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Protein kinase C, zeta
Symbols PRKCZ; PKC2
External IDs OMIM176982 MGI97602 HomoloGene55681 GeneCards: PRKCZ Gene
EC number
RNA expression pattern
PBB GE PRKCZ 202178 at tn.png
More reference expression data
Species Human Mouse
Entrez 5590 18762
Ensembl ENSG00000067606 ENSMUSG00000029053
UniProt Q05513 Q3UHM5
RefSeq (mRNA) NM_001033581 NM_001039079
RefSeq (protein) NP_001028753 NP_001034168
Location (UCSC) Chr 1:
1.97 - 2.11 Mb
Chr 4:
154.1 - 154.21 Mb
PubMed search [1] [2]

Protein kinase C, zeta (PKCζ) also known as PRKCZ is an enzyme which 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. The truncated PKMζ is thought to be responsible for maintaining long-term memories in the brain.



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 autoinhibition of the PKC catalytic 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.[1]

PKMζ is the independent catalytic domain of protein kinase Cζ (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 mammalian brain, is translated from its own brain-specific mRNA, that is transcribed by an internal promoter within the PKCζ gene.[1] 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.




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.[2]


PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP).[3][4][5] This theory arose from the observation that PKMζ perfused postsynaptically into neurons causes synaptic potentiation, and selective inhibitors of PKMζ, 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[5], and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.[6] 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.[7][8] PKMζ is thus the first molecule shown to be a component of the storage mechanism of long-term memory.

Recent research has demonstrated alteration in PKMζ in Alzheimer's disease (see Long-term potentiation), providing a potential link between this kinase and neurodegeneration.[9]


PRKCZ has been shown to interact with CENTA1,[10] PDPK1,[11][12][13][14] PARD6A,[15][16][17] Src,[18] NFATC2,[19] PAWR,[20] YWHAQ,[21] WWC1,[22] C-Raf,[21] AKT3,[23] PARD6B,[17] RELA,[24] FEZ1,[25] YWHAB,[21] FEZ2,[26] C1QBP,[27] YWHAZ[10][21] and MAP2K5.[28]


