View source for PRKCE

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{About|the enzyme|the OAuth security extension PKCE|OAuth#Security_issues}}

{{Infobox_gene}}
'''Protein kinase C epsilon type''' ('''PKCε''') is an [[enzyme]] that in humans is encoded by the ''PRKCE'' [[gene]].<ref name="pmid1382605">{{cite journal | vauthors = Basta P, Strickland MB, Holmes W, Loomis CR, Ballas LM, Burns DJ | title = Sequence and expression of human protein kinase C-epsilon | journal = Biochimica et Biophysica Acta | volume = 1132 | issue = 2 | pages = 154–60 | date = Sep 1992 | pmid = 1382605 | doi = 10.1016/0167-4781(92)90006-l }}</ref><ref name="pmid7877991">{{cite journal | vauthors = Lehel C, Olah Z, Jakab G, Anderson WB | title = Protein kinase C epsilon is localized to the Golgi via its zinc-finger domain and modulates Golgi function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 5 | pages = 1406–10 | date = Feb 1995 | pmid = 7877991 | pmc = 42528 | doi = 10.1073/pnas.92.5.1406 | doi-access = free }}</ref> PKCε is an [[isoform]] of the large [[protein kinase C|PKC]] family of [[protein kinase]]s that play many roles in different tissues. In [[cardiac muscle]] cells, PKCε regulates [[muscle contraction]] through its actions at [[sarcomere|sarcomeric proteins]], and PKCε modulates cardiac cell [[metabolism]] through its actions at [[mitochondria]]. PKCε is clinically significant in that it is a central player in [[cardioprotection]] against [[reperfusion injury|ischemic injury]] and in the development of [[cardiac hypertrophy]].

== Structure ==

Human ''PRKCE'' gene (Ensembl ID: ENSG00000171132) encodes the [[protein]] PKCε (Uniprot ID: Q02156), which is 737 amino acids in length with a molecular weight of 83.7 kDa. The PKC family of [[serine]]-[[threonine]] [[kinase]]s contains thirteen PKC [[isoform]]s, and each [[isoform]] can be distinguished by differences in [[primary structure]], [[gene expression]], subcellular localization, and modes of activation.<ref>{{cite journal | vauthors = Dekker LV, Parker PJ | title = Protein kinase C--a question of specificity | journal = Trends in Biochemical Sciences | volume = 19 | issue = 2 | pages = 73–7 | date = Feb 1994 | pmid = 8160269 | doi = 10.1016/0968-0004(94)90038-8 }}</ref> The epsilon [[isoform]] of PKC is abundantly expressed in adult [[cardiomyocyte]]s,<ref>{{cite journal | vauthors = Rybin VO, Steinberg SF | title = Protein kinase C isoform expression and regulation in the developing rat heart | journal = Circulation Research | volume = 74 | issue = 2 | pages = 299–309 | date = Feb 1994 | pmid = 8293569 | doi=10.1161/01.res.74.2.299| doi-access = free }}</ref><ref name="Disatnik MH 1994">{{cite journal | vauthors = Disatnik MH, Buraggi G, Mochly-Rosen D | title = Localization of protein kinase C isozymes in cardiac myocytes | journal = Experimental Cell Research | volume = 210 | issue = 2 | pages = 287–97 | date = Feb 1994 | pmid = 8299726 | doi = 10.1006/excr.1994.1041 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bogoyevitch MA, Parker PJ, Sugden PH | title = Characterization of protein kinase C isotype expression in adult rat heart. Protein kinase C-epsilon is a major isotype present, and it is activated by phorbol esters, epinephrine, and endothelin | journal = Circulation Research | volume = 72 | issue = 4 | pages = 757–67 | date = Apr 1993 | pmid = 8443867 | doi=10.1161/01.res.72.4.757| doi-access = free }}</ref><ref>{{cite journal | vauthors = Pucéat M, Hilal-Dandan R, Strulovici B, Brunton LL, Brown JH | title = Differential regulation of protein kinase C isoforms in isolated neonatal and adult rat cardiomyocytes | journal = The Journal of Biological Chemistry | volume = 269 | issue = 24 | pages = 16938–44 | date = Jun 1994 | doi = 10.1016/S0021-9258(19)89480-2 | pmid = 8207017 | doi-access = free }}</ref> being the most highly expressed of all novel isoforms, PKC-δ, -ζ, and –η.<ref name="ReferenceB">{{cite journal | vauthors = Ping P, Zhang J, Qiu Y, Tang XL, Manchikalapudi S, Cao X, Bolli R | title = Ischemic preconditioning induces selective translocation of protein kinase C isoforms epsilon and eta in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity | journal = Circulation Research | volume = 81 | issue = 3 | pages = 404–14 | date = Sep 1997 | pmid = 9285643 | doi=10.1161/01.res.81.3.404}}</ref> PKCε and other PKC [[isoform]]s require [[phosphorylation]] at sites [[Threonine]]-566, [[Threonine]]-710, and [[Serine]]-729 for [[kinase]] maturation.<ref name="ReferenceA">{{cite journal | vauthors = Akita Y | title = Protein kinase C-epsilon (PKC-epsilon): its unique structure and function | journal = Journal of Biochemistry | volume = 132 | issue = 6 | pages = 847–52 | date = Dec 2002 | pmid = 12473185 | doi=10.1093/oxfordjournals.jbchem.a003296}}</ref> The epsilon [[isoform]] of [[protein kinase C|PKC]] differs from other [[isoform]]s by the position of the C2, [[pseudosubstrate]], and C1 domains; various [[second messenger]]s in different combinations can act on the C1 domain to direct subcellular translocation of PKCε.<ref name="Disatnik MH 1994"/><ref>{{cite journal | vauthors = Shirai Y, Kashiwagi K, Yagi K, Sakai N, Saito N | title = Distinct effects of fatty acids on translocation of gamma- and epsilon-subspecies of protein kinase C | journal = The Journal of Cell Biology | volume = 143 | issue = 2 | pages = 511–21 | date = Oct 1998 | pmid = 9786959 | doi=10.1083/jcb.143.2.511 | pmc=2132830}}</ref>

