Biology:PRKCE

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 is 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 (RACK/RACK2) isoform; specifically, the C2 domain of PKCε at amino acids 14–21 (also known as εV1-2) binds (RACK/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 (RACK/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.[38]

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[40][41] and subsequent studies have identified the F0/F1 ATP synthase as a core inner mitochondrial membrane component[42][43][44][45] and Bax and Bak as potential outer membrane components[46] 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.[47] PKCε also interacts with Bax in cancer cells, and PKCε modulates its dimerization and function.[48][49] 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.[50] 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.[51] PKCε induction occurs in the development of cardiac hypertrophy, following stimuli such as myotrophin,[52] mechanical stretch and hypertension.[53] The precise role of PKCε in hypertrophic induction has been debated. The inhibition of PKCε during transition from hypertrophy to heart failure enhances longevity;[54] however, inhibition of PKCε translocation via a peptide inhibitor increases cardiomyocyte size and expression of hypertrophic gene panel.[55] 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.[56][57] PKCε also regulates CapZ dynamics following cyclic strain.[58]

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.[59] A later study unveiled that the aging of PKCε transgenic mice brought on dilated cardiomyopathy and heart failure by 12 months of age,[60]] characterized by a preserved Frank-Starling mechanism and exhausted contractile reserve.[61] 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.[62]

Cardioprotection against Ischemic injury

JM Downey was the first to introduce the role of PKC in cardioprotection against ischemia-reperfusion injury in 1994,;[63] 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][64] This finding was validated by multiple independent studies occurring shortly thereafter,[65][66] and has since been observed in multiple animal models[67][68][69] and human tissue,[70] as well as in studies employing transgenesis and PKCε activators/inhibitors.[71]

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.[72][73] Moreover, PKCε interacts with cytochrome c oxidase subunit IV (COIV), and preconditioning stimuli evoked phosphorylation of COIV and stabilization of COIV protein and activity.[74] The mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) also interacts with PKCε; phosphorylation of mitoK(ATP) following preconditioning stimuli potentiates channel opening.[75][76] PKCε modulates the interaction between subunit Kir6.1 of mitoK(ATP) and connexin-43, whose interaction confers cardioprotection.[77] 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.[50]

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.[78][79] Activation of PKCε by εRACK prior to ischemia was also found to phosphorylate Ventricular myosin light chain-2,[50] however the functional significance remains elusive. Actin-capping protein, CapZ appears to affect the localization of PKCε to Z-lines[80] and modulates the cardiomyocyte response to ischemic injury. Cardioprotection in mice with reduction of CapZ showed enhancement in PKCε translocation to sarcomeres,[81] 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[82] and alcohol.[83][84] It also plays a role lipopolysaccharide (LPS)-mediated signaling in activated macrophages and in controlling anxiety-like behavior.[85]

Substrates and interactions

PKC-epsilon has a wide variety of substrates, including ion channels, other signalling molecules and cytoskeletal proteins.[86]

PKC-epsilon has been shown to interact with:


