Protein kinase C zeta type

Protein kinase C, zeta
Identifiers
Symbols	PRKCZ ; PKC-ZETA; PKC2
External IDs	OMIM: 176982 MGI: 97602 HomoloGene: 55681 IUPHAR: 1491 ChEMBL: 3438 GeneCards: PRKCZ Gene
EC number	2.7.11.13
Gene ontology Molecular function • protein kinase activity • protein serine/threonine kinase activity • protein kinase C activity • protein binding • ATP binding • potassium channel regulator activity • protein kinase binding • protein domain specific binding • phospholipase binding • insulin receptor substrate binding • metal ion binding • 14-3-3 protein binding Cellular component • nuclear envelope • cytoplasm • endosome • microtubule organizing center • cytosol • plasma membrane • cell-cell junction • bicellular tight junction • membrane • apical plasma membrane • nuclear matrix • cell junction • cell leading edge • filamentous actin • myelin sheath abaxonal region • axon hillock • membrane raft • apical cortex • perinuclear region of cytoplasm • extracellular exosome Biological process • microtubule cytoskeleton organization • positive regulation of cell-matrix adhesion • protein phosphorylation • inflammatory response • signal transduction • transforming growth factor beta receptor signaling pathway • blood coagulation • long-term memory • positive regulation of cell proliferation • insulin receptor signaling pathway • cell migration • peptidyl-serine phosphorylation • establishment of cell polarity • platelet activation • negative regulation of protein complex assembly • actin cytoskeleton reorganization • activation of phospholipase D activity • activation of protein kinase B activity • positive regulation of interleukin-4 production • negative regulation of apoptotic process • positive regulation of T-helper 2 cell differentiation • positive regulation of glucose import • negative regulation of insulin receptor signaling pathway • positive regulation of insulin receptor signaling pathway • vesicle transport along microtubule • vascular endothelial growth factor receptor signaling pathway • negative regulation of peptidyl-tyrosine phosphorylation • positive regulation of NF-kappaB transcription factor activity • protein heterooligomerization • negative regulation of hydrolase activity • membrane depolarization • membrane hyperpolarization • long-term synaptic potentiation • positive regulation of ERK1 and ERK2 cascade • protein kinase C signaling • protein localization to plasma membrane • neuron projection extension • positive regulation of excitatory postsynaptic potential • positive regulation of T-helper 2 cell cytokine production • positive regulation of interleukin-5 secretion • positive regulation of interleukin-13 secretion • positive regulation of interleukin-10 secretion Sources: Amigo / QuickGO
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_001039079
RefSeq (protein)	NP_001028753	NP_001034168
Location (UCSC)	Chr 1: 2.05 – 2.19 Mb	Chr 4: 155.26 – 155.36 Mb
PubMed search

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.^[1]

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.^[2]

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.^[2] 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.^[3]

PKMζ

PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP);^[4][5][6] However, transgenic mice lacking PKMζ demonstrate normal LTP.^[7] LTP is one of the major cellular mechanisms that are widely considered to underlie learning and memory.^[8] 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,^[6] and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.^[9] When ZIP was injected into rats' sensorimotor cortices, it erased muscle memories for a task, even after several weeks of training.^[10] 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.^[11][12] The protein also seems to be involved, through the nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction.^[13] PKMζ is thus the first molecule shown to be a component of the storage mechanism of long-term memory, however this function has recently been challenged.^[14][15]

Recent research has demonstrated alteration in PKMζ in Alzheimer's disease (see Long-term potentiation), providing a potential link between this kinase and neurodegeneration.^[16]

Prkcz knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Abnormal[17]
Clinical chemistry	Abnormal[18]
Plasma immunoglobulins	Normal
Haematology	Normal
Micronucleus test	Normal
Heart weight	Normal
Tail epidermis wholemount	Normal
Skin Histopathology	Abnormal
Brain histopathology	Normal
Salmonella infection	Normal[19]
Citrobacter infection	Normal[20]
All tests and analysis from[21][22]

Model organisms

Model organisms have been used in the study of PRKCZ function. A conditional knockout mouse line, called Prkcz^{tm1a(EUCOMM)Wtsi[23][24]} 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.^[25][26][27]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[21][28] Twenty five tests were carried out on mutant mice and three significant abnormalities were observed.^[21] Homozygous mutant males had Bergmeister's papilla, while both sexes had atypical plasma chemistry and abnormal melanocyte morphology.^[21]

Inhibitors

• 1,3,5-Trisubstituted Pyrazolines^[29]

Interactions

PRKCZ has been shown to interact with:

• AKT3,^[30]
• C-Raf,^[31]
• C1QBP,^[32]
• CENTA1,^[33]
• FEZ1,^[34]
• FEZ2,^[35]
• MAP2K5,^[36]
• NFATC2,^[37]
• PARD6A,^[38][39][40]
• PARD6B,^[40]
• PAWR,^[41]
• PDPK1,^{[42][43][44][45]}
• RELA,^[46]
• Src,^[47]
• WWC1,^[48]
• YWHAB,^[31] and
• YWHAQ,^[31]
• YWHAZ.^[31][33]

References

1. 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 47352. PMID 8378304.
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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL (2013). "PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory". Nature 493 (7432): 420–423. doi:10.1038/nature11802. PMC 3830948. PMID 23283174.
8. 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.
9. 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.
10. 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 2886075. PMID 20559553.
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12. 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.
13. 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. PMID 22348011.
14. 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 3830948. PMID 23283174.
15. 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 3548047. PMID 23283171.
16. 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.
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30. 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.
31. 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.
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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.