Receptors for activated C-kinase (RACK) have been found to anchor active [[protein kinase C|PKC]] in close proximity to [[substrate (biochemistry)|substrate]]s.<ref>{{cite journal | vauthors = Mochly-Rosen D | title = Localization of protein kinases by anchoring proteins: a theme in signal transduction | journal = Science | volume = 268 | issue = 5208 | pages = 247–51 | date = Apr 1995 | pmid = 7716516 | doi=10.1126/science.7716516| bibcode = 1995Sci...268..247M }}</ref> PKCε appears to have preferred affinity to the (RACK/RACK2) isoform; specifically, the C2 domain of PKCε at [[amino acid]]s 14–21 (also known as εV1-2) binds (RACK/RACK2), and peptide inhibitors targeting εV1-2 inhibit PKCε translocation and function in [[cardiomyocyte]]s,<ref>{{cite journal | vauthors = Johnson JA, Gray MO, Chen CH, Mochly-Rosen D | title = A protein kinase C translocation inhibitor as an isozyme-selective antagonist of cardiac function | journal = The Journal of Biological Chemistry | volume = 271 | issue = 40 | pages = 24962–6 | date = Oct 1996 | pmid = 8798776 | doi=10.1074/jbc.271.40.24962| doi-access = free }}</ref> while peptide agonists augment translocation.<ref>{{cite journal | vauthors = Dorn GW, Souroujon MC, Liron T, Chen CH, Gray MO, Zhou HZ, Csukai M, Wu G, Lorenz JN, Mochly-Rosen D | title = Sustained in vivo cardiac protection by a rationally designed peptide that causes epsilon protein kinase C translocation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 22 | pages = 12798–803 | date = Oct 1999 | pmid = 10536002 | doi=10.1073/pnas.96.22.12798 | pmc=23103| doi-access = free }}</ref> It has been demonstrated that altering the dynamics of the (RACK/RACK2) and (RACK1) interaction with PKCε can influence [[cardiac muscle]] phenotypes.<ref>{{cite journal | vauthors = Pass JM, Zheng Y, Wead WB, Zhang J, Li RC, Bolli R, Ping P | title = PKCepsilon activation induces dichotomous cardiac phenotypes and modulates PKCepsilon-RACK interactions and RACK expression | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 280 | issue = 3 | pages = H946–55 | date = Mar 2001 | pmid = 11179034 | doi = 10.1152/ajpheart.2001.280.3.H946 | s2cid = 17268552 }}</ref>

Activated PKCε translocates to various intracellular targets.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Newton AC | title = Protein kinase C: poised to signal | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 298 | issue = 3 | pages = E395–402 | date = Mar 2010 | pmid = 19934406 | doi = 10.1152/ajpendo.00477.2009 | pmc=2838521}}</ref> In [[cardiac muscle]], PKCε translocates to [[sarcomere]]s at [[sarcomere|Z-lines]] following [[adrenergic receptor|α-adrenergic]] and [[endothelin receptor|endothelin (ET)<sub>A</sub>]]-receptor stimulation.<ref name="Disatnik MH 1994"/><ref>{{cite journal | vauthors = Robia SL, Ghanta J, Robu VG, Walker JW | title = Localization and kinetics of protein kinase C-epsilon anchoring in cardiac myocytes | journal = Biophysical Journal | volume = 80 | issue = 5 | pages = 2140–51 | date = May 2001 | pmid = 11325717 | doi = 10.1016/S0006-3495(01)76187-5 | pmc=1301406| bibcode = 2001BpJ....80.2140R }}</ref> A myriad of [[agonist]]s have also been shown to induce the translocation of PKCε from the [[cytosol]]ic to particulate fraction in [[cardiomyocyte]]s, including but not limited to [[Phorbol 12-myristate 13-acetate|PMA]] or [[norepinephrine]];<ref name="Disatnik MH 1994"/>[[arachidonic acid]];<ref>{{cite journal | vauthors = Huang XP, Pi Y, Lokuta AJ, Greaser ML, Walker JW | title = Arachidonic acid stimulates protein kinase C-epsilon redistribution in heart cells | journal = Journal of Cell Science | volume = 110 | pages = 1625–34 | date = Jul 1997 | pmid = 9247196 | issue=14| doi = 10.1242/jcs.110.14.1625 }}</ref>[[endothelin receptor|ET-1]] and [[phenylephrine]];<ref>{{cite journal | vauthors = Clerk A, Bogoyevitch MA, Anderson MB, Sugden PH | title = Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts | journal = The Journal of Biological Chemistry | volume = 269 | issue = 52 | pages = 32848–57 | date = Dec 1994 | doi = 10.1016/S0021-9258(20)30069-7 | pmid = 7806510 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Grimm M, Mahnecke N, Soja F, El-Armouche A, Haas P, Treede H, Reichenspurner H, Eschenhagen T | title = The MLCK-mediated alpha1-adrenergic inotropic effect in atrial myocardium is negatively modulated by PKCepsilon signaling | journal = British Journal of Pharmacology | volume = 148 | issue = 7 | pages = 991–1000 | date = Aug 2006 | pmid = 16783412 | doi = 10.1038/sj.bjp.0706803 | pmc=1751924}}</ref> [[angiotensin|angiotensin II]] and [[diastole|diastolic]] stretch;<ref>{{cite journal | vauthors = Paul K, Ball NA, Dorn GW, Walsh RA | title = Left ventricular stretch stimulates angiotensin II--mediated phosphatidylinositol hydrolysis and protein kinase C epsilon isoform translocation in adult guinea pig hearts | journal = Circulation Research | volume = 81 | issue = 5 | pages = 643–50 | date = Nov 1997 | pmid = 9351436 | doi=10.1161/01.res.81.5.643}}</ref> [[adenosine]];<ref>{{cite journal | vauthors = Yang Z, Sun W, Hu K | title = Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1823 | issue = 4 | pages = 950–8 | date = Apr 2012 | pmid = 22233927 | doi = 10.1016/j.bbamcr.2011.12.012 | doi-access = free }}</ref> [[C3orf58|hypoxia and Akt-induced stem cell factor]];<ref>{{cite journal | vauthors = Huang J, Guo J, Beigi F, Hodgkinson CP, Facundo HT, Zhang Z, Espinoza-Derout J, Zhou X, Pratt RE, Mirotsou M, Dzau VJ | title = HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection | journal = Journal of Molecular and Cellular Cardiology | volume = 66 | pages = 157–64 | date = Jan 2014 | pmid = 24269490 | doi = 10.1016/j.yjmcc.2013.11.010 | pmc=3897274}}</ref> [[reactive oxygen species|ROS]] generated via pharmacologic activation of the [[ATP-sensitive potassium channel|mitochondrial potassium-sensitive ATP channel (mitoK(ATP))]]<ref>{{cite journal | vauthors = Li H, Yang T, Long Z, Cheng J | title = Effect of mitochondrial ATP-sensitive potassium channel opening on the translocation of protein kinase C epsilon in adult rat ventricular myocytes | journal = Genetics and Molecular Research | volume = 13 | issue = 2 | pages = 4516–22 | date = 17 June 2014 | pmid = 25036356 | doi = 10.4238/2014.June.17.3 | doi-access = free }}</ref> and the endogenous [[G-protein coupled receptor]] [[ligand]], [[apelin]].<ref>{{cite journal | vauthors = Perjés Á, Skoumal R, Tenhunen O, Kónyi A, Simon M, Horváth IG, Kerkelä R, Ruskoaho H, Szokodi I | title = Apelin increases cardiac contractility via protein kinase Cε- and extracellular signal-regulated kinase-dependent mechanisms | journal = PLOS ONE | volume = 9 | issue = 4 | pages = e93473 | date = 2014 | pmid = 24695532 | doi = 10.1371/journal.pone.0093473 | pmc=3973555| bibcode = 2014PLoSO...993473P | doi-access = free }}</ref>

== Function ==

[[Protein kinase C]] (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger [[diacylglycerol]]. PKC family members [[phosphorylation|phosphorylate]] a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for [[phorbol]] esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been shown to be involved in many different cellular functions, such as [[apoptosis]], cardioprotection from [[ischemia]], [[heat shock]] response, as well as insulin [[exocytosis]].

