Jump to content

PRKCE

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by HeartBD2K Scruggssb (talk | contribs) at 23:11, 1 January 2016 (→‎Clinical significance). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Template:PBB 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, protein 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.[10][11]

Receptors for activated C-kinase (RACK) have been found to anchor active PKC in close proximity to substrates.[12] 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[13], while peptide agonists augment translocation.[14] It has been demonstrated that altering the dynamics of the RACK2 and RACK1 interaction with PKCε can influence cardiac muscle phenotypes.[15]

Activated PKCε translocates to various intracellular targets.[16][17] In cardiac muscle, PKCε translocates to sarcomeres at Z-lines following α-adrenergic and endothelin (ET)A-receptor stimulation.[18][19] 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;[20]arachidonic acid;[21]ET-1 and phenylephrine;[22][23] angiotensin II and diastolic stretch;[24] adenosine;[25] hypoxia and Akt-induced stem cell factor;[26] ROS generated via pharmacologic activation of the mitochondrial potassium-sensitive ATP channel (mitoK(ATP))[27] and the endogenous G-protein coupled receptor ligand, apelin.[28]

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.

Role in 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;[29] PKCε also binds at costameres to syndecan-4.[30] PKCε has been shown to bind F-actin in neurons, which modulates synaptic function and differentiation;[31][32] however it is unknown whether PKCε binds sarcomeric actin in muscle cells.

PKCε binds and phosphorylates cardiac troponin I (cTnI) and cardiac troponin T (cTnT) in complex with troponin C (cTnC);[33] phosphorylation on cTnI at residues Serine-43, Serine-45, and Threonine-144 cause depression of actomyosin S1 MgATPase function.[34][35] 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.[36] Phosphorylation on cTnI at Serine-5/6 also showed this depressive effect.[37] Further support was gained from in vivo studies in which mice expressing a mutant cTnI (Serine43/45Alanine) exhibited enhanced cardiac contractility.[38]

Clinical significance

Studies of PKCε phosphorylation in mouse have been verified in human cardiac fibers, where PKCε has been shown to phosphorylate cTnI, cTnT and myosin binding protein-C (MyBPC), which decreases myofilament calcium sensitivity (Kooij et al., 2010) [PMID 19655190].

Knockout and molecular studies in mice suggest that this kinase is important for regulating behavioural response to morphine[39] and alcohol.[40][41] It also plays a role lipopolysaccharide (LPS)-mediated signaling in activated macrophages and in controlling anxiety-like behavior.[42]

Substrates and interactions

PKC-epsilon has a wide variety of substrates, including ion channels, other signalling molecules and cytoskeletal proteins.[43]

PKC-epsilon has been shown to interact with:

See also

References

  1. ^ Basta P, Strickland MB, Holmes W, Loomis CR, Ballas LM, Burns DJ (Sep 1992). "Sequence and expression of human protein kinase C-epsilon". Biochimica Et Biophysica Acta. 1132 (2): 154–60. doi:10.1016/0167-4781(92)90006-l. PMID 1382605.
  2. ^ Lehel C, Olah Z, Jakab G, Anderson WB (Feb 1995). "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. doi:10.1073/pnas.92.5.1406. PMC 42528. PMID 7877991.
  3. ^ Dekker, LV; Parker, PJ (February 1994). "Protein kinase C--a question of specificity". Trends in biochemical sciences. 19 (2): 73–7. PMID 8160269.
  4. ^ Rybin, VO; Steinberg, SF (February 1994). "Protein kinase C isoform expression and regulation in the developing rat heart". Circulation research. 74 (2): 299–309. PMID 8293569.
  5. ^ Disatnik, MH; Buraggi, G; Mochly-Rosen, D (February 1994). "Localization of protein kinase C isozymes in cardiac myocytes". Experimental cell research. 210 (2): 287–97. PMID 8299726.
  6. ^ Bogoyevitch, MA; Parker, PJ; Sugden, PH (April 1993). "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. PMID 8443867.
  7. ^ Pucéat, M; Hilal-Dandan, R; Strulovici, B; Brunton, LL; Brown, JH (17 June 1994). "Differential regulation of protein kinase C isoforms in isolated neonatal and adult rat cardiomyocytes". The Journal of biological chemistry. 269 (24): 16938–44. PMID 8207017.
  8. ^ Ping, P; Zhang, J; Qiu, Y; Tang, XL; Manchikalapudi, S; Cao, X; Bolli, R (September 1997). "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. PMID 9285643.
  9. ^ Akita, Y (December 2002). "Protein kinase C-epsilon (PKC-epsilon): its unique structure and function". Journal of biochemistry. 132 (6): 847–52. PMID 12473185.
  10. ^ Shirai, Y; Kashiwagi, K; Yagi, K; Sakai, N; Saito, N (19 October 1998). "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. PMID 9786959.
  11. ^ Disatnik, MH; Buraggi, G; Mochly-Rosen, D (February 1994). "Localization of protein kinase C isozymes in cardiac myocytes". Experimental cell research. 210 (2): 287–97. PMID 8299726.
  12. ^ Mochly-Rosen, D (14 April 1995). "Localization of protein kinases by anchoring proteins: a theme in signal transduction". Science (New York, N.Y.). 268 (5208): 247–51. PMID 7716516.
  13. ^ Johnson, JA; Gray, MO; Chen, CH; Mochly-Rosen, D (4 October 1996). "A protein kinase C translocation inhibitor as an isozyme-selective antagonist of cardiac function". The Journal of biological chemistry. 271 (40): 24962–6. PMID 8798776.
  14. ^ Dorn GW, 2nd; Souroujon, MC; Liron, T; Chen, CH; Gray, MO; Zhou, HZ; Csukai, M; Wu, G; Lorenz, JN; Mochly-Rosen, D (26 October 1999). "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. PMID 10536002.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  15. ^ Pass, JM; Zheng, Y; Wead, WB; Zhang, J; Li, RC; Bolli, R; Ping, P (March 2001). "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. PMID 11179034.
  16. ^ Akita, Y (December 2002). "Protein kinase C-epsilon (PKC-epsilon): its unique structure and function". Journal of biochemistry. 132 (6): 847–52. PMID 12473185.
  17. ^ Newton, AC (March 2010). "Protein kinase C: poised to signal". American journal of physiology. Endocrinology and metabolism. 298 (3): E395-402. PMID 19934406.
  18. ^ Robia, SL; Ghanta, J; Robu, VG; Walker, JW (May 2001). "Localization and kinetics of protein kinase C-epsilon anchoring in cardiac myocytes". Biophysical journal. 80 (5): 2140–51. PMID 11325717.
  19. ^ Disatnik, MH; Buraggi, G; Mochly-Rosen, D (February 1994). "Localization of protein kinase C isozymes in cardiac myocytes". Experimental cell research. 210 (2): 287–97. PMID 8299726.
  20. ^ Disatnik, MH; Buraggi, G; Mochly-Rosen, D (February 1994). "Localization of protein kinase C isozymes in cardiac myocytes". Experimental cell research. 210 (2): 287–97. PMID 8299726.
  21. ^ Huang, XP; Pi, Y; Lokuta, AJ; Greaser, ML; Walker, JW (July 1997). "Arachidonic acid stimulates protein kinase C-epsilon redistribution in heart cells". Journal of cell science. 110 ( Pt 14): 1625–34. PMID 9247196.
  22. ^ Clerk, A; Bogoyevitch, MA; Anderson, MB; Sugden, PH (30 December 1994). "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. PMID 7806510.
  23. ^ Grimm, M; Mahnecke, N; Soja, F; El-Armouche, A; Haas, P; Treede, H; Reichenspurner, H; Eschenhagen, T (August 2006). "The MLCK-mediated alpha1-adrenergic inotropic effect in atrial myocardium is negatively modulated by PKCepsilon signaling". British journal of pharmacology. 148 (7): 991–1000. PMID 16783412.
