protein kinase C zeta type

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.{{cite journal | vauthors = Hernandez AI, Blace N, Crary JF, Serrano PA, Leitges M, Libien JM, Weinstein G, Tcherapanov A, Sacktor TC | title = 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 | journal = J. Biol. Chem. | volume = 278 | issue = 41 | pages = 40305–16 | date = October 2003 | pmid = 12857744 | doi = 10.1074/jbc.M307065200 | doi-access = free }}

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. 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.{{cite journal | vauthors = Bandyopadhyay G, Sajan MP, Kanoh Y, Standaert ML, Quon MJ, Lea-Currie R, Sen A, Farese RV | title = PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human adipocytes | journal = J. Clin. Endocrinol. Metab. | volume = 87 | issue = 2 | pages = 716–23 | date = February 2002 | doi = 10.1210/jcem.87.2.8252 | pmid = 11836310 | doi-access = free }}

PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP).{{cite journal | vauthors = Ling DS, Benardo LS, Serrano PA, Blace N, Kelly MT, Crary JF, Sacktor TC | title = Protein kinase Mzeta is necessary and sufficient for LTP maintenance | journal = Nat. Neurosci. | volume = 5 | issue = 4 | pages = 295–6 | year = 2002 | pmid = 11914719 | doi = 10.1038/nn829 | s2cid = 11200668 }}{{cite journal | vauthors = Serrano P, Yao Y, Sacktor TC | title = Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation | journal = J Neurosci | volume = 25 | issue = 8 | pages = 1979–84 | year = 2005 | pmid = 15728837 | doi = 10.1523/JNEUROSCI.5132-04.2005 | pmc = 6726070 | doi-access = free }}{{cite journal | vauthors = Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC | title = Storage of spatial information by the maintenance mechanism of LTP | journal = Science | volume = 313 | issue = 5790 | pages = 1141–4 | year = 2006 | pmid = 16931766 | doi = 10.1126/science.1128657 | bibcode = 2006Sci...313.1141P | citeseerx = 10.1.1.453.2136 | s2cid = 7260010 }}{{Cite web | vauthors = Dolan EW |date=2024-10-22 |title=Scientists discover "glue" that holds memory together in fascinating neuroscience breakthrough |url=https://www.psypost.org/scientists-discover-glue-that-holds-memory-together-in-fascinating-neuroscience-breakthrough/ |access-date=2024-11-04 |website=PsyPost - Psychology News |language=en-US}} LTP is one of the major cellular mechanisms that are widely considered to underlie learning and memory.{{cite journal | vauthors = Cooke SF, Bliss TV | title = Plasticity in the human central nervous system | journal = Brain | volume = 129 | issue = Pt 7 | pages = 1659–73 | year = 2006 | pmid = 16672292 | doi = 10.1093/brain/awl082 | doi-access = free }} 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, and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.{{cite journal | vauthors = 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 | title = PKMζ maintains spatial, instrumental, and classically conditioned long-term memories | journal = PLOS Biology | volume = 6 | issue = 12 | pages = 2698–706 | year = 2008 | pmid = 19108606 | pmc = 2605920 | doi = 10.1371/journal.pbio.0060318 | veditors = Lu B | doi-access = free }} When ZIP was injected into rats' sensorimotor cortices, it erased muscle memories for a task, even after several weeks of training.{{cite journal | vauthors = von Kraus LM, Sacktor TC, Francis JT | title = Erasing Sensorimotor Memories via PKMζ Inhibition | journal = PLOS ONE | volume = 5 | issue = 6 | pages = e11125 | year = 2010 | pmid = 20559553 | pmc = 2886075 | doi = 10.1371/journal.pone.0011125 | bibcode = 2010PLoSO...511125V | veditors = Brezina V | doi-access = free }} PKMζ may form a self-perpetuating, positive feedback loop that can persist for months to maintain very long-term memories.