=== Cardiac muscle sarcomeric contractile function ===

PKCε translocates to [[cardiac muscle]] [[sarcomere]]s and modulates [[contractility]] of the [[myocardium]]. PKCε binds [[RACK|RACK2]] at [[sarcomere|Z-lines]] with an EC<sub>50</sub> of 86 nM;<ref>{{cite journal | vauthors = Huang X, Walker JW | title = Myofilament anchoring of protein kinase C-epsilon in cardiac myocytes | journal = Journal of Cell Science | volume = 117 | issue = Pt 10 | pages = 1971–8 | date = Apr 2004 | pmid = 15039458 | doi = 10.1242/jcs.01044 | doi-access = free }}</ref> PKCε also binds at [[costamere]]s to [[SDC4|syndecan-4]].<ref>{{cite journal | vauthors = VanWinkle WB, Snuggs MB, De Hostos EL, Buja LM, Woods A, Couchman JR | title = Localization of the transmembrane proteoglycan syndecan-4 and its regulatory kinases in costameres of rat cardiomyocytes: a deconvolution microscopic study | journal = The Anatomical Record | volume = 268 | issue = 1 | pages = 38–46 | date = Sep 2002 | pmid = 12209563 | doi = 10.1002/ar.10130 | s2cid = 25711666 }}</ref> PKCε has been shown to bind [[F-actin]] in [[neuron]]s, which modulates synaptic function and differentiation;<ref>{{cite journal | vauthors = Prekeris R, Mayhew MW, Cooper JB, Terrian DM | title = Identification and localization of an actin-binding motif that is unique to the epsilon isoform of protein kinase C and participates in the regulation of synaptic function | journal = The Journal of Cell Biology | volume = 132 | issue = 1–2 | pages = 77–90 | date = Jan 1996 | pmid = 8567732 | doi=10.1083/jcb.132.1.77 | pmc=2120693}}</ref><ref>{{cite journal | vauthors = Zeidman R, Trollér U, Raghunath A, Påhlman S, Larsson C | title = Protein kinase Cepsilon actin-binding site is important for neurite outgrowth during neuronal differentiation | journal = Molecular Biology of the Cell | volume = 13 | issue = 1 | pages = 12–24 | date = Jan 2002 | pmid = 11809819 | doi = 10.1091/mbc.01-04-0210 | pmc=65069}}</ref> however it is unknown whether PKCε binds [[sarcomere|sarcomeric]] [[ACTC1|actin]] in muscle cells. [[Sarcomere|Sarcomeric]] proteins have been identified in PKCε signaling complexes, including [[ACTC1|actin]], [[TNNT2|cTnT]], [[TPM1|tropomyosin]], [[desmin]], and [[MYL7|myosin light chain-2]]; in mice expressing a constitutively-active PKCε, all [[sarcomere|sarcomeric]] proteins showed greater association with PKCε, and the [[TNNT2|cTnT]], [[TPM1|tropomyosin]], [[desmin]] and [[MYL7|myosin light chain-2]] exhibited changes in post-translational modifications.<ref name="ReferenceC">{{cite journal | vauthors = Ping P, Zhang J, Pierce WM, Bolli R | title = Functional proteomic analysis of protein kinase C epsilon signaling complexes in the normal heart and during cardioprotection | journal = Circulation Research | volume = 88 | issue = 1 | pages = 59–62 | date = Jan 2001 | pmid = 11139474 | doi=10.1161/01.res.88.1.59| doi-access = free }}</ref>

PKCε binds and [[phosphorylate]]s [[TNNI3|cardiac troponin I (cTnI)]] and [[TNNT2|cardiac troponin T (cTnT)]] in complex with [[TNNC1|troponin C (cTnC)]];<ref>{{cite journal | vauthors = Jideama NM, Noland TA, Raynor RL, Blobe GC, Fabbro D, Kazanietz MG, Blumberg PM, Hannun YA, Kuo JF | title = Phosphorylation specificities of protein kinase C isozymes for bovine cardiac troponin I and troponin T and sites within these proteins and regulation of myofilament properties | journal = The Journal of Biological Chemistry | volume = 271 | issue = 38 | pages = 23277–83 | date = Sep 1996 | pmid = 8798526 | doi=10.1074/jbc.271.38.23277| doi-access = free }}</ref> [[phosphorylation]] on cTnI at residues [[Serine]]-43, [[Serine]]-45, and [[Threonine]]-144 cause depression of actomyosin S1 MgATPase function.<ref>{{cite journal | vauthors = Noland TA, Raynor RL, Jideama NM, Guo X, Kazanietz MG, Blumberg PM, Solaro RJ, Kuo JF | title = Differential regulation of cardiac actomyosin S-1 MgATPase by protein kinase C isozyme-specific phosphorylation of specific sites in cardiac troponin I and its phosphorylation site mutants | journal = Biochemistry | volume = 35 | issue = 47 | pages = 14923–31 | date = Nov 1996 | pmid = 8942657 | doi = 10.1021/bi9616357 }}</ref><ref>{{cite journal | vauthors = Noland TA, Guo X, Raynor RL, Jideama NM, Averyhart-Fullard V, Solaro RJ, Kuo JF | title = Cardiac troponin I mutants. Phosphorylation by protein kinases C and A and regulation of Ca(2+)-stimulated MgATPase of reconstituted actomyosin S-1 | journal = The Journal of Biological Chemistry | volume = 270 | issue = 43 | pages = 25445–54 | date = Oct 1995 | pmid = 7592712 | doi=10.1074/jbc.270.43.25445| doi-access = free }}</ref> These studies were further supported by those performed in isolated, skinned [[cardiac muscle]] fibers, showing that in vitro [[phosphorylation]] of [[TNNI3|cTnI]] by PKCε or [[Serine]]-43/45 mutation to [[Glutamate]] to mimic [[phosphorylation]] desensitized myofilaments to [[calcium]] and decreased maximal tension and filament sliding speed.<ref>{{cite journal | vauthors = Burkart EM, Sumandea MP, Kobayashi T, Nili M, Martin AF, Homsher E, Solaro RJ | title = Phosphorylation or glutamic acid substitution at protein kinase C sites on cardiac troponin I differentially depress myofilament tension and shortening velocity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 13 | pages = 11265–72 | date = Mar 2003 | pmid = 12551921 | doi = 10.1074/jbc.M210712200 | doi-access = free }}</ref> Phosphorylation on [[TNNI3|cTnI]] at [[Serine]]-5/6 also showed this depressive effect.<ref>{{cite journal | vauthors = Henze M, Patrick SE, Hinken A, Scruggs SB, Goldspink P, de Tombe PP, Kobayashi M, Ping P, Kobayashi T, Solaro RJ | title = New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1833 | issue = 4 | pages = 823–32 | date = Apr 2013 | pmid = 22940544 | doi = 10.1016/j.bbamcr.2012.08.012 | pmc=3548050}}</ref> Further support was gained from in vivo studies in which mice expressing a mutant cTnI ([[Serine]]43/45[[Alanine]]) exhibited enhanced cardiac [[contractility]].<ref>{{cite journal | vauthors = Roman BB, Goldspink PH, Spaite E, Urboniene D, McKinney R, Geenen DL, Solaro RJ, Buttrick PM | title = Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 286 | issue = 6 | pages = H2089–95 | date = Jun 2004 | pmid = 14726296 | doi = 10.1152/ajpheart.00582.2003 | s2cid = 15072977 }}</ref>

