PRKCE: Difference between revisions
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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}}</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 }}</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}}</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 | pmid = 8207017 }}</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> | 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}}</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 }}</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}}</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 | pmid = 8207017 }}</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}}</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}}</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}}</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 }}</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}}</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}}</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}}</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 }}</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}}</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}}</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 | pmid = 7806510 }}</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 | volume = 1823 | issue = 4 | pages = 950–8 | date = Apr 2012 | pmid = 22233927 | doi = 10.1016/j.bbamcr.2011.12.012 }}</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 }}</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}}</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}}</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}}</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 | pmid = 7806510 }}</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 | volume = 1823 | issue = 4 | pages = 950–8 | date = Apr 2012 | pmid = 22233927 | doi = 10.1016/j.bbamcr.2011.12.012 }}</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 }}</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}}</ref> | ||
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=== Cardiac hypertrophy and heart failure === | === 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}}</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}}</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 }}</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 }}</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 }}</ref> | 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}}</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}}</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 }}</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 }}</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}}</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 }}</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 }}</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> | [[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}}</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 }}</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 }}</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> | ||
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[[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}}</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 }}</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>{{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> | [[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}}</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 }}</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>{{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> | ||
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 }}</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 }}</ref> Activation of PKCε by εRACK prior to [[myocardial infarction|ischemia]] was also found to [[phosphorylation|phosphorylate]] [[MYL2|Ventricular myosin light chain-2]],<ref>{{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> 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}}</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. | 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 }}</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 }}</ref> Activation of PKCε by εRACK prior to [[myocardial infarction|ischemia]] was also found to [[phosphorylation|phosphorylate]] [[MYL2|Ventricular myosin light chain-2]],<ref>{{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> 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}}</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 === | === 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 }}</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| accessdate = }}</ref> | 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| accessdate = }}</ref> | ||
==Substrates and interactions== | ==Substrates and interactions== |
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Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the PRKCE gene.[1][2] PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulates muscle contraction through its actions at sarcomeric proteins, and PKCε modulates cardiac cell metabolism through its actions at mitochondria. PKCε is clinically significant in that it a central player in cardioprotection against 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 kinases contains thirteen PKC isoforms, and each isoform can be distinguished by differences in primary structure, gene expression, subcellular localization, and modes of activation.[3] The epsilon isoform of PKC is abundantly expressed in adult cardiomyocytes,[4][5][6][7] being the most highly expressed of all novel isoforms, PKC-δ, -ζ, and –η.[8] PKCε and other PKC isoforms require phosphorylation at sites Threonine-566, Threonine-710, and Serine-729 for kinase maturation.[9] The epsilon isoform of PKC differs from other isoforms by the position of the C2, pseudosubstrate, and C1 domains; various second messengers in different combinations can act on the C1 domain to direct subcellular translocation of PKCε.[5][10]
