Protein kinase C zeta type

Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein in humans that 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 SUNY Downstate Medical Center in 1993.[5]

PRKCZ
Identifiers
AliasesPRKCZ, PKC-ZETA, PKC2, protein kinase C zeta
External IDsOMIM: 176982 MGI: 97602 HomoloGene: 55681 GeneCards: PRKCZ
Orthologs
SpeciesHumanMouse
Entrez

5590

18762

Ensembl

ENSG00000067606

ENSMUSG00000029053

UniProt

Q05513

Q02956

RefSeq (mRNA)

NM_001039079
NM_008860
NM_001355178

RefSeq (protein)

NP_001034168
NP_032886
NP_001342107

Location (UCSC)Chr 1: 2.05 – 2.19 MbChr 4: 155.34 – 155.45 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[6]

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.[6] 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.[7]

PKMζ

PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP).[8][9][10] LTP is one of the major cellular mechanisms that are widely considered to underlie learning and memory.[11] This theory arose from the observation that PKMζ perfused 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 was thought to be 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,[10] and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.[12] When ZIP was injected into rats' sensorimotor cortices, it erased muscle memories for a task, even after several weeks of training.[13] 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.[14][15] The protein also seems to be involved, through the nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction.[16] Although results from PKCζ/PKMζ-null mice demonstrate LTP and memory appear largely the same as wild-type mice,[17][18] 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.[19][20][21]

Alteration in PKMζ may be involved in neurodegeneration Alzheimer's disease.[22]

Model organisms

Model organisms have been used in the study of PRKCZ function. A conditional knockout mouse line, called Prkcztm1a(EUCOMM)Wtsi[29][30] 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.[31][32][33]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[27][34] Twenty five tests were carried out on mutant mice and three significant abnormalities were observed.[27] Homozygous mutant males had Bergmeister's papilla, while both sexes had atypical plasma chemistry and abnormal melanocyte morphology.[27]

Inhibitors

  • 1,3,5-Trisubstituted Pyrazolines[35]

Interactions

PRKCZ has been shown to interact with:

References

  1. GRCh38: Ensembl release 89: ENSG00000067606 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000029053 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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. Bibcode:1993PNAS...90.8342S. doi:10.1073/pnas.90.18.8342. PMC 47352. PMID 8378304.
  6. 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.
  7. 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/jcem.87.2.8252. PMID 11836310.
  8. 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. S2CID 11200668.
  9. 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. PMC 6726070. PMID 15728837.
  10. 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. Bibcode:2006Sci...313.1141P. CiteSeerX 10.1.1.453.2136. doi:10.1126/science.1128657. PMID 16931766. S2CID 7260010.
  11. 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.
  12. 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 2605920. PMID 19108606.
  13. von Kraus LM, Sacktor TC, Francis JT (2010). Brezina V (ed.). "Erasing Sensorimotor Memories via PKMζ Inhibition". PLOS ONE. 5 (6): e11125. Bibcode:2010PLoSO...511125V. doi:10.1371/journal.pone.0011125. PMC 2886075. PMID 20559553.
  14. 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. Bibcode:2007Sci...317..951S. doi:10.1126/science.1144334. PMID 17702943. S2CID 15707301.
  15. 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 2661244. PMID 19181618.
  16. 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. Bibcode:2012PLoSO...730502C. doi:10.1371/journal.pone.0030502. PMC 3277594. PMID 22348011.
  17. 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. Bibcode:2013Natur.493..420V. doi:10.1038/nature11802. PMC 3830948. PMID 23283174.
  18. 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. Bibcode:2013Natur.493..416L. doi:10.1038/nature11803. PMC 3548047. PMID 23283171.
  19. 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 (2016). "Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice". eLife. 5: e14846. doi:10.7554/eLife.14846. PMC 4869915. PMID 27187150.
  20. Morris RG (17 May 2016). "Forget me not". eLife. 5: e16597. doi:10.7554/eLife.16597. PMC 4869910. PMID 27187147.
  21. Frankland PW, Josselyn SA (July 2016). "Neuroscience: In search of the memory molecule". Nature. 535 (7610): 41–2. Bibcode:2016Natur.535...41F. doi:10.1038/nature18903. PMID 27362229.
  22. 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.
  23. "Eye morphology data for Prkcz". Wellcome Trust Sanger Institute.
  24. "Clinical chemistry data for Prkcz". Wellcome Trust Sanger Institute.
  25. "Salmonella infection data for Prkcz". Wellcome Trust Sanger Institute.
  26. "Citrobacter infection data for Prkcz". Wellcome Trust Sanger Institute.
  27. 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. S2CID 85911512.
  28. Mouse Resources Portal, Wellcome Trust Sanger Institute.
  29. "International Knockout Mouse Consortium".
  30. "Mouse Genome Informatics".
  31. 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 3572410. PMID 21677750.
  32. Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  33. 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. S2CID 18872015.
  34. 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 3218837. PMID 21722353.
  35. Abdel-Halim M, Diesel B, Kiemer AK, Abadi AH, Hartmann RW, Engel M (August 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.
  36. 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.
  37. 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 1220759. PMID 10620507.
  38. 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.
  39. 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.
  40. 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 2132904. PMID 9971736.
  41. 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.
  42. 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 99575. PMID 11158308.
  43. 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.
  44. 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. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
  45. 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 444862. PMID 15254234.
  46. 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.
  47. 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. S2CID 15675524.
  48. 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.
  49. 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.
  50. 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. Bibcode:1998Sci...281.2042A. doi:10.1126/science.281.5385.2042. PMID 9748166.
  51. 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 1171384. PMID 10357815.
  52. 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.
  53. 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.
  54. 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.
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