=== Cardiac muscle mitochondrial metabolism and function ===
In addition to [[sarcomere]]s, PKCε also targets [[cardiac muscle|cardiac]] [[mitochondria]].<ref name="ReferenceC"/><ref name="pmid12663490"/> [[Proteomics|Proteomic]] analysis of PKCε signaling complexes in mice expressing a constitutively-active, overexpressed PKCε identified several interacting partners at [[mitochondria]] whose protein abundance and [[posttranslational modification]]s were altered in the [[transgenic]] mice.<ref name="ReferenceC"/> This study was the first to demonstrate PKCε at the [[inner mitochondrial membrane]],<ref name="ReferenceC"/> and it was found that PKCε binds several [[mitochondria]]l proteins involved in [[glycolysis]], [[TCA cycle]], [[beta oxidation]], and [[ion transport]].<ref>{{cite journal | vauthors = Edmondson RD, Vondriska TM, Biederman KJ, Zhang J, Jones RC, Zheng Y, Allen DL, Xiu JX, Cardwell EM, Pisano MR, Ping P | title = Protein kinase C epsilon signaling complexes include metabolism- and transcription/translation-related proteins: {{sic|complimentary|nolink=y|expected=complementary}} separation techniques with LC/MS/MS | journal = Molecular & Cellular Proteomics | volume = 1 | issue = 6 | pages = 421–33 | date = Jun 2002 | pmid = 12169683 | doi=10.1074/mcp.m100036-mcp200| doi-access = free }}</ref> However, it remained unclear how PKCε translocates from the [[outer mitochondrial membrane|outer]] to [[inner mitochondrial membrane]] until Budas et al. discovered that [[heat shock protein 90]] (Hsp90) coordinates with the [[TOMM20|translocase of the outer mitochondrial membrane-20]] (Tom20) to translocate PKCε following a preconditioning stimulus.<ref name="Mitochondrial import of PKCepsilon">{{cite journal | vauthors = Budas GR, Churchill EN, Disatnik MH, Sun L, Mochly-Rosen D | title = Mitochondrial import of PKCepsilon is mediated by HSP90: a role in cardioprotection from ischaemia and reperfusion injury | journal = Cardiovascular Research | volume = 88 | issue = 1 | pages = 83–92 | date = Oct 2010 | pmid = 20558438 | doi = 10.1093/cvr/cvq154 | pmc=2936125}}</ref><ref>{{cite journal | vauthors = Yang Z, Sun W, Hu K | title = Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1823 | issue = 4 | pages = 950–958 | date = Apr 2012 | pmid = 22233927 | doi = 10.1016/j.bbamcr.2011.12.012 | doi-access = free }}</ref>  Specifically, a seven [[amino acid]] peptide, termed TAT-εHSP90, homologous to the [[Heat shock protein 90|Hsp90]] sequence within the PKCε C2 domain induced translocation of PKCε to the [[inner mitochondrial membrane]] and [[cardioprotection]].<ref name="Mitochondrial import of PKCepsilon"/>

PKCε has also been shown to play a role in modulating [[mitochondrial permeability transition]] (MPT); the addition of PKCε to [[cardiomyocyte]]s inhibits MPT,<ref name="pmid12663490"/> though the mechanism is unclear. Initially, PKCε was thought to protect mitochondria from MPT through its association with [[VDAC1]], [[ANT1|ANT]], and [[HK2|hexokinase II]];<ref name="pmid12663490"/> however, genetic studies have since ruled this out<ref>{{cite journal | vauthors = Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC | title = The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore | journal = Nature | volume = 427 | issue = 6973 | pages = 461–5 | date = Jan 2004 | pmid = 14749836 | doi = 10.1038/nature02229 | pmc=3049806| bibcode = 2004Natur.427..461K }}</ref><ref>{{cite journal | vauthors = Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD | title = Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death | journal = Nature Cell Biology | volume = 9 | issue = 5 | pages = 550–5 | date = May 2007 | pmid = 17417626 | doi = 10.1038/ncb1575 | pmc=2680246}}</ref> and subsequent studies have identified the F0/F1 [[ATP synthase]] as a core inner mitochondrial membrane component<ref>{{cite journal | vauthors = Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabó I, Lippe G, Bernardi P | title = Dimers of mitochondrial ATP synthase form the permeability transition pore | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 15 | pages = 5887–92 | date = Apr 2013 | pmid = 23530243 | doi = 10.1073/pnas.1217823110 | pmc=3625323| bibcode = 2013PNAS..110.5887G | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P | title = Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition | journal = Cell Cycle | volume = 12 | issue = 4 | pages = 674–83 | date = Feb 2013 | pmid = 23343770 | doi = 10.4161/cc.23599 | pmc=3594268}}</ref><ref>{{cite journal | vauthors = Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park HA, Licznerski P, Li H, Nabili P, Hockensmith K, Graham M, Porter GA, Jonas EA | title = An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 29 | pages = 10580–5 | date = Jul 2014 | pmid = 24979777 | doi = 10.1073/pnas.1401591111 | pmc=4115574| bibcode = 2014PNAS..11110580A | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bernardi P, Di Lisa F | title = The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection | journal = Journal of Molecular and Cellular Cardiology | volume = 78 | pages = 100–6 | date = Jan 2015 | pmid = 25268651 | doi = 10.1016/j.yjmcc.2014.09.023 | pmc=4294587}}</ref> and Bax and Bak as potential outer membrane components<ref>{{cite journal | vauthors = Karch J, Kwong JQ, Burr AR, Sargent MA, Elrod JW, Peixoto PM, Martinez-Caballero S, Osinska H, Cheng EH, Robbins J, Kinnally KW, Molkentin JD | title = Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice | journal = eLife | volume = 2 | pages = e00772 | date = 27 August 2013 | pmid = 23991283 | doi = 10.7554/eLife.00772 | pmc=3755340 | doi-access = free }}</ref> These findings have opened up new avenues of investigation for the role of PKCε at [[mitochondria]]. Several likely targets of PKCε action affecting MPT have been discovered. PKCε interacts with [[Extracellular signal-regulated kinases|ERK]], [[JNK]]s and [[p38 mitogen-activated protein kinases|p38]], and PKCε directly or indirectly [[phosphorylate]]s [[Extracellular signal-regulated kinases|ERK]] and subsequently [[Bcl-2-associated death promoter|Bad]].<ref>{{cite journal | vauthors = Baines CP, Zhang J, Wang GW, Zheng YT, Xiu JX, Cardwell EM, Bolli R, Ping P | title = Mitochondrial PKCepsilon and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCepsilon-MAPK interactions and differential MAPK activation in PKCepsilon-induced cardioprotection | journal = Circulation Research | volume = 90 | issue = 4 | pages = 390–7 | date = Mar 2002 | pmid = 11884367 | doi=10.1161/01.res.0000012702.90501.8d| doi-access = free }}</ref> PKCε also interacts with [[Bcl-2-associated X protein|Bax]] in [[cancer]] cells, and PKCε modulates its dimerization and function.<ref>{{cite journal | vauthors = McJilton MA, Van Sikes C, Wescott GG, Wu D, Foreman TL, Gregory CW, Weidner DA, Harris Ford O, Morgan Lasater A, Mohler JL, Terrian DM | title = Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells | journal = Oncogene | volume = 22 | issue = 39 | pages = 7958–68 | date = Sep 2003 | pmid = 12970744 | doi = 10.1038/sj.onc.1206795 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lu D, Sivaprasad U, Huang J, Shankar E, Morrow S, Basu A | title = Protein kinase C-epsilon protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation | journal = Apoptosis | volume = 12 | issue = 10 | pages = 1893–900 | date = Oct 2007 | pmid = 17668322 | doi = 10.1007/s10495-007-0111-7 | s2cid = 33583520 }}</ref> Activation of PKCε with the specific activator, εRACK, prior to ischemic injury has shown to be associated with [[phosphorylation]] of the F0/F1 [[ATP synthase]].<ref name="Identification of εPKC targets duri">{{cite journal | vauthors = Budas G, Costa HM, Ferreira JC, Teixeira da Silva Ferreira A, Perales J, Krieger JE, Mochly-Rosen D, Schechtman D | title = Identification of εPKC targets during cardiac ischemic injury | journal = Circulation Journal | volume = 76 | issue = 6 | pages = 1476–85 | date = 2012 | pmid = 22453000 | doi=10.1253/circj.cj-11-1360 | pmc=3527096}}</ref> Moreover, the modulatory component, [[ANT1|ANT]] is regulated by PKCε.<ref name="pmid12663490"/> These data suggest that PKCε may act at multiple modulatory targets of MPT function; further studies are required to unveil the specific mechanism.