See also

Notes

References

  1. ↑ "Sequence and expression of human protein kinase C-epsilon". Biochimica et Biophysica Acta 1132 (2): 154–60. Sep 1992. doi:10.1016/0167-4781(92)90006-l. PMID 1382605. 
  2. ↑ "Protein kinase C epsilon is localized to the Golgi via its zinc-finger domain and modulates Golgi function". Proceedings of the National Academy of Sciences of the United States of America 92 (5): 1406–10. Feb 1995. doi:10.1073/pnas.92.5.1406. PMID 7877991. 
  3. ↑ "Protein kinase C--a question of specificity". Trends in Biochemical Sciences 19 (2): 73–7. Feb 1994. doi:10.1016/0968-0004(94)90038-8. PMID 8160269. 
  4. ↑ "Protein kinase C isoform expression and regulation in the developing rat heart". Circulation Research 74 (2): 299–309. Feb 1994. doi:10.1161/01.res.74.2.299. PMID 8293569. 
  5. ↑ 5.0 5.1 5.2 5.3 "Localization of protein kinase C isozymes in cardiac myocytes". Experimental Cell Research 210 (2): 287–97. Feb 1994. doi:10.1006/excr.1994.1041. PMID 8299726. 
  6. ↑ "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". Circulation Research 72 (4): 757–67. Apr 1993. doi:10.1161/01.res.72.4.757. PMID 8443867. 
  7. ↑ "Differential regulation of protein kinase C isoforms in isolated neonatal and adult rat cardiomyocytes". The Journal of Biological Chemistry 269 (24): 16938–44. Jun 1994. doi:10.1016/S0021-9258(19)89480-2. PMID 8207017. 
  8. ↑ 8.0 8.1 "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". Circulation Research 81 (3): 404–14. Sep 1997. doi:10.1161/01.res.81.3.404. PMID 9285643. 
  9. ↑ 9.0 9.1 "Protein kinase C-epsilon (PKC-epsilon): its unique structure and function". Journal of Biochemistry 132 (6): 847–52. Dec 2002. doi:10.1093/oxfordjournals.jbchem.a003296. PMID 12473185. 
  10. ↑ "Distinct effects of fatty acids on translocation of gamma- and epsilon-subspecies of protein kinase C". The Journal of Cell Biology 143 (2): 511–21. Oct 1998. doi:10.1083/jcb.143.2.511. PMID 9786959. 
  11. ↑ "Localization of protein kinases by anchoring proteins: a theme in signal transduction". Science 268 (5208): 247–51. Apr 1995. doi:10.1126/science.7716516. PMID 7716516. Bibcode: 1995Sci...268..247M. 
  12. ↑ "A protein kinase C translocation inhibitor as an isozyme-selective antagonist of cardiac function". The Journal of Biological Chemistry 271 (40): 24962–6. Oct 1996. doi:10.1074/jbc.271.40.24962. PMID 8798776. 
  13. ↑ "Sustained in vivo cardiac protection by a rationally designed peptide that causes epsilon protein kinase C translocation". Proceedings of the National Academy of Sciences of the United States of America 96 (22): 12798–803. Oct 1999. doi:10.1073/pnas.96.22.12798. PMID 10536002. 
  14. ↑ "PKCepsilon activation induces dichotomous cardiac phenotypes and modulates PKCepsilon-RACK interactions and RACK expression". American Journal of Physiology. Heart and Circulatory Physiology 280 (3): H946–55. Mar 2001. doi:10.1152/ajpheart.2001.280.3.H946. PMID 11179034. 
  15. ↑ "Protein kinase C: poised to signal". American Journal of Physiology. Endocrinology and Metabolism 298 (3): E395–402. Mar 2010. doi:10.1152/ajpendo.00477.2009. PMID 19934406. 
  16. ↑ "Localization and kinetics of protein kinase C-epsilon anchoring in cardiac myocytes". Biophysical Journal 80 (5): 2140–51. May 2001. doi:10.1016/S0006-3495(01)76187-5. PMID 11325717. Bibcode: 2001BpJ....80.2140R. 
  17. ↑ "Arachidonic acid stimulates protein kinase C-epsilon redistribution in heart cells". Journal of Cell Science 110 (14): 1625–34. Jul 1997. doi:10.1242/jcs.110.14.1625. PMID 9247196. 