Receptors for activated C-kinase (RACK) have been found to anchor active PKC in close proximity to substrates.[11] PKCε appears to have preferred affinity to the RACK2 isoform; specifically, the C2 domain of PKCε at amino acids 14–21 (also known as εV1-2) binds RACK2, and peptide inhibitors targeting εV1-2 inhibit PKCε translocation and function in cardiomyocytes,[12] while peptide agonists augment translocation.[13] It has been demonstrated that altering the dynamics of the RACK2 and RACK1 interaction with PKCε can influence cardiac muscle phenotypes.[14]
Activated PKCε translocates to various intracellular targets.[9][15] In cardiac muscle, PKCε translocates to sarcomeres at Z-lines following α-adrenergic and endothelin (ET)A-receptor stimulation.[5][16] A myriad of agonists have also been shown to induce the translocation of PKCε from the cytosolic to particulate fraction in cardiomyocytes, including but not limited to PMA or norepinephrine;[5]arachidonic acid;[17]ET-1 and phenylephrine;[18][19] angiotensin II and diastolic stretch;[20] adenosine;[21] hypoxia and Akt-induced stem cell factor;[22] ROS generated via pharmacologic activation of the mitochondrial potassium-sensitive ATP channel (mitoK(ATP))[23] and the endogenous G-protein coupled receptor ligand, apelin.[24]
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 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 sarcomeres and modulates contractility of the myocardium. PKCε binds RACK2 at Z-lines with an EC50 of 86 nM;[25] PKCε also binds at costameres to syndecan-4.[26] PKCε has been shown to bind F-actin in neurons, which modulates synaptic function and differentiation;[27][28] however it is unknown whether PKCε binds sarcomeric actin in muscle cells. Sarcomeric proteins have been identified in PKCε signaling complexes, including actin, cTnT, tropomyosin, desmin, and myosin light chain-2; in mice expressing a constitutively-active PKCε, all sarcomeric proteins showed greater association with PKCε, and the cTnT, tropomyosin, desmin and myosin light chain-2 exhibited changes in post-translational modifications.[29]
PKCε binds and phosphorylates cardiac troponin I (cTnI) and cardiac troponin T (cTnT) in complex with troponin C (cTnC);[30] phosphorylation on cTnI at residues Serine-43, Serine-45, and Threonine-144 cause depression of actomyosin S1 MgATPase function.[31][32] These studies were further supported by those performed in isolated, skinned cardiac muscle fibers, showing that in vitro phosphorylation of 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.[33] Phosphorylation on cTnI at Serine-5/6 also showed this depressive effect.[34] Further support was gained from in vivo studies in which mice expressing a mutant cTnI (Serine43/45Alanine) exhibited enhanced cardiac contractility.[35]
Cardiac muscle mitochondrial metabolism and function
In addition to sarcomeres, PKCε also targets cardiac mitochondria.[29][36] 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 modifications were altered in the transgenic mice.[29] This study was the first to demonstrate PKCε at the inner mitochondrial membrane,[29] and it was found that PKCε binds several mitochondrial proteins involved in glycolysis, TCA cycle, beta oxidation, and ion transport.[37] However, it remained unclear how PKCε translocates from the outer to inner mitochondrial membrane until Budas et al. discovered that heat shock protein 90 (Hsp90) coordinates with the translocase of the outer mitochondrial membrane-20 (Tom20) to translocate PKCε following a preconditioning stimulus.[38][39] Specifically, a seven amino acid peptide, termed TAT-εHSP90, homologous to the Hsp90 sequence within the PKCε C2 domain induced translocation of PKCε to the inner mitochondrial membrane and cardioprotection.[40]
PKCε has also been shown to play a role in modulating mitochondrial permeability transition (MPT); the addition of PKCε to cardiomyocytes inhibits MPT,[36] though the mechanism is unclear. Initially, PKCε was thought to protect mitochondria from MPT through its association with VDAC1, ANT, and hexokinase II;[36] however, genetic studies have since ruled this out[41][42] and subsequent studies have identified the F0/F1 ATP synthase as a core inner mitochondrial membrane component[43][44][45][46] and Bax and Bak as potential outer membrane components[47] 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 ERK, JNKs and p38, and PKCε directly or indirectly phosphorylates ERK and subsequently Bad.[48] PKCε also interacts with Bax in cancer cells, and PKCε modulates its dimerization and function.[49][50] 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.[51] Moreover, the modulatory component, ANT is regulated by PKCε.[36] 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 phosphorylates cTnI, cTnT, and MyBPC and depresses the sensitivity of myofilaments to calcium.[52] PKCε induction occurs in the development of cardiac hypertrophy, following stimuli such as myotrophin,[53] mechanical stretch and hypertension.[54] The precise role of PKCε in hypertrophic induction has been debated. The inhibition of PKCε during transition from hypertrophy to heart failure enhances longevity;[55] however, inhibition of PKCε translocation via a peptide inhibitor increases cardiomyocyte size and expression of hypertrophic gene panel.[56] A role for focal adhesion kinase at costameres in strain-sensing and modulation of sarcomere length has been linked to hypertrophy. The activation of FAK by PKCε occurs following a hypertrophic stimulus, which modulates sarcomere assembly.[57][58] PKCε also regulates CapZ dynamics following cyclic strain.[59]