== Clinical significance ==

=== Cardiac hypertrophy and heart failure ===

Findings of PKCε [[phosphorylation]] in animal models have been verified in humans; PKCε [[phosphorylate]]s [[TNNI3|cTnI]], [[TNNT2|cTnT]], and [[MYBPC3|MyBPC]] and depresses the sensitivity of myofilaments to calcium.<ref>{{cite journal | vauthors = Kooij V, Boontje N, Zaremba R, Jaquet K, dos Remedios C, Stienen GJ, van der Velden J | title = Protein kinase C alpha and epsilon phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium | journal = Basic Research in Cardiology | volume = 105 | issue = 2 | pages = 289–300 | date = Mar 2010 | pmid = 19655190 | doi = 10.1007/s00395-009-0053-z | pmc=2807945}}</ref> PKCε induction occurs in the development of [[cardiac hypertrophy]], following stimuli such as [[myotrophin]],<ref>{{cite journal | vauthors = Sil P, Kandaswamy V, Sen S | title = Increased protein kinase C activity in myotrophin-induced myocyte growth | journal = Circulation Research | volume = 82 | issue = 11 | pages = 1173–88 | date = Jun 1998 | pmid = 9633917 | doi=10.1161/01.res.82.11.1173| doi-access = free }}</ref> mechanical stretch and [[hypertension]].<ref>{{cite journal | vauthors = Inagaki K, Iwanaga Y, Sarai N, Onozawa Y, Takenaka H, Mochly-Rosen D, Kihara Y | title = Tissue angiotensin II during progression or ventricular hypertrophy to heart failure in hypertensive rats; differential effects on PKC epsilon and PKC beta | journal = Journal of Molecular and Cellular Cardiology | volume = 34 | issue = 10 | pages = 1377–85 | date = Oct 2002 | pmid = 12392998 | doi=10.1016/s0022-2828(02)92089-4}}</ref> The precise role of PKCε in [[cardiac hypertrophy|hypertrophic]] induction has been debated. The inhibition of PKCε during transition from [[cardiac hypertrophy|hypertrophy]] to [[heart failure]] enhances longevity;<ref>{{cite journal | vauthors = Inagaki K, Koyanagi T, Berry NC, Sun L, Mochly-Rosen D | title = Pharmacological inhibition of epsilon-protein kinase C attenuates cardiac fibrosis and dysfunction in hypertension-induced heart failure | journal = Hypertension | volume = 51 | issue = 6 | pages = 1565–9 | date = Jun 2008 | pmid = 18413490 | doi = 10.1161/HYPERTENSIONAHA.107.109637 | pmc=3646632}}</ref> however, inhibition of PKCε translocation via a peptide inhibitor increases cardiomyocyte size and expression of [[cardiac hypertrophy|hypertrophic]] gene panel.<ref>{{cite journal | vauthors = Mochly-Rosen D, Wu G, Hahn H, Osinska H, Liron T, Lorenz JN, Yatani A, Robbins J, Dorn GW | title = Cardiotrophic effects of protein kinase C epsilon: analysis by in vivo modulation of PKCepsilon translocation | journal = Circulation Research | volume = 86 | issue = 11 | pages = 1173–9 | date = Jun 2000 | pmid = 10850970 | doi=10.1161/01.res.86.11.1173| doi-access = free }}</ref> A role for [[PTK2|focal adhesion kinase]] at [[costamere]]s in strain-sensing and modulation of sarcomere length has been linked to hypertrophy. The activation of [[PTK2|FAK]] by PKCε occurs following a [[cardiac hypertrophy|hypertrophic]] stimulus, which modulates [[sarcomere]] assembly.<ref>{{cite journal | vauthors = Heidkamp MC, Bayer AL, Scully BT, Eble DM, Samarel AM | title = Activation of focal adhesion kinase by protein kinase C epsilon in neonatal rat ventricular myocytes | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 285 | issue = 4 | pages = H1684–96 | date = Oct 2003 | pmid = 12829427 | doi = 10.1152/ajpheart.00016.2003 | s2cid = 2800040 }}</ref><ref>{{cite journal | vauthors = Mansour H, de Tombe PP, Samarel AM, Russell B | title = Restoration of resting sarcomere length after uniaxial static strain is regulated by protein kinase Cepsilon and focal adhesion kinase | journal = Circulation Research | volume = 94 | issue = 5 | pages = 642–9 | date = Mar 2004 | pmid = 14963000 | doi = 10.1161/01.RES.0000121101.32286.C8 | doi-access = free }}</ref> PKCε also regulates [[CAPZB|CapZ]] dynamics following cyclic strain.<ref>{{cite journal | vauthors = Lin YH, Swanson ER, Li J, Mkrtschjan MA, Russell B | title = Cyclic mechanical strain of myocytes modifies CapZβ1 post translationally via PKCε | journal = Journal of Muscle Research and Cell Motility | volume = 36 | issue = 4–5 | pages = 329–37 | date = Oct 2015 | pmid = 26429793 | doi = 10.1007/s10974-015-9420-6 | pmc = 5226411 }}</ref>