  24. ^ Paul, K; Ball, NA; Dorn GW, 2nd; Walsh, RA (November 1997). "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. PMID 9351436.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  25. ^ Yang, Z; Sun, W; Hu, K (April 2012). "Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C.". Biochimica et biophysica acta. 1823 (4): 950–8. PMID 22233927.
  26. ^ Huang, J; Guo, J; Beigi, F; Hodgkinson, CP; Facundo, HT; Zhang, Z; Espinoza-Derout, J; Zhou, X; Pratt, RE; Mirotsou, M; Dzau, VJ (January 2014). "HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection". Journal of molecular and cellular cardiology. 66: 157–64. PMID 24269490.
  27. ^ Li, H; Yang, T; Long, Z; Cheng, J (17 June 2014). "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 : GMR. 13 (2): 4516–22. PMID 25036356.
  28. ^ Perjés, Á; Skoumal, R; Tenhunen, O; Kónyi, A; Simon, M; Horváth, IG; Kerkelä, R; Ruskoaho, H; Szokodi, I (2014). "Apelin increases cardiac contractility via protein kinase Cε- and extracellular signal-regulated kinase-dependent mechanisms". PloS one. 9 (4): e93473. PMID 24695532.
  29. ^ Huang, X; Walker, JW (15 April 2004). "Myofilament anchoring of protein kinase C-epsilon in cardiac myocytes". Journal of cell science. 117 (Pt 10): 1971–8. PMID 15039458.
  30. ^ VanWinkle, WB; Snuggs, MB; De Hostos, EL; Buja, LM; Woods, A; Couchman, JR (1 September 2002). "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. PMID 12209563.
  31. ^ Prekeris, R; Mayhew, MW; Cooper, JB; Terrian, DM (January 1996). "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. PMID 8567732.
  32. ^ Zeidman, R; Trollér, U; Raghunath, A; Påhlman, S; Larsson, C (January 2002). "Protein kinase Cepsilon actin-binding site is important for neurite outgrowth during neuronal differentiation". Molecular biology of the cell. 13 (1): 12–24. PMID 11809819.
  33. ^ Jideama, NM; Noland TA, Jr; Raynor, RL; Blobe, GC; Fabbro, D; Kazanietz, MG; Blumberg, PM; Hannun, YA; Kuo, JF (20 September 1996). "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. PMID 8798526.
  34. ^ Noland TA, Jr; Raynor, RL; Jideama, NM; Guo, X; Kazanietz, MG; Blumberg, PM; Solaro, RJ; Kuo, JF (26 November 1996). "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. PMID 8942657.
  35. ^ Noland TA, Jr; Guo, X; Raynor, RL; Jideama, NM; Averyhart-Fullard, V; Solaro, RJ; Kuo, JF (27 October 1995). "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. PMID 7592712.
  36. ^ Burkart, EM; Sumandea, MP; Kobayashi, T; Nili, M; Martin, AF; Homsher, E; Solaro, RJ (28 March 2003). "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. PMID 12551921.
  37. ^ Henze, M; Patrick, SE; Hinken, A; Scruggs, SB; Goldspink, P; de Tombe, PP; Kobayashi, M; Ping, P; Kobayashi, T; Solaro, RJ (April 2013). "New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I.". Biochimica et biophysica acta. 1833 (4): 823–32. PMID 22940544.
  38. ^ Roman, BB; Goldspink, PH; Spaite, E; Urboniene, D; McKinney, R; Geenen, DL; Solaro, RJ; Buttrick, PM (June 2004). "Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo". American journal of physiology. Heart and circulatory physiology. 286 (6): H2089-95. PMID 14726296.
  39. ^ 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. PMID 16899053.
  40. ^ 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.
  41. ^ Amygdala protein kinase C epsilon controls alcohol consumption http://www3.interscience.wiley.com/journal/122210376/abstract
  42. ^ "Entrez Gene: PRKCE protein kinase C, epsilon".
  43. ^ 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.
  44. ^ a b c d 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.
  45. ^ a b 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  46. ^ Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P (May 2003). "Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria". Circulation Research. 92 (8): 873–80. doi:10.1161/01.RES.0000069215.36389.8D. PMID 12663490.
  47. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)

Further reading


Stub icon

This article on a gene on human chromosome 2 is a stub. You can help Wikipedia by expanding it.

Retrieved from "https://en.wikipedia.org/w/index.php?title=PRKCE&oldid=697789128"