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 ventricular wall thickness.[60] A later study unveiled that the aging of PKCε transgenic mice brought on dilated cardiomyopathy and heart failure by 12 months of age,[61]] characterized by a preserved Frank-Starling mechanism and exhausted contractile reserve.[62] Crossing PKCε transgenic mice with mutant 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.[63]
Cardioprotection against Ischemic injury
JM Downey was the first to introduce the role of PKC in cardioprotection against ischemia-reperfusion injury in 1994,;[64] this seminal idea stimulated a series of studies which examined the different isoforms of PKC. PKCε has been demonstrated to be a central player in preconditioning in multiple independent studies, with its best known actions at cardiac mitochondria. It was first demonstrated by Ping et al. that in five distinct preconditioning regimens in conscious rabbits, the epsilon isoform of PKC specifically translocated from the cytosolic to particulate fraction.[8][65] This finding was validated by multiple independent studies occurring shortly thereafter,[66][67] and has since been observed in multiple animal models[68][69][70] and human tissue,[71] as well as in studies employing transgenesis and PKCε activators/inhibitors.[72]
Mitochondrial 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 phosphorylate alcohol dehydrogenase 2 (ALDH2) following preconditioning stimuli, which increased the activity of ALDH2 and reduced infarct size.[73][74] Moreover, PKCε interacts with cytochrome c oxidase subunit IV (COIV), and preconditioning stimuli evoked phosphorylation of COIV and stabilization of COIV protein and activity.[75] The mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) also interacts with PKCε; phosphorylation of mitoK(ATP) following preconditioning stimuli potentiates channel opening.[76][77] PKCε modulates the interaction between subunit Kir6.1 of mitoK(ATP) and connexin-43, whose interaction confers cardioprotection.[78] Lastly, several mitochondrial metabolic targets of PKCε phosphorylation involved in cardioprotection following activation with εRACK have been identified, including mitochondrial respiratory complexes I, II and III, as well as proteins involved in glycolysis, lipid oxidation, ketone body metabolism and heat shock proteins.[79]
The role of PKCε acting in non-mitochondrial regions of cardiomyocytes is less well understood, though some studies have identified sarcomeric targets. PKCε translocation to sarcomeres and phosphorylation of cTnI and cMyBPC is involved in the κ-opioid- and α-adrenergic-dependent preconditioning that slows myosin cycling rate, thus protecting the contractile apparatus from damage.[80][81] Activation of PKCε by εRACK prior to ischemia was also found to phosphorylate Ventricular myosin light chain-2,[82] however the functional significance remains elusive. Actin-capping protein, CapZ appears to affect the localization of PKCε to Z-lines[83] and modulates the cardiomyocyte response to ischemic injury. Cardioprotection in mice with reduction of CapZ showed enhancement in PKCε translocation to sarcomeres,[84] thus suggesting that 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[85] and alcohol.[86][87] It also plays a role lipopolysaccharide (LPS)-mediated signaling in activated macrophages and in controlling anxiety-like behavior.[88]
Substrates and interactions
PKC-epsilon has a wide variety of substrates, including ion channels, other signalling molecules and cytoskeletal proteins.[89]
PKC-epsilon has been shown to interact with:
See also
Notes
The 2016 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: {{#property:P2093|from=Q38867832}} ({{#property:P577|from=Q38867832}}). "{{#property:P1476|from=Q38867832}}". Gene. {{#property:P478|from=Q38867832}} ({{#property:P433|from=Q38867832}}): {{#property:P304|from=Q38867832}}. doi:{{#property:P356|from=Q38867832}} Check |doi= value (help). PMC {{#property:P932|from=Q38867832}} Check |pmc= value (help). PMID {{#property:P698|from=Q38867832}} Check |pmid= value (help). Check date values in: |date= (help) |
References
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- ↑ 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 (27 August 2013). "Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice". eLife. 2: e00772. doi:10.7554/eLife.00772. PMC 3755340. PMID 23991283.
- ↑ Baines CP, Zhang J, Wang GW, Zheng YT, Xiu JX, Cardwell EM, Bolli R, Ping P (Mar 2002). "Mitochondrial PKCepsilon and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCepsilon-MAPK interactions and differential MAPK activation in PKCepsilon-induced cardioprotection". Circulation Research. 90 (4): 390–7. doi:10.1161/01.res.0000012702.90501.8d. PMID 11884367.
- ↑ 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 (Sep 2003). "Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells". Oncogene. 22 (39): 7958–68. doi:10.1038/sj.onc.1206795. PMID 12970744.