[[Transgenic]] studies involving PKCε have also shed light on its function in vivo. Cardiac-specific overexpression of constitutively-active PKCε (9-fold increase in PKCε protein, 4-fold increase in activity) induced [[cardiac hypertrophy]] characterizes by enhanced anterior and posterior [[left ventricle|left ventricular]] wall thickness.<ref>{{cite journal | vauthors = Takeishi Y, Ping P, Bolli R, Kirkpatrick DL, Hoit BD, Walsh RA | title = Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy | journal = Circulation Research | volume = 86 | issue = 12 | pages = 1218–23 | date = Jun 2000 | pmid = 10864911 | doi=10.1161/01.res.86.12.1218| doi-access = free }}</ref> A later study unveiled that the aging of PKCε [[transgenic]] mice brought on [[dilated cardiomyopathy]] and [[heart failure]] by 12 months of age,<ref>{{cite journal | vauthors = Goldspink PH, Montgomery DE, Walker LA, Urboniene D, McKinney RD, Geenen DL, Solaro RJ, Buttrick PM | title = Protein kinase Cepsilon overexpression alters myofilament properties and composition during the progression of heart failure | journal = Circulation Research | volume = 95 | issue = 4 | pages = 424–32 | date = Aug 2004 | pmid = 15242976 | doi = 10.1161/01.RES.0000138299.85648.92 | doi-access = free }}</ref>] characterized by a preserved [[Frank-Starling]] mechanism and exhausted contractile reserve.<ref>{{cite journal | vauthors = Montgomery DE, Rundell VL, Goldspink PH, Urboniene D, Geenen DL, de Tombe PP, Buttrick PM | title = Protein kinase C epsilon induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 289 | issue = 5 | pages = H1881–8 | date = Nov 2005 | pmid = 15951344 | doi = 10.1152/ajpheart.00454.2005 | s2cid = 37813298 }}</ref> Crossing PKCε [[transgenic]] mice with mutant [[TNNI3|cTnI]] mice lacking PKCε [[phosphorylation]] sites ([[Serine]]-43/[[Serine]]-45 mutated to [[Alanine]]) attenuated the contractile dysfunction and hypertrophic marker expression, offering critical mechanistic insights.<ref>{{cite journal | vauthors = Scruggs SB, Walker LA, Lyu T, Geenen DL, Solaro RJ, Buttrick PM, Goldspink PH | title = Partial replacement of cardiac troponin I with a non-phosphorylatable mutant at serines 43/45 attenuates the contractile dysfunction associated with PKCepsilon phosphorylation | journal = Journal of Molecular and Cellular Cardiology | volume = 40 | issue = 4 | pages = 465–73 | date = Apr 2006 | pmid = 16445938 | doi = 10.1016/j.yjmcc.2005.12.009 }}</ref>

=== Cardioprotection against Ischemic injury ===
JM Downey was the first to introduce the role of [[protein kinase C|PKC]] in [[cardioprotection]] against [[myocardial infarction|ischemia-reperfusion injury]] in 1994,;<ref>{{cite journal | vauthors = Ytrehus K, Liu Y, Downey JM | title = Preconditioning protects ischemic rabbit heart by protein kinase C activation | journal = The American Journal of Physiology | volume = 266 | issue = 3 Pt 2 | pages = H1145–52 | date = Mar 1994 | pmid = 8160817 | doi = 10.1152/ajpheart.1994.266.3.H1145 | s2cid = 1642830 }}</ref> this seminal idea stimulated a series of studies which examined the different [[isoform]]s of [[protein kinase C|PKC]]. PKCε has been demonstrated to be a central player in [[preconditioning]] in multiple independent studies, with its best known actions at [[cardiac muscle|cardiac]] [[mitochondria]]. It was first demonstrated by Ping et al. that in five distinct [[preconditioning]] regimens in conscious rabbits, the epsilon isoform of [[protein kinase C|PKC]] specifically translocated from the [[cytosol]]ic to particulate fraction.<ref name="ReferenceB"/><ref>{{cite journal | vauthors = Bolli R, Dawn B, Tang XL, Qiu Y, Ping P, Xuan YT, Jones WK, Takano H, Guo Y, Zhang J | title = The nitric oxide hypothesis of late preconditioning | journal = Basic Research in Cardiology | volume = 93 | issue = 5 | pages = 325–38 | date = Oct 1998 | pmid = 9833145 | doi=10.1007/s003950050101 | pmc=3701309}}</ref> This finding was validated by multiple independent studies occurring shortly thereafter,<ref>{{cite journal | vauthors = Gray MO, Karliner JS, Mochly-Rosen D | title = A selective epsilon-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death | journal = The Journal of Biological Chemistry | volume = 272 | issue = 49 | pages = 30945–51 | date = Dec 1997 | pmid = 9388241 | doi=10.1074/jbc.272.49.30945| doi-access = free }}</ref><ref>{{cite journal | vauthors = Liu GS, Cohen MV, Mochly-Rosen D, Downey JM | title = Protein kinase C-epsilon is responsible for the protection of preconditioning in rabbit cardiomyocytes | journal = Journal of Molecular and Cellular Cardiology | volume = 31 | issue = 10 | pages = 1937–48 | date = Oct 1999 | pmid = 10525430 | doi = 10.1006/jmcc.1999.1026 }}</ref> and has since been observed in multiple animal models<ref>{{cite journal | vauthors = Wilson S, Song W, Karoly K, Ravingerova T, Vegh A, Papp J, Tomisawa S, Parratt JR, Pyne NJ | title = Delayed cardioprotection is associated with the sub-cellular relocalisation of ventricular protein kinase C epsilon, but not p42/44MAPK | journal = Molecular and Cellular Biochemistry | volume = 160–161 | pages = 225–30 | date = 1996 | pmid = 8901477 | doi=10.1007/bf00240053| s2cid = 2878489 }}</ref><ref>{{cite journal | vauthors = Kawamura S, Yoshida K, Miura T, Mizukami Y, Matsuzaki M | title = Ischemic preconditioning translocates PKC-delta and -epsilon, which mediate functional protection in isolated rat heart | journal = The American Journal of Physiology | volume = 275 | issue = 6 Pt 2 | pages = H2266–71 | date = Dec 1998 | pmid = 9843828 | doi = 10.1152/ajpheart.1998.275.6.H2266 }}</ref><ref>{{cite journal | vauthors = Tong H, Chen W, Steenbergen C, Murphy E | title = Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C | journal = Circulation Research | volume = 87 | issue = 4 | pages = 309–15 | date = Aug 2000 | pmid = 10948065 | doi=10.1161/01.res.87.4.309| doi-access = free }}</ref> and human tissue,<ref>{{cite journal | vauthors = Hassouna A, Matata BM, Galiñanes M | title = PKC-epsilon is upstream and PKC-alpha is downstream of mitoKATP channels in the signal transduction pathway of ischemic preconditioning of human myocardium | journal = American Journal of Physiology. Cell Physiology | volume = 287 | issue = 5 | pages = C1418–25 | date = Nov 2004 | pmid = 15294852 | doi = 10.1152/ajpcell.00144.2004 | s2cid = 37574971 }}</ref> as well as in studies employing transgenesis and PKCε activators/inhibitors.<ref>{{cite journal | vauthors = Gregory KN, Hahn H, Haghighi K, Marreez Y, Odley A, Dorn GW, Kranias EG | title = Increased particulate partitioning of PKC epsilon reverses susceptibility of phospholamban knockout hearts to ischemic injury | journal = Journal of Molecular and Cellular Cardiology | volume = 36 | issue = 2 | pages = 313–8 | date = Feb 2004 | pmid = 14871559 | doi = 10.1016/j.yjmcc.2003.12.001 }}</ref>