  18. ↑ "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". The Journal of Biological Chemistry 269 (52): 32848–57. Dec 1994. doi:10.1016/S0021-9258(20)30069-7. PMID 7806510. 
  19. ↑ "The MLCK-mediated alpha1-adrenergic inotropic effect in atrial myocardium is negatively modulated by PKCepsilon signaling". British Journal of Pharmacology 148 (7): 991–1000. Aug 2006. doi:10.1038/sj.bjp.0706803. PMID 16783412. 
  20. ↑ "Left ventricular stretch stimulates angiotensin II--mediated phosphatidylinositol hydrolysis and protein kinase C epsilon isoform translocation in adult guinea pig hearts". Circulation Research 81 (5): 643–50. Nov 1997. doi:10.1161/01.res.81.5.643. PMID 9351436. 
  21. ↑ "Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1823 (4): 950–8. Apr 2012. doi:10.1016/j.bbamcr.2011.12.012. PMID 22233927. 
  22. ↑ "HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection". Journal of Molecular and Cellular Cardiology 66: 157–64. Jan 2014. doi:10.1016/j.yjmcc.2013.11.010. PMID 24269490. 
  23. ↑ "Effect of mitochondrial ATP-sensitive potassium channel opening on the translocation of protein kinase C epsilon in adult rat ventricular myocytes". Genetics and Molecular Research 13 (2): 4516–22. 17 June 2014. doi:10.4238/2014.June.17.3. PMID 25036356. 
  24. ↑ "Apelin increases cardiac contractility via protein kinase Cε- and extracellular signal-regulated kinase-dependent mechanisms". PLOS ONE 9 (4): e93473. 2014. doi:10.1371/journal.pone.0093473. PMID 24695532. Bibcode: 2014PLoSO...993473P. 
  25. ↑ "Myofilament anchoring of protein kinase C-epsilon in cardiac myocytes". Journal of Cell Science 117 (Pt 10): 1971–8. Apr 2004. doi:10.1242/jcs.01044. PMID 15039458. 
  26. ↑ "Localization of the transmembrane proteoglycan syndecan-4 and its regulatory kinases in costameres of rat cardiomyocytes: a deconvolution microscopic study". The Anatomical Record 268 (1): 38–46. Sep 2002. doi:10.1002/ar.10130. PMID 12209563. 
  27. ↑ "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". The Journal of Cell Biology 132 (1–2): 77–90. Jan 1996. doi:10.1083/jcb.132.1.77. PMID 8567732. 
  28. ↑ "Protein kinase Cepsilon actin-binding site is important for neurite outgrowth during neuronal differentiation". Molecular Biology of the Cell 13 (1): 12–24. Jan 2002. doi:10.1091/mbc.01-04-0210. PMID 11809819. 
  29. ↑ 29.0 29.1 29.2 29.3 "Functional proteomic analysis of protein kinase C epsilon signaling complexes in the normal heart and during cardioprotection". Circulation Research 88 (1): 59–62. Jan 2001. doi:10.1161/01.res.88.1.59. PMID 11139474. 
  30. ↑ "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". The Journal of Biological Chemistry 271 (38): 23277–83. Sep 1996. doi:10.1074/jbc.271.38.23277. PMID 8798526. 
  31. ↑ "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". Biochemistry 35 (47): 14923–31. Nov 1996. doi:10.1021/bi9616357. PMID 8942657. 
  32. ↑ "Cardiac troponin I mutants. Phosphorylation by protein kinases C and A and regulation of Ca(2+)-stimulated MgATPase of reconstituted actomyosin S-1". The Journal of Biological Chemistry 270 (43): 25445–54. Oct 1995. doi:10.1074/jbc.270.43.25445. PMID 7592712. 
  33. ↑ "Phosphorylation or glutamic acid substitution at protein kinase C sites on cardiac troponin I differentially depress myofilament tension and shortening velocity". The Journal of Biological Chemistry 278 (13): 11265–72. Mar 2003. doi:10.1074/jbc.M210712200. PMID 12551921. 
  34. ↑ "New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1833 (4): 823–32. Apr 2013. doi:10.1016/j.bbamcr.2012.08.012. PMID 22940544. 
