biol. 21 (4): 1218–27. doi:10.1128/MCB.21.4.1218-1227.2001. PMC 99575Freely accessible. PMID 11158308.
  42. San-Antonio B, Iñiguez MA, Fresno M (2002). "Protein kinase Czeta phosphorylates nuclear factor of activated T cells and regulates its transactivating activity". J. Biol. Chem. 277 (30): 27073–80. doi:10.1074/jbc.M106983200. PMID 12021260.
  43. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
  44. Liu XF, Ishida H, Raziuddin R, Miki T (2004). "Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase Czeta (PKCzeta) and regulates PKCzeta activity". Mol. Cell. Biol. 24 (15): 6665–75. doi:10.1128/MCB.24.15.6665-6675.2004. PMC 444862Freely accessible. PMID 15254234.
  45. 1 2 Noda Y, Takeya R, Ohno S, Naito S, Ito T, Sumimoto H (2001). "Human homologues of the Caenorhabditis elegans cell polarity protein PAR6 as an adaptor that links the small GTPases Rac and Cdc42 to atypical protein kinase C". Genes Cells. 6 (2): 107–19. doi:10.1046/j.1365-2443.2001.00404.x. PMID 11260256.
  46. Díaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L, Moscat J (1996). "The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C". Cell. 86 (5): 777–86. doi:10.1016/S0092-8674(00)80152-X. PMID 8797824.
  47. Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR (2000). "A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Czeta (PKCzeta ) and PKC-related kinase 2 by PDK1". J. Biol. Chem. 275 (27): 20806–13. doi:10.1074/jbc.M000421200. PMID 10764742.
  48. Hodgkinson CP, Sale GJ (2002). "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry. 41 (2): 561–9. doi:10.1021/bi010719z. PMID 11781095.
  49. Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ (1998). "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science. 281 (5385): 2042–5. doi:10.1126/science.281.5385.2042. PMID 9748166.
  50. Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA (1999). "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway". EMBO J. 18 (11): 3024–33. doi:10.1093/emboj/18.11.3024. PMC 1171384Freely accessible. PMID 10357815.
  51. Leitges M, Sanz L, Martin P, Duran A, Braun U, García JF, Camacho F, Diaz-Meco MT, Rennert PD, Moscat J (2001). "Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway". Mol. Cell. 8 (4): 771–80. doi:10.1016/S1097-2765(01)00361-6. PMID 11684013.
  52. Seibenhener ML, Roehm J, White WO, Neidigh KB, Vandenplas ML, Wooten MW (1999). "Identification of Src as a novel atypical protein kinase C-interacting protein". Mol. Cell Biol. Res. Commun. 2 (1): 28–31. doi:10.1006/mcbr.1999.0140. PMID 10527887.
  53. Büther K, Plaas C, Barnekow A, Kremerskothen J (2004). "KIBRA is a novel substrate for protein kinase Czeta". Biochem. Biophys. Res. Commun. 317 (3): 703–7. doi:10.1016/j.bbrc.2004.03.107. PMID 15081397.

Further reading

  • Slater SJ, Ho C, Stubbs CD (2003). "The use of fluorescent phorbol esters in studies of protein kinase C-membrane interactions". Chem. Phys. Lipids. 116 (1–2): 75–91. doi:10.1016/S0009-3084(02)00021-X. PMID 12093536. 
  • Carter CA, Kane CJ (2005). "Therapeutic potential of natural compounds that regulate the activity of protein kinase C". Curr. Med. Chem. 11 (21): 2883–902. doi:10.2174/0929867043364090. PMID 15544481. 
This article is issued from Wikipedia - version of the 11/13/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.