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.{{cite journal | vauthors = Shema R, Sacktor TC, Dudai Y | title = Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMζ | journal = Science | volume = 317 | issue = 5840 | pages = 951–3 | year = 2007 | pmid = 17702943 | doi = 10.1126/science.1144334 | bibcode = 2007Sci...317..951S | s2cid = 15707301 }}{{cite journal | vauthors = Shema R, Hazvi S, Sacktor TC, Dudai Y | title = Boundary conditions for the maintenance of memory by PKMζ in neocortex | journal = Learn. Mem. | volume = 16 | issue = 2 | pages = 122–8 | year = 2009 | pmid = 19181618 | pmc = 2661244 | doi = 10.1101/lm.1183309 }} The protein also seems to be involved, through the nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction.{{cite journal | vauthors = Crespo JA, Stöckl P, Ueberall F, Jenny M, Saria A, Zernig G | title = Activation of PKCzeta and PKMzeta in the nucleus accumbens core is necessary for the retrieval, consolidation and reconsolidation of the drug memory | journal = PLOS ONE | volume = 7 | issue = 2 | pages = e30502 | date = February 2012 | pmid = 22348011 | doi = 10.1371/journal.pone.0030502 | pmc=3277594| bibcode = 2012PLoSO...730502C | doi-access = free }} Although results from PKCζ/PKMζ-null mice demonstrate LTP and memory appear largely the same as wild-type mice,{{cite journal | vauthors = Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL | title = PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory | journal = Nature | volume = 493 | issue = 7432 | pages = 420–3 | date = January 2013 | pmid = 23283174 | pmc = 3830948 | doi = 10.1038/nature11802 | bibcode = 2013Natur.493..420V }}{{cite journal | vauthors = Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C, McMahon T, Dadgar J, Fischbach-Weiss SC, Messing RO | title = Prkcz null mice show normal learning and memory | journal = Nature | volume = 493 | issue = 7432 | pages = 416–9 | date = January 2013 | pmid = 23283171 | pmc = 3548047 | doi = 10.1038/nature11803 | bibcode = 2013Natur.493..416L }} 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.{{cite journal | vauthors = 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 | title = Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice | volume = 5 | pages = e14846 | doi = 10.7554/eLife.14846 | pmid = 27187150 | pmc = 4869915 | journal=eLife| year = 2016 | doi-access = free }}{{cite journal | vauthors = Morris RG | date = 17 May 2016 | title = Forget me not | journal = eLife | volume = 5 | pages = e16597 | doi = 10.7554/eLife.16597 | pmid = 27187147 | pmc = 4869910 | doi-access = free }}{{cite journal | vauthors = Frankland PW, Josselyn SA | title = Neuroscience: In search of the memory molecule | journal = Nature | volume = 535 | issue = 7610 | pages = 41–2 | date = July 2016 | pmid = 27362229 | doi = 10.1038/nature18903 | bibcode = 2016Natur.535...41F | doi-access = free }} It has been also shown that PKMζ works together with KIBRA in anchoring its activity so that when a protein degrades and needs to be replaced, the other remains in place, therefore more crucial than each molecule individually is the interaction between them in the persistency of memory.{{cite journal | vauthors = Vogt-Eisele A, Krüger C, Duning K, Weber D, Spoelgen R, Pitzer C, Plaas C, Eisenhardt G, Meyer A, Vogt G, Krieger M, Handwerker E, Wennmann DO, Weide T, Skryabin BV, Klugmann M, Pavenstädt H, Huentelmann MJ, Kremerskothen J, Schneider A | title = KIBRA (KIdney/BRAin protein) regulates learning and memory and stabilizes Protein kinase Mζ | journal = Journal of Neurochemistry | volume = 128 | issue = 5 | pages = 686–700 | date = March 2014 | pmid = 24117625 | pmc = 3947452 | doi = 10.1111/jnc.12480 }}{{cite journal | vauthors = Tsokas P, Hsieh C, Flores-Obando RE, Bernabo M, Tcherepanov A, Hernández AI, Thomas C, Bergold PJ, Cottrell JE, Kremerskothen J, Shouval HZ, Nader K, Fenton AA, Sacktor TC | title = KIBRA anchoring the action of PKMζ maintains the persistence of memory | journal = Science Advances | volume = 10 | issue = 26 | pages = eadl0030 | date = June 2024 | pmid = 38924398 | pmc = 11204205 | doi = 10.1126/sciadv.adl0030 }}

Alteration in PKMζ may be involved in neurodegeneration Alzheimer's disease.{{cite journal | vauthors = Crary JF, Shao CY, Mirra SS, Hernandez AI, Sacktor TC | title = Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease | journal = J. Neuropathol. Exp. Neurol. | volume = 65 | issue = 4 | pages = 319–26 | date = April 2006 | pmid = 16691113 | doi = 10.1097/01.jnen.0000218442.07664.04 | s2cid = 17924780 | doi-access = }}