  35. ↑ "Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo". American Journal of Physiology. Heart and Circulatory Physiology 286 (6): H2089–95. Jun 2004. doi:10.1152/ajpheart.00582.2003. PMID 14726296. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 "Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria". Circulation Research 92 (8): 873–80. May 2003. doi:10.1161/01.RES.0000069215.36389.8D. PMID 12663490. 
  37. ↑ "Protein kinase C epsilon signaling complexes include metabolism- and transcription/translation-related proteins: complimentary [sic] separation techniques with LC/MS/MS". Molecular & Cellular Proteomics 1 (6): 421–33. Jun 2002. doi:10.1074/mcp.m100036-mcp200. PMID 12169683. 
  38. ↑ 38.0 38.1 "Mitochondrial import of PKCepsilon is mediated by HSP90: a role in cardioprotection from ischaemia and reperfusion injury". Cardiovascular Research 88 (1): 83–92. Oct 2010. doi:10.1093/cvr/cvq154. PMID 20558438. 
  39. ↑ "Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1823 (4): 950–958. Apr 2012. doi:10.1016/j.bbamcr.2011.12.012. PMID 22233927. 
  40. ↑ "The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore". Nature 427 (6973): 461–5. Jan 2004. doi:10.1038/nature02229. PMID 14749836. Bibcode: 2004Natur.427..461K. 
  41. ↑ "Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death". Nature Cell Biology 9 (5): 550–5. May 2007. doi:10.1038/ncb1575. PMID 17417626. 
  42. ↑ "Dimers of mitochondrial ATP synthase form the permeability transition pore". Proceedings of the National Academy of Sciences of the United States of America 110 (15): 5887–92. Apr 2013. doi:10.1073/pnas.1217823110. PMID 23530243. Bibcode: 2013PNAS..110.5887G. 
  43. ↑ "Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition". Cell Cycle 12 (4): 674–83. Feb 2013. doi:10.4161/cc.23599. PMID 23343770. 
  44. ↑ "An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore". Proceedings of the National Academy of Sciences of the United States of America 111 (29): 10580–5. Jul 2014. doi:10.1073/pnas.1401591111. PMID 24979777. Bibcode: 2014PNAS..11110580A. 
  45. ↑ "The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection". Journal of Molecular and Cellular Cardiology 78: 100–6. Jan 2015. doi:10.1016/j.yjmcc.2014.09.023. PMID 25268651. 
  46. ↑ "Bax and Bak function as the outer membrane component of the mitochondrial permeability pore in regulating necrotic cell death in mice". eLife 2: e00772. 27 August 2013. doi:10.7554/eLife.00772. PMID 23991283. 
  47. ↑ "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. Mar 2002. doi:10.1161/01.res.0000012702.90501.8d. PMID 11884367. 
  48. ↑ "Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells". Oncogene 22 (39): 7958–68. Sep 2003. doi:10.1038/sj.onc.1206795. PMID 12970744. 
  49. ↑ "Protein kinase C-epsilon protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation". Apoptosis 12 (10): 1893–900. Oct 2007. doi:10.1007/s10495-007-0111-7. PMID 17668322. 
  50. ↑ 50.0 50.1 50.2 "Identification of εPKC targets during cardiac ischemic injury". Circulation Journal 76 (6): 1476–85. 2012. doi:10.1253/circj.cj-11-1360. PMID 22453000. 
  51. ↑ "Protein kinase C alpha and epsilon phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium". Basic Research in Cardiology 105 (2): 289–300. Mar 2010. doi:10.1007/s00395-009-0053-z. PMID 19655190. 
  52. ↑ "Increased protein kinase C activity in myotrophin-induced myocyte growth". Circulation Research 82 (11): 1173–88. Jun 1998. doi:10.1161/01.res.82.11.1173. PMID 9633917. 