[[Mitochondria]]l targets of PKCε involved in [[cardioprotection]] have been actively pursued, since the translocation of PKCε to mitochondria following protective stimuli is one of the most well-accepted cardioprotective paradigms. PKCε has been shown to target and [[phosphorylation|phosphorylate]] [[ALDH2|alcohol dehydrogenase 2]] (ALDH2) following preconditioning stimuli, which increased the activity of [[ALDH2]] and reduced [[myocardial infarction|infarct]] size.<ref>{{cite journal | vauthors = Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D | title = Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart | journal = Science | volume = 321 | issue = 5895 | pages = 1493–5 | date = Sep 2008 | pmid = 18787169 | doi = 10.1126/science.1158554 | pmc=2741612| bibcode = 2008Sci...321.1493C }}</ref><ref>{{cite journal | vauthors = Ping P | title = Getting to the heart of proteomics | journal = The New England Journal of Medicine | volume = 360 | issue = 5 | pages = 532–4 | date = Jan 2009 | pmid = 19179323 | doi = 10.1056/NEJMcibr0808487 | pmc=2692588}}</ref> Moreover, PKCε interacts with [[cytochrome c oxidase]] subunit IV (COIV), and preconditioning stimuli evoked [[phosphorylation]] of COIV and stabilization of COIV protein and activity.<ref>{{cite journal | vauthors = Ogbi M, Johnson JA | title = Protein kinase Cepsilon interacts with cytochrome c oxidase subunit IV and enhances cytochrome c oxidase activity in neonatal cardiac myocyte preconditioning | journal = The Biochemical Journal | volume = 393 | issue = Pt 1 | pages = 191–9 | date = Jan 2006 | pmid = 16336199 | doi = 10.1042/BJ20050757 | pmc=1383677}}</ref> The [[mitochondria]]l [[ATP-sensitive potassium channel]] (mitoK(ATP)) also interacts with PKCε; [[phosphorylation]] of [[ATP-sensitive potassium channel|mitoK(ATP)]] following preconditioning stimuli potentiates channel opening.<ref>{{cite journal | vauthors = Jabůrek M, Costa AD, Burton JR, Costa CL, Garlid KD | title = Mitochondrial PKC epsilon and mitochondrial ATP-sensitive K+ channel copurify and coreconstitute to form a functioning signaling module in proteoliposomes | journal = Circulation Research | volume = 99 | issue = 8 | pages = 878–83 | date = Oct 2006 | pmid = 16960097 | doi = 10.1161/01.RES.0000245106.80628.d3 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Costa AD, Garlid KD | title = Intramitochondrial signaling: interactions among mitoKATP, PKCepsilon, ROS, and MPT | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 295 | issue = 2 | pages = H874–82 | date = Aug 2008 | pmid = 18586884 | doi = 10.1152/ajpheart.01189.2007 | pmc=2519212}}</ref> PKCε modulates the interaction between subunit [[Kir6.1]] of [[ATP-sensitive potassium channel|mitoK(ATP)]] and [[connexin-43]], whose interaction confers [[cardioprotection]].<ref>{{cite journal | vauthors = Waza AA, Andrabi K, Hussain MU | title = Protein kinase C (PKC) mediated interaction between conexin43 (Cx43) and K(+)(ATP) channel subunit (Kir6.1) in cardiomyocyte mitochondria: Implications in cytoprotection against hypoxia induced cell apoptosis | journal = Cellular Signalling | volume = 26 | issue = 9 | pages = 1909–17 | date = Sep 2014 | pmid = 24815185 | doi = 10.1016/j.cellsig.2014.05.002 }}</ref> Lastly, several mitochondrial [[metabolism|metabolic]] targets of PKCε [[phosphorylation]] involved in [[cardioprotection]] following activation with εRACK have been identified, including [[oxidative phosphorylation#Eukaryotic electron transport chains|mitochondrial respiratory complexes I, II and III]], as well as proteins involved in [[glycolysis]], [[lipid oxidation]], [[ketone body]] metabolism and [[heat shock protein]]s.<ref name="Identification of εPKC targets duri"/>

The role of PKCε acting in non-[[mitochondria]]l regions of [[cardiomyocyte]]s is less well understood, though some studies have identified [[sarcomere|sarcomeric]] targets. PKCε translocation to [[sarcomere]]s and [[phosphorylation]] of [[TNNI3|cTnI]] and [[MYBPC3|cMyBPC]] is involved in the [[κ-opioid receptor|κ-opioid]]- and [[adrenergic receptor|α-adrenergic]]-dependent preconditioning that slows [[MYH7|myosin]] cycling rate, thus protecting the contractile apparatus from damage.<ref>{{cite journal | vauthors = Pyle WG, Smith TD, Hofmann PA | title = Cardioprotection with kappa-opioid receptor stimulation is associated with a slowing of cross-bridge cycling | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 279 | issue = 4 | pages = H1941–8 | date = Oct 2000 | pmid = 11009483 | doi = 10.1152/ajpheart.2000.279.4.H1941 | s2cid = 7497152 }}</ref><ref>{{cite journal | vauthors = Pyle WG, Chen Y, Hofmann PA | title = Cardioprotection through a PKC-dependent decrease in myofilament ATPase | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 285 | issue = 3 | pages = H1220–8 | date = Sep 2003 | pmid = 12763745 | doi = 10.1152/ajpheart.00076.2003 | s2cid = 15914929 }}</ref> Activation of PKCε by εRACK prior to [[myocardial infarction|ischemia]] was also found to [[phosphorylation|phosphorylate]] [[MYL2|Ventricular myosin light chain-2]],<ref name="Identification of εPKC targets duri"/> however the functional significance  remains elusive. [[CAPZB|Actin-capping protein, CapZ]] appears to affect the localization of PKCε to [[sarcomere|Z-lines]]<ref>{{cite journal | vauthors = Pyle WG, Hart MC, Cooper JA, Sumandea MP, de Tombe PP, Solaro RJ | title = Actin capping protein: an essential element in protein kinase signaling to the myofilaments | journal = Circulation Research | volume = 90 | issue = 12 | pages = 1299–306 | date = Jun 2002 | pmid = 12089068 | doi=10.1161/01.res.0000024389.03152.22| doi-access = free }}</ref> and modulates the [[cardiomyocyte]] response to [[myocardial infarction|ischemic injury]]. [[Cardioprotection]] in mice with reduction of [[CAPZB|CapZ]] showed enhancement in PKCε translocation to [[sarcomere]]s,<ref>{{cite journal | vauthors = Yang FH, Pyle WG | title = Reduced cardiac CapZ protein protects hearts against acute ischemia-reperfusion injury and enhances preconditioning | journal = Journal of Molecular and Cellular Cardiology | volume = 52 | issue = 3 | pages = 761–72 | date = Mar 2012 | pmid = 22155006 | doi = 10.1016/j.yjmcc.2011.11.013 }}</ref> thus suggesting that [[CAPZB|CapZ]] may compete with PKCε for the binding of RACK2.