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- ↑ Budas G, Costa HM, Ferreira JC, Teixeira da Silva Ferreira A, Perales J, Krieger JE, Mochly-Rosen D, Schechtman D (2012). "Identification of εPKC targets during cardiac ischemic injury". Circulation Journal. 76 (6): 1476–85. doi:10.1253/circj.cj-11-1360. PMC 3527096. PMID 22453000.
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- ↑ Kawamura S, Yoshida K, Miura T, Mizukami Y, Matsuzaki M (Dec 1998). "Ischemic preconditioning translocates PKC-delta and -epsilon, which mediate functional protection in isolated rat heart". The American Journal of Physiology. 275 (6 Pt 2): H2266–71. PMID 9843828.
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- ↑ Hassouna A, Matata BM, Galiñanes M (Nov 2004). "PKC-epsilon is upstream and PKC-alpha is downstream of mitoKATP channels in the signal transduction pathway of ischemic preconditioning of human myocardium". American Journal of Physiology. Cell Physiology. 287 (5): C1418–25. doi:10.1152/ajpcell.00144.2004. PMID 15294852.
- ↑ Gregory KN, Hahn H, Haghighi K, Marreez Y, Odley A, Dorn GW, Kranias EG (Feb 2004). "Increased particulate partitioning of PKC epsilon reverses susceptibility of phospholamban knockout hearts to ischemic injury". Journal of Molecular and Cellular Cardiology. 36 (2): 313–8. doi:10.1016/j.yjmcc.2003.12.001. PMID 14871559.
- ↑ Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (Sep 2008). "Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart". Science. 321 (5895): 1493–5. doi:10.1126/science.1158554. PMC 2741612. PMID 18787169.
- ↑ Ping P (Jan 2009). "Getting to the heart of proteomics". The New England Journal of Medicine. 360 (5): 532–4. doi:10.1056/NEJMcibr0808487. PMC 2692588. PMID 19179323.
- ↑ Ogbi M, Johnson JA (Jan 2006). "Protein kinase Cepsilon interacts with cytochrome c oxidase subunit IV and enhances cytochrome c oxidase activity in neonatal cardiac myocyte preconditioning". The Biochemical Journal. 393 (Pt 1): 191–9. doi:10.1042/BJ20050757. PMC 1383677. PMID 16336199.
- ↑ Jabůrek M, Costa AD, Burton JR, Costa CL, Garlid KD (Oct 2006). "Mitochondrial PKC epsilon and mitochondrial ATP-sensitive K+ channel copurify and coreconstitute to form a functioning signaling module in proteoliposomes". Circulation Research. 99 (8): 878–83. doi:10.1161/01.RES.0000245106.80628.d3. PMID 16960097.
- ↑ Costa AD, Garlid KD (Aug 2008). "Intramitochondrial signaling: interactions among mitoKATP, PKCepsilon, ROS, and MPT". American Journal of Physiology. Heart and Circulatory Physiology. 295 (2): H874–82. doi:10.1152/ajpheart.01189.2007. PMC 2519212. PMID 18586884.
- ↑ Waza AA, Andrabi K, Hussain MU (Sep 2014). "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". Cellular Signalling. 26 (9): 1909–17. doi:10.1016/j.cellsig.2014.05.002. PMID 24815185.
- ↑ Budas G, Costa HM, Ferreira JC, Teixeira da Silva Ferreira A, Perales J, Krieger JE, Mochly-Rosen D, Schechtman D (2012). "Identification of εPKC targets during cardiac ischemic injury". Circulation Journal. 76 (6): 1476–85. doi:10.1253/circj.cj-11-1360. PMC 3527096. PMID 22453000.
- ↑ Pyle WG, Smith TD, Hofmann PA (Oct 2000). "Cardioprotection with kappa-opioid receptor stimulation is associated with a slowing of cross-bridge cycling". American Journal of Physiology. Heart and Circulatory Physiology. 279 (4): H1941–8. doi:10.1152/ajpheart.2000.279.4.H1941. PMID 11009483.
- ↑ Pyle WG, Chen Y, Hofmann PA (Sep 2003). "Cardioprotection through a PKC-dependent decrease in myofilament ATPase". American Journal of Physiology. Heart and Circulatory Physiology. 285 (3): H1220–8. doi:10.1152/ajpheart.00076.2003. PMID 12763745.