  53. ↑ "Tissue angiotensin II during progression or ventricular hypertrophy to heart failure in hypertensive rats; differential effects on PKC epsilon and PKC beta". Journal of Molecular and Cellular Cardiology 34 (10): 1377–85. Oct 2002. doi:10.1016/s0022-2828(02)92089-4. PMID 12392998. 
  54. ↑ "Pharmacological inhibition of epsilon-protein kinase C attenuates cardiac fibrosis and dysfunction in hypertension-induced heart failure". Hypertension 51 (6): 1565–9. Jun 2008. doi:10.1161/HYPERTENSIONAHA.107.109637. PMID 18413490. 
  55. ↑ "Cardiotrophic effects of protein kinase C epsilon: analysis by in vivo modulation of PKCepsilon translocation". Circulation Research 86 (11): 1173–9. Jun 2000. doi:10.1161/01.res.86.11.1173. PMID 10850970. 
  56. ↑ "Activation of focal adhesion kinase by protein kinase C epsilon in neonatal rat ventricular myocytes". American Journal of Physiology. Heart and Circulatory Physiology 285 (4): H1684–96. Oct 2003. doi:10.1152/ajpheart.00016.2003. PMID 12829427. 
  57. ↑ "Restoration of resting sarcomere length after uniaxial static strain is regulated by protein kinase Cepsilon and focal adhesion kinase". Circulation Research 94 (5): 642–9. Mar 2004. doi:10.1161/01.RES.0000121101.32286.C8. PMID 14963000. 
  58. ↑ "Cyclic mechanical strain of myocytes modifies CapZβ1 post translationally via PKCε". Journal of Muscle Research and Cell Motility 36 (4–5): 329–37. Oct 2015. doi:10.1007/s10974-015-9420-6. PMID 26429793. 
  59. ↑ "Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy". Circulation Research 86 (12): 1218–23. Jun 2000. doi:10.1161/01.res.86.12.1218. PMID 10864911. 
  60. ↑ "Protein kinase Cepsilon overexpression alters myofilament properties and composition during the progression of heart failure". Circulation Research 95 (4): 424–32. Aug 2004. doi:10.1161/01.RES.0000138299.85648.92. PMID 15242976. 
  61. ↑ "Protein kinase C epsilon induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism". American Journal of Physiology. Heart and Circulatory Physiology 289 (5): H1881–8. Nov 2005. doi:10.1152/ajpheart.00454.2005. PMID 15951344. 
  62. ↑ "Partial replacement of cardiac troponin I with a non-phosphorylatable mutant at serines 43/45 attenuates the contractile dysfunction associated with PKCepsilon phosphorylation". Journal of Molecular and Cellular Cardiology 40 (4): 465–73. Apr 2006. doi:10.1016/j.yjmcc.2005.12.009. PMID 16445938. 
  63. ↑ "Preconditioning protects ischemic rabbit heart by protein kinase C activation". The American Journal of Physiology 266 (3 Pt 2): H1145–52. Mar 1994. doi:10.1152/ajpheart.1994.266.3.H1145. PMID 8160817. 
  64. ↑ "The nitric oxide hypothesis of late preconditioning". Basic Research in Cardiology 93 (5): 325–38. Oct 1998. doi:10.1007/s003950050101. PMID 9833145. 
  65. ↑ "A selective epsilon-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death". The Journal of Biological Chemistry 272 (49): 30945–51. Dec 1997. doi:10.1074/jbc.272.49.30945. PMID 9388241. 
  66. ↑ "Protein kinase C-epsilon is responsible for the protection of preconditioning in rabbit cardiomyocytes". Journal of Molecular and Cellular Cardiology 31 (10): 1937–48. Oct 1999. doi:10.1006/jmcc.1999.1026. PMID 10525430. 
  67. ↑ "Delayed cardioprotection is associated with the sub-cellular relocalisation of ventricular protein kinase C epsilon, but not p42/44MAPK". Molecular and Cellular Biochemistry 160–161: 225–30. 1996. doi:10.1007/bf00240053. PMID 8901477. 
  68. ↑ "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. Dec 1998. doi:10.1152/ajpheart.1998.275.6.H2266. PMID 9843828. 