=== Other functions ===

Knockout and molecular studies in mice suggest that this kinase is important for regulating behavioural response to morphine<ref name="pmid16899053">{{cite journal | vauthors = Newton PM, Kim JA, McGeehan AJ, Paredes JP, Chu K, Wallace MJ, Roberts AJ, Hodge CW, Messing RO | title = Increased response to morphine in mice lacking protein kinase C epsilon | journal = Genes, Brain and Behavior | volume = 6 | issue = 4 | pages = 329–38 | date = Jun 2007 | pmid = 16899053 | doi = 10.1111/j.1601-183X.2006.00261.x | pmc = 4264050 }}</ref> and alcohol.<ref name="pmid16102840">{{cite journal | vauthors = Newton PM, Messing RO | title = Intracellular signaling pathways that regulate behavioral responses to ethanol | journal = Pharmacology & Therapeutics | volume = 109 | issue = 1–2 | pages = 227–37 | date = Jan 2006 | pmid = 16102840 | doi = 10.1016/j.pharmthera.2005.07.004 }}</ref><ref name="pmid19243450">{{cite journal | vauthors = Lesscher HM, Wallace MJ, Zeng L, Wang V, Deitchman JK, McMahon T, Messing RO, Newton PM | title = Amygdala protein kinase C epsilon controls alcohol consumption | journal = Genes, Brain and Behavior | volume = 8 | issue = 5 | pages = 493–9 | date = Jul 2009 | pmid = 19243450 | pmc = 2714877 | doi = 10.1111/j.1601-183X.2009.00485.x }}</ref> It also plays a role lipopolysaccharide (LPS)-mediated signaling in activated macrophages and in controlling anxiety-like behavior.<ref>{{cite web | title = Entrez Gene: PRKCE protein kinase C, epsilon| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5581}}</ref>

==Substrates and interactions==
PKC-epsilon has a wide variety of substrates, including [[ion channel]]s, other signalling molecules and [[cytoskeletal]] proteins.<ref name="pmid20350291">{{cite journal | vauthors = Newton PM, Messing RO | title = The substrates and binding partners of protein kinase Cepsilon | journal = The Biochemical Journal | volume = 427 | issue = 2 | pages = 189–96 | date = Apr 2010 | pmid = 20350291 | pmc = 2966297 | doi = 10.1042/BJ20091302 }}</ref>

PKC-epsilon has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[Actin, alpha 1|ACTA1]],<ref name=pmid11897493/>
* [[COPB2]],<ref name="pmid11897493">{{cite journal | vauthors = England K, Ashford D, Kidd D, Rumsby M | title = PKC epsilon is associated with myosin IIA and actin in fibroblasts | journal = Cellular Signalling | volume = 14 | issue = 6 | pages = 529–36 | date = Jun 2002 | pmid = 11897493 | doi = 10.1016/S0898-6568(01)00277-7 }}</ref>
* [[Cystic fibrosis transmembrane conductance regulator|CFTR]],<ref name="pmid11956211">{{cite journal | vauthors = Liedtke CM, Yun CH, Kyle N, Wang D | title = Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor | journal = The Journal of Biological Chemistry | volume = 277 | issue = 25 | pages = 22925–33 | date = Jun 2002 | pmid = 11956211 | doi = 10.1074/jbc.M201917200 | doi-access = free }}</ref>
* [[Keratin 1|KRT1]],<ref name=pmid11897493/> 
* [[GNB2L1]],<ref name=pmid11956211/>
* [[MYH9]],<ref name=pmid11897493/>
* [[VDAC1]],<ref name="pmid12663490">{{cite journal | vauthors = Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P | title = Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria | journal = Circulation Research | volume = 92 | issue = 8 | pages = 873–80 | date = May 2003 | pmid = 12663490 | doi = 10.1161/01.RES.0000069215.36389.8D | pmc=3691672}}</ref> and
* [[YWHAZ]].<ref name="pmid11950841">{{cite journal | vauthors = Gannon-Murakami L, Murakami K | title = Selective association of protein kinase C with 14-3-3 zeta in neuronally differentiated PC12 Cells. Stimulatory and inhibitory effect of 14-3-3 zeta in vivo | journal = The Journal of Biological Chemistry | volume = 277 | issue = 26 | pages = 23116–22 | date = Jun 2002 | pmid = 11950841 | doi = 10.1074/jbc.M201478200 | doi-access = free }}</ref>
{{Div col end}}

== See also ==
*[[Protein kinase C]]

==Notes==
{{Academic-written review|Q=Q38867832}}

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Newton PM, Messing RO | title = The substrates and binding partners of protein kinase Cepsilon | journal = The Biochemical Journal | volume = 427 | issue = 2 | pages = 189–96 | date = Apr 2010 | pmid = 20350291 | pmc = 2966297 | doi = 10.1042/BJ20091302 }}
* {{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 = Chemistry and Physics of Lipids | volume = 116 | issue = 1–2 | pages = 75–91 | date = Jun 2002 | pmid = 12093536 | doi = 10.1016/S0009-3084(02)00021-X }}
* {{cite journal | vauthors = Aksoy E, Goldman M, Willems F | title = Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders | journal = The International Journal of Biochemistry & Cell Biology | volume = 36 | issue = 2 | pages = 183–8 | date = Feb 2004 | pmid = 14643884 | doi = 10.1016/S1357-2725(03)00210-3 }}
* {{cite journal | vauthors = Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M | title = HIV/SIV escape from immune surveillance: focus on Nef | journal = Current HIV Research | volume = 2 | issue = 2 | pages = 141–51 | date = Apr 2004 | pmid = 15078178 | doi = 10.2174/1570162043484924 }}
{{refend}}

== External links ==
* {{PDBe-KB2|Q02156|Protein kinase C epsilon type}}

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[[Category:EC 2.7.11]]