  1. ^ a b 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.  
  2. ^ 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. PMID 11836310.  
  3. ^ Ling D, Benardo L, Serrano P, Blace N, Kelly M, Crary J, Sacktor T (2002). "Protein kinase Mzeta is necessary and sufficient for LTP maintenance". Nat. Neurosci. 5 (4): 295–6. doi:10.1038/nn829. PMID 11914719.  
  4. ^ Serrano P, Yao Y, Sacktor T (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.  
  5. ^ a b Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton A, Sacktor T (2006). "Storage of spatial information by the maintenance mechanism of LTP". Science 313 (5790): 1141–4. doi:10.1126/science.1128657. PMID 16931766.  
  6. ^ Serrano P et al. (2008). "PKMζ maintains spatial, instrumental, and classically conditioned long-term memories.". PLoS Biology 6 (12): 2698–706. doi:10.1371/journal.pbio.0060318. PMID 19108606.  
  7. ^ Shema R, Sacktor T, 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.  
  8. ^ Shema R, Hazvi S, Sacktor T, 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. PMID 19181618.  
  9. ^ 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.  
  10. ^ a b Zemlickova, Eva; Dubois Thierry, Kerai Preeti, Clokie Sam, Cronshaw Andy D, Wakefield Robert I D, Johannes Franz-Josef, Aitken Alastair (Aug. 2003). "Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C". Biochem. Biophys. Res. Commun. (United States) 307 (3): 459–65. ISSN 0006-291X. PMID 12893243.  
  11. ^ Balendran, A; Biondi R M, Cheung P C, Casamayor A, Deak M, Alessi D R (Jul. 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. (UNITED STATES) 275 (27): 20806–13. doi:10.1074/jbc.M000421200. ISSN 0021-9258. PMID 10764742.  
  12. ^ Hodgkinson, Conrad P; Sale Graham J (Jan. 2002). "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry (United States) 41 (2): 561–9. ISSN 0006-2960. PMID 11781095.  
  13. ^ Le Good, J A; Ziegler W H, Parekh D B, Alessi D R, Cohen P, Parker P J (Sep. 1998). "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science (UNITED STATES) 281 (5385): 2042–5. ISSN 0036-8075. PMID 9748166.  
  14. ^ Park, J; Leong M L, Buse P, Maiyar A C, Firestone G L, Hemmings B A (Jun. 1999). "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway". EMBO J. (ENGLAND) 18 (11): 3024–33. doi:10.1093/emboj/18.11.3024. ISSN 0261-4189. PMID 10357815.  
  15. ^ Rual, Jean-François; Venkatesan Kavitha, Hao Tong, Hirozane-Kishikawa Tomoko, Dricot Amélie, Li Ning, Berriz Gabriel F, Gibbons Francis D, Dreze Matija, Ayivi-Guedehoussou Nono, Klitgord Niels, Simon Christophe, Boxem Mike, Milstein Stuart, Rosenberg Jennifer, Goldberg Debra S, Zhang Lan V, Wong Sharyl L, Franklin Giovanni, Li Siming, Albala Joanna S, Lim Janghoo, Fraughton Carlene, Llamosas Estelle, Cevik Sebiha, Bex Camille, Lamesch Philippe, Sikorski Robert S, Vandenhaute Jean, Zoghbi Huda Y, Smolyar Alex, Bosak Stephanie, Sequerra Reynaldo, Doucette-Stamm Lynn, Cusick Michael E, Hill David E, Roth Frederick P, Vidal Marc (Oct. 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature (England) 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.  
  16. ^ Liu, Xiu-Fen; Ishida Hiroshi, Raziuddin Razi, Miki Toru (Aug. 2004). "Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase Czeta (PKCzeta) and regulates PKCzeta activity". Mol. Cell. Biol. (United States) 24 (15): 6665–75. doi:10.1128/MCB.24.15.6665-6675.2004. ISSN 0270-7306. PMID 15254234.  
  17. ^ a b Noda, Y; Takeya R, Ohno S, Naito S, Ito T, Sumimoto H (Feb. 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 (England) 6 (2): 107–19. ISSN 1356-9597. PMID 11260256.  
  18. ^ Seibenhener, M L; Roehm J, White W O, Neidigh K B, Vandenplas M L, Wooten M W (Jul. 1999). "Identification of Src as a novel atypical protein kinase C-interacting protein". Mol. Cell Biol. Res. Commun. (UNITED STATES) 2 (1): 28–31. doi:10.1006/mcbr.1999.0140. ISSN 1522-4724. PMID 10527887.  
  19. ^ San-Antonio, Belén; Iñiguez Miguel A, Fresno Manuel (Jul. 2002). "Protein kinase Czeta phosphorylates nuclear factor of activated T cells and regulates its transactivating activity". J. Biol. Chem. (United States) 277 (30): 27073–80. doi:10.1074/jbc.M106983200. ISSN 0021-9258. PMID 12021260.  
  20. ^ Díaz-Meco, M T; Municio M M, Frutos S, Sanchez P, Lozano J, Sanz L, Moscat J (Sep. 1996). "The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C". Cell (UNITED STATES) 86 (5): 777–86. ISSN 0092-8674. PMID 8797824.  
  21. ^ a b c d Van Der Hoeven, P C; Van Der Wal J C, Ruurs P, Van Dijk M C, Van Blitterswijk J (Jan. 2000). "14-3-3 isotypes facilitate coupling of protein kinase C-zeta to Raf-1: negative regulation by 14-3-3 phosphorylation". Biochem. J. (ENGLAND) 345 Pt 2: 297–306. ISSN 0264-6021. PMID 10620507.  
  22. ^ Büther, Katrin; Plaas Christian, Barnekow Angelika, Kremerskothen Joachim (May. 2004). "KIBRA is a novel substrate for protein kinase Czeta". Biochem. Biophys. Res. Commun. (United States) 317 (3): 703–7. doi:10.1016/j.bbrc.2004.03.107. ISSN 0006-291X. PMID 15081397.  
  23. ^ Hodgkinson, Conrad P; Sale Elizabeth M, Sale Graham J (Aug. 2002). "Characterization of PDK2 activity against protein kinase B gamma". Biochemistry (United States) 41 (32): 10351–9. ISSN 0006-2960. PMID 12162751.  
  24. ^ Leitges, M; Sanz L, Martin P, Duran A, Braun U, García J F, Camacho F, Diaz-Meco M T, Rennert P D, Moscat J (Oct. 2001). "Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway". Mol. Cell (United States) 8 (4): 771–80. ISSN 1097-2765. PMID 11684013.  
  25. ^ Kuroda, S; Nakagawa N, Tokunaga C, Tatematsu K, Tanizawa K (Feb. 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. (UNITED STATES) 144 (3): 403–11. ISSN 0021-9525. PMID 9971736.  
  26. ^ Fujita, Toshitsugu; Ikuta Junko, Hamada Juri, Okajima Toshihide, Tatematsu Kenji, Tanizawa Katsuyuki, Kuroda Shun'ichi (Jan. 2004). "Identification of a tissue-non-specific homologue of axonal fasciculation and elongation protein zeta-1". Biochem. Biophys. Res. Commun. (United States) 313 (3): 738–44. ISSN 0006-291X. PMID 14697253.  
  27. ^ Storz, P; Hausser A, Link G, Dedio J, Ghebrehiwet B, Pfizenmaier K, Johannes F J (Aug. 2000). "Protein kinase C [micro] is regulated by the multifunctional chaperon protein p32". J. Biol. Chem. (UNITED STATES) 275 (32): 24601–7. doi:10.1074/jbc.M002964200. ISSN 0021-9258. PMID 10831594.  
  28. ^ Diaz-Meco, M T; Moscat J (Feb. 2001). "MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling". Mol. Cell. Biol. (United States) 21 (4): 1218–27. doi:10.1128/MCB.21.4.1218-1227.2001. ISSN 0270-7306. PMID 11158308.  

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. PMID 15544481.  


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