  69. ↑ "Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C". Circulation Research 87 (4): 309–15. Aug 2000. doi:10.1161/01.res.87.4.309. PMID 10948065. 
  70. ↑ "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. Nov 2004. doi:10.1152/ajpcell.00144.2004. PMID 15294852. 
  71. ↑ "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. Feb 2004. doi:10.1016/j.yjmcc.2003.12.001. PMID 14871559. 
  72. ↑ "Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart". Science 321 (5895): 1493–5. Sep 2008. doi:10.1126/science.1158554. PMID 18787169. Bibcode: 2008Sci...321.1493C. 
  73. ↑ "Getting to the heart of proteomics". The New England Journal of Medicine 360 (5): 532–4. Jan 2009. doi:10.1056/NEJMcibr0808487. PMID 19179323. 
  74. ↑ "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. Jan 2006. doi:10.1042/BJ20050757. PMID 16336199. 
  75. ↑ "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. Oct 2006. doi:10.1161/01.RES.0000245106.80628.d3. PMID 16960097. 
  76. ↑ "Intramitochondrial signaling: interactions among mitoKATP, PKCepsilon, ROS, and MPT". American Journal of Physiology. Heart and Circulatory Physiology 295 (2): H874–82. Aug 2008. doi:10.1152/ajpheart.01189.2007. PMID 18586884. 
  77. ↑ "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. Sep 2014. doi:10.1016/j.cellsig.2014.05.002. PMID 24815185. 
  78. ↑ "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. Oct 2000. doi:10.1152/ajpheart.2000.279.4.H1941. PMID 11009483. 
  79. ↑ "Cardioprotection through a PKC-dependent decrease in myofilament ATPase". American Journal of Physiology. Heart and Circulatory Physiology 285 (3): H1220–8. Sep 2003. doi:10.1152/ajpheart.00076.2003. PMID 12763745. 
  80. ↑ "Actin capping protein: an essential element in protein kinase signaling to the myofilaments". Circulation Research 90 (12): 1299–306. Jun 2002. doi:10.1161/01.res.0000024389.03152.22. PMID 12089068. 
  81. ↑ "Reduced cardiac CapZ protein protects hearts against acute ischemia-reperfusion injury and enhances preconditioning". Journal of Molecular and Cellular Cardiology 52 (3): 761–72. Mar 2012. doi:10.1016/j.yjmcc.2011.11.013. PMID 22155006. 
  82. ↑ "Increased response to morphine in mice lacking protein kinase C epsilon". Genes, Brain and Behavior 6 (4): 329–38. Jun 2007. doi:10.1111/j.1601-183X.2006.00261.x. PMID 16899053. 
  83. ↑ "Intracellular signaling pathways that regulate behavioral responses to ethanol". Pharmacology & Therapeutics 109 (1–2): 227–37. Jan 2006. doi:10.1016/j.pharmthera.2005.07.004. PMID 16102840. 
  84. ↑ "Amygdala protein kinase C epsilon controls alcohol consumption". Genes, Brain and Behavior 8 (5): 493–9. Jul 2009. doi:10.1111/j.1601-183X.2009.00485.x. PMID 19243450. 
  85. ↑ "Entrez Gene: PRKCE protein kinase C, epsilon". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5581. 
  86. ↑ "The substrates and binding partners of protein kinase Cepsilon". The Biochemical Journal 427 (2): 189–96. Apr 2010. doi:10.1042/BJ20091302. PMID 20350291. 
  87. ↑ 87.0 87.1 87.2 87.3 "PKC epsilon is associated with myosin IIA and actin in fibroblasts". Cellular Signalling 14 (6): 529–36. Jun 2002. doi:10.1016/S0898-6568(01)00277-7. PMID 11897493. 
  88. ↑ 88.0 88.1 "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. Jun 2002. doi:10.1074/jbc.M201917200. PMID 11956211. 
  89. ↑ "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. Jun 2002. doi:10.1074/jbc.M201478200. PMID 11950841. 

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: Q02156 (Protein kinase C epsilon type) at the PDBe-KB.



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