• 1,3,5-Trisubstituted Pyrazolines{{cite journal | vauthors = Abdel-Halim M, Diesel B, Kiemer AK, Abadi AH, Hartmann RW, Engel M | title = Discovery and optimization of 1,3,5-trisubstituted pyrazolines as potent and highly selective allosteric inhibitors of protein kinase C-ζ | journal = Journal of Medicinal Chemistry | volume = 57 | issue = 15 | pages = 6513–30 | date = August 2014 | pmid = 25058929 | doi = 10.1021/jm500521n | url = https://figshare.com/articles/journal_contribution/2264590 }}

PRKCZ has been shown to interact with:

{{div col|colwidth=20em}}

• AKT3,{{cite journal | vauthors = Hodgkinson CP, Sale EM, Sale GJ | title = Characterization of PDK2 activity against protein kinase B gamma | journal = Biochemistry | volume = 41 | issue = 32 | pages = 10351–9 | year = 2002 | pmid = 12162751 | doi = 10.1021/bi026065r }}
• C-Raf,
• C1QBP,{{cite journal | vauthors = Storz P, Hausser A, Link G, Dedio J, Ghebrehiwet B, Pfizenmaier K, Johannes FJ | title = Protein kinase C [micro] is regulated by the multifunctional chaperon protein p32 | journal = J. Biol. Chem. | volume = 275 | issue = 32 | pages = 24601–7 | year = 2000 | pmid = 10831594 | doi = 10.1074/jbc.M002964200| doi-access = free }}
• CENTA1,{{cite journal | vauthors = Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, Johannes FJ, Aitken A | title = Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C | journal = Biochem. Biophys. Res. Commun. | volume = 307 | issue = 3 | pages = 459–65 | year = 2003 | pmid = 12893243 | doi = 10.1016/S0006-291X(03)01187-2 }}
• FEZ1,{{cite journal | vauthors = Kuroda S, Nakagawa N, Tokunaga C, Tatematsu K, Tanizawa K | title = Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein | journal = J. Cell Biol. | volume = 144 | issue = 3 | pages = 403–11 | year = 1999 | pmid = 9971736 | pmc = 2132904 | doi = 10.1083/jcb.144.3.403 }}
• FEZ2,{{cite journal | vauthors = Fujita T, Ikuta J, Hamada J, Okajima T, Tatematsu K, Tanizawa K, Kuroda S | title = Identification of a tissue-non-specific homologue of axonal fasciculation and elongation protein zeta-1 | journal = Biochem. Biophys. Res. Commun. | volume = 313 | issue = 3 | pages = 738–44 | year = 2004 | pmid = 14697253 | doi = 10.1016/j.bbrc.2003.12.006 }}
• MAP2K5,{{cite journal | vauthors = Diaz-Meco MT, Moscat J | title = MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling | journal = Mol. Cell. Biol. | volume = 21 | issue = 4 | pages = 1218–27 | year = 2001 | pmid = 11158308 | pmc = 99575 | doi = 10.1128/MCB.21.4.1218-1227.2001}}
• NFATC2,{{cite journal | vauthors = San-Antonio B, Iñiguez MA, Fresno M | title = Protein kinase Czeta phosphorylates nuclear factor of activated T cells and regulates its transactivating activity | journal = J. Biol. Chem. | volume = 277 | issue = 30 | pages = 27073–80 | year = 2002 | pmid = 12021260 | doi = 10.1074/jbc.M106983200 | doi-access = free }}
• PARD6A,{{cite journal | vauthors = 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 | title = Towards a proteome-scale map of the human protein–protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | year = 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R | s2cid = 4427026 }}{{cite journal | vauthors = Liu XF, Ishida H, Raziuddin R, Miki T | title = Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase Czeta (PKCzeta) and regulates PKCzeta activity | journal = Mol. Cell. Biol. | volume = 24 | issue = 15 | pages = 6665–75 | year = 2004 | pmid = 15254234 | pmc = 444862 | doi = 10.1128/MCB.24.15.6665-6675.2004 }}{{cite journal | vauthors = Noda Y, Takeya R, Ohno S, Naito S, Ito T, Sumimoto H | title = 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 | journal = Genes Cells | volume = 6 | issue = 2 | pages = 107–19 | year = 2001 | pmid = 11260256 | doi = 10.1046/j.1365-2443.2001.00404.x | doi-access = free }}
• PARD6B,
