Open Access Articles- Top Results for PKC alpha

PKC alpha

SymbolsPRKCA ; AAG6; PKC-alpha; PKCA; PRKACA
External IDsOMIM176960 HomoloGene55679 IUPHAR: 1482 ChEMBL: 299 GeneCards: PRKCA Gene
EC number2.7.11.13
RefSeq (mRNA)NM_002737NM_011101
RefSeq (protein)NP_002728NP_035231
Location (UCSC)Chr 17:
64.3 – 64.81 Mb
Chr 11:
107.93 – 108.34 Mb
PubMed search[1][2]

Protein kinase C alpha (PKCα) is an enzyme that in humans is encoded by the PRKCA gene.


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 reported to play roles in many different cellular processes, such as cell adhesion, cell transformation, cell cycle checkpoint, and cell volume control. Knockout studies in mice suggest that this kinase may be a fundamental regulator of cardiac contractility and Ca2+ handling in myocytes.[1]

Protein kinase C-alpha (PKC-α) is a specific member of the protein kinase family. These enzymes are characterized by their ability to add a phosphate group to other proteins, thus changing their function. PKC-α has been widely studied in the tissues of many organisms including drosophila, xenopus, cow, dog, chicken, human, monkey, mouse, pig, and rabbit. Many studies are currently being conducted investigating the structure, function, and regulation of this enzyme. The most recent investigations concerning this enzyme include its general regulation, hepatic function, and cardiac function.


PKC-α is unique in its mode of regulation compared to other kinases within this family. In general, the protein kinase family is regulated by allosteric regulation, the binding of a modulating molecule that effects a conformational change in the enzyme and thus a change in the enzyme’s activity. The primary mode of PKC-α’s regulation, however, involves its interaction with the cell membrane, not direct interaction with specific molecules.[2] The cell membrane consists of phospholipids. At warmer temperatures, phospholipids exist in a more fluid state as a result of increased intramolecular motion. The more fluid the cell membrane, the greater PKC-α’s activity. At cooler temperatures, phospholipids are found in a solid state with constricted motion. As phospholipids become stationary, they assume a particular orientation within the membrane. Phospholipids that solidify at an irregular or angled orientation with respect to the membrane, can reduce PKC-α’s activity.[2]

The composition of the cell membrane can also affect PKC-α’s function. The presence of calcium ions, magnesium ions, and diacylglycerols (DAGs) are the most important because they influence the hydrophobic domain of the membrane. Varying concentrations of these three components constitute a longer or shorter length of the hydrophobic domain. Membranes with long hydrophobic domains result in decreased activity because it is harder for PKC-α to insert into the membrane. At low concentrations, the hydrophobic domain is shorter allowing PKC-α to readily insert into the membrane and its activity increases.[2]

File:Dioctanoyl glycerol.svg
Example of DAG Regulator, long carbon-hydrogen tails increase the hydrophobic domain of the cell membrane and decrease PKC-α’s activity

Secondary structure

Using infrared spectroscopy techniques, researchers have demonstrated that the secondary structure of PKC alpha consists of around 44% beta sheets and nearly 22% alpha helices at 20°C.[3] Upon addition of calcium ions, a slight increase in beta sheets to 48% was observed. Additional ligands normally associated with PKC alpha, such as PMA, ATP, and phospholipids had no effect on secondary structure.[3]

The structure of PKC alpha was better preserved during denaturation of the enzyme at 75°C in the presence of calcium ions than in their absence. In one study, beta sheet composition only decreased by 13% with calcium ions present compared to 19% when absent.[3]



Another field of research has indicated that PKC-α plays a vital role in epithelial tissue, the tissue that covers all external and internal surfaces of the body. Specifically, PKC-α is involved in altering the function of tight junctions. Tight junctions exist at the meeting point between two cells. Here, tight junctions fuse together to form an impermeable barrier to not only large molecules such as proteins, but also smaller molecules like water. This prevents foreign molecules from entering the cell and helps regulate the internal environment of the cell. Cells infected with certain types of epithelial cancer exhibit increased PKC-α activity. This is a result of a change in the shape of the cell membrane, particularly in the areas where tight junctions exists.[4] With greater activity of PKC-α, the tight junctions lose their ability to form a tight barrier.[5] This causes an increased leakiness of the tight junctions and thus movement of molecules into the cells. In intestinal areas, luminal growth factors are able to enter the cell and increase the rate of cell growth. This is thought to be a promotional event that may prolong certain epithelial cancers.