- ↑ Budas G, Costa HM, Ferreira JC, Teixeira da Silva Ferreira A, Perales J, Krieger JE, Mochly-Rosen D, Schechtman D (2012). "Identification of εPKC targets during cardiac ischemic injury". Circulation Journal. 76 (6): 1476–85. doi:10.1253/circj.cj-11-1360. PMC 3527096. PMID 22453000.
- ↑ Pyle WG, Hart MC, Cooper JA, Sumandea MP, de Tombe PP, Solaro RJ (Jun 2002). "Actin capping protein: an essential element in protein kinase signaling to the myofilaments". Circulation Research. 90 (12): 1299–306. doi:10.1161/01.res.0000024389.03152.22. PMID 12089068.
- ↑ Yang FH, Pyle WG (Mar 2012). "Reduced cardiac CapZ protein protects hearts against acute ischemia-reperfusion injury and enhances preconditioning". Journal of Molecular and Cellular Cardiology. 52 (3): 761–72. doi:10.1016/j.yjmcc.2011.11.013. PMID 22155006.
- ↑ Newton PM, Kim JA, McGeehan AJ, Paredes JP, Chu K, Wallace MJ, Roberts AJ, Hodge CW, Messing RO (Jun 2007). "Increased response to morphine in mice lacking protein kinase C epsilon". Genes, Brain, and Behavior. 6 (4): 329–38. doi:10.1111/j.1601-183X.2006.00261.x. PMC 4264050. PMID 16899053.
- ↑ Newton PM, Messing RO (Jan 2006). "Intracellular signaling pathways that regulate behavioral responses to ethanol". Pharmacology & Therapeutics. 109 (1–2): 227–37. doi:10.1016/j.pharmthera.2005.07.004. PMID 16102840.
- ↑ Lesscher HM, Wallace MJ, Zeng L, Wang V, Deitchman JK, McMahon T, Messing RO, Newton PM (Jul 2009). "Amygdala protein kinase C epsilon controls alcohol consumption". Genes, Brain, and Behavior. 8 (5): 493–9. doi:10.1111/j.1601-183X.2009.00485.x. PMC 2714877. PMID 19243450.
- ↑ "Entrez Gene: PRKCE protein kinase C, epsilon".
- ↑ Newton PM, Messing RO (Apr 2010). "The substrates and binding partners of protein kinase Cepsilon". The Biochemical Journal. 427 (2): 189–96. doi:10.1042/BJ20091302. PMC 2966297. PMID 20350291.
- ↑ 90.0 90.1 90.2 90.3 England K, Ashford D, Kidd D, Rumsby M (Jun 2002). "PKC epsilon is associated with myosin IIA and actin in fibroblasts". Cellular Signalling. 14 (6): 529–36. doi:10.1016/S0898-6568(01)00277-7. PMID 11897493.
- ↑ 91.0 91.1 Liedtke CM, Yun CH, Kyle N, Wang D (Jun 2002). "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". The Journal of Biological Chemistry. 277 (25): 22925–33. doi:10.1074/jbc.M201917200. PMID 11956211.
- ↑ Gannon-Murakami L, Murakami K (Jun 2002). "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". The Journal of Biological Chemistry. 277 (26): 23116–22. doi:10.1074/jbc.M201478200. PMID 11950841.
Further reading
- Newton PM, Messing RO (Apr 2010). "The substrates and binding partners of protein kinase Cepsilon". The Biochemical Journal. 427 (2): 189–96. doi:10.1042/BJ20091302. PMC 2966297. PMID 20350291.
- Slater SJ, Ho C, Stubbs CD (Jun 2002). "The use of fluorescent phorbol esters in studies of protein kinase C-membrane interactions". Chemistry and Physics of Lipids. 116 (1–2): 75–91. doi:10.1016/S0009-3084(02)00021-X. PMID 12093536.
- Aksoy E, Goldman M, Willems F (Feb 2004). "Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders". The International Journal of Biochemistry & Cell Biology. 36 (2): 183–8. doi:10.1016/S1357-2725(03)00210-3. PMID 14643884.
- Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (Apr 2004). "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178.
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