• PAWR,{{cite journal | vauthors = Díaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L, Moscat J | title = The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C | journal = Cell | volume = 86 | issue = 5 | pages = 777–86 | year = 1996 | pmid = 8797824 | doi = 10.1016/S0092-8674(00)80152-X | s2cid = 15675524 | doi-access = free }}
• PDPK1,{{cite journal | vauthors = Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR | title = 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 | journal = J. Biol. Chem. | volume = 275 | issue = 27 | pages = 20806–13 | year = 2000 | pmid = 10764742 | doi = 10.1074/jbc.M000421200 | doi-access =free }}{{cite journal | vauthors = Hodgkinson CP, Sale GJ | title = Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment | journal = Biochemistry | volume = 41 | issue = 2 | pages = 561–9 | year = 2002 | pmid = 11781095 | doi = 10.1021/bi010719z }}{{cite journal | vauthors = Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ | title = Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1 | journal = Science | volume = 281 | issue = 5385 | pages = 2042–5 | year = 1998 | pmid = 9748166 | doi = 10.1126/science.281.5385.2042| bibcode = 1998Sci...281.2042A }}{{cite journal | vauthors = Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA | title = Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway | journal = EMBO J. | volume = 18 | issue = 11 | pages = 3024–33 | year = 1999 | pmid = 10357815 | pmc = 1171384 | doi = 10.1093/emboj/18.11.3024 }}
• RELA,{{cite journal | vauthors = Leitges M, Sanz L, Martin P, Duran A, Braun U, García JF, Camacho F, Diaz-Meco MT, Rennert PD, Moscat J | title = Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway | journal = Mol. Cell | volume = 8 | issue = 4 | pages = 771–80 | year = 2001 | pmid = 11684013 | doi = 10.1016/S1097-2765(01)00361-6 | doi-access = free }}
• Src,{{cite journal | vauthors = Seibenhener ML, Roehm J, White WO, Neidigh KB, Vandenplas ML, Wooten MW | title = Identification of Src as a novel atypical protein kinase C-interacting protein | journal = Mol. Cell Biol. Res. Commun. | volume = 2 | issue = 1 | pages = 28–31 | year = 1999 | pmid = 10527887 | doi = 10.1006/mcbr.1999.0140 }}
• WWC1,{{cite journal | vauthors = Büther K, Plaas C, Barnekow A, Kremerskothen J | title = KIBRA is a novel substrate for protein kinase Czeta | journal = Biochem. Biophys. Res. Commun. | volume = 317 | issue = 3 | pages = 703–7 | year = 2004 | pmid = 15081397 | doi = 10.1016/j.bbrc.2004.03.107 }}
• YWHAB, and
• YWHAQ,{{cite journal | vauthors = Van Der Hoeven PC, Van Der Wal JC, Ruurs P, Van Dijk MC, Van Blitterswijk J | title = 14-3-3 isotypes facilitate coupling of protein kinase C-zeta to Raf-1: negative regulation by 14-3-3 phosphorylation | journal = Biochem. J. | volume = 345 | issue = 2 | pages = 297–306 | year = 2000 | pmid = 10620507 | pmc = 1220759 | doi = 10.1042/0264-6021:3450297 }}
• YWHAZ.

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{{reflist|35em}}

{{refbegin}}

• {{cite journal | vauthors = Slater SJ, Ho C, Stubbs CD | title = The use of fluorescent phorbol esters in studies of protein kinase C-membrane interactions | journal = Chem. Phys. Lipids | volume = 116 | issue = 1–2 | pages = 75–91 | year = 2003 | pmid = 12093536 | doi = 10.1016/S0009-3084(02)00021-X }}
• {{cite journal | vauthors = Carter CA, Kane CJ | title = Therapeutic potential of natural compounds that regulate the activity of protein kinase C | journal = Curr. Med. Chem. | volume = 11 | issue = 21 | pages = 2883–902 | year = 2005 | pmid = 15544481 | doi = 10.2174/0929867043364090 }}

{{refend}}

{{Serine/threonine-specific protein kinases|g1}}

{{Enzymes}}

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{{DEFAULTSORT:Protein kinase M zeta Protein kinase C zeta}}

Category:Genes mutated in mice

Category:EC 2.7.11