File:Pkc and tight junction.gif
PKC family of proteins and their role in tight junctions


Much of the research of PKC alpha pertaining to its role in liver tissue involves the effects of bile acids on the phosphorylation mechanism of the PKC family of proteins. Past research has affirmed that the bile acid CDCA inhibits the healthy glucagon response through a phosphorylation-related sequence. In related studies further testing the effects of CDCA on hepatocytes, CDCA was shown to have induced PKC translocation to the plasma membrane.[6] PKC alpha was favored in this process over PKC delta. The implications of this finding are that increased interaction between the glucagon receptor and PKC alpha could occur.[7]


PKC alpha is one of the lesser studied proteins of the PKC family because it is not highly regulated in the serious medical condition known as acute myocardial ischemia, which results from a lack of blood supply to the myocardium (heart muscle tissue). Recent research into the role of PKC alpha in cardiac tissue has indicated that it has an important role in stimulating hypertrophy. This was demonstrated by the ability of agonist-mediated hypertrophy to be stopped only as a result of the inhibition of PKC alpha in an experiment in situ. However, in further in vivo research using mice, the transgenic overexpression of PKC alpha showed no effect on cardiac growth, and the inhibition of PKC alpha showed no effect on hypertrophic response to increased cardiac pressure. On the contrary, research has shown that removing PKC alpha altogether improved the hearts ability to contract.[8]

In summary, research is pointing in the direction that PKC alpha’s role in cardiac tissue has more impact as a regulator of contractility than of hypertrophy. In another study, the binding peptides, RACK and others derived from PKC beta, were expressed in mouse hearts. The genetic code for these proteins are similar to those of all isoforms of the PKC family (alpha, beta, and gamma). As such, RACK and other proteins can regulate the expression of all PKC family proteins. In this particular study, however, only PKC alpha was affected. Again, overexpression caused decreased contractile performance, whereas inhibition saw increased performance.[8]

Memory and PTSD

The scientists led by neuroscientist Dominique de Quervain of the University of Basel in Switzerland used memory tests and DNA studies to conclude that people who carried a particular DNA signature in at least one copy of a gene that encodes protein kinase C alpha had stronger memory than their peers; and brain scans of people with the genetic signature show stronger brain activation in parts of the prefrontal cortex compared with those who lacked the genetic feature. The team looked at the Rwandan refuges who had survive the 1994 genocide and found that the risk of PTSD in the refugees with strong memory signature is twice of that in the refugees without the genetic signature.[9]

Cell membrane

File:Reaction scheme.GIF
Typical Reaction Scheme of PKC alpha

PKC-α shows important regulation of phospholipase D. Phospholipase D is located on the plasma membrane and is responsible for hydrolyzing phosphatidylcholine to phosphatidic acid and choline. Research has indicated that phospholipase D may play roles in tumorigenesis by altering cellular events such as invasion and migration. Point mutations at particular phenylalanine residues have shown to inhibit PKC-α’s ability to activate phospholipase D.[10] Current research is being conducted investigating PKC-α’s inhibitory affects. Researchers hope to learn how to exploit PKC-α’s ability to turn down phospholipase D’s activity and use this function to create anti-cancer drugs.

Another breakthrough branch of research concerning PKC-α concerns its role in erythrocyte (red blood cell) development. Currently, researchers understand that PKC-α is correlated with the differentiation of erythroid progenitor cells in bone marrow.[11] These undifferentiated cells give rise to the mass of red blood cells present in blood. Future research endeavors seek to find whether it is activation or inhibition of PKC-α which affects the development of erythrocytes.[11] By answering this question, scientists hope to gain insight into various types of hematologic diseases such as aplastic anemia and leukemia.


Increased activation of PKCα is associated with the growth and invasion of cancers.[12][13] High levels of PKCα are linked to malignant brain cancer.[14] Moreover, a high proliferation rate of glioma tumor cells is the result of overexpression of isozyme PKCα.[15]



PKC alpha has been shown to interact with:


  1. ^ EntrezGene 5578
  2. ^ a b c Micol V, Sánchez-Piñera P, Villalaín J, de Godos A, Gómez-Fernández JC (February 1999). "Correlation between protein kinase C alpha activity and membrane phase behavior". Biophys. J. 76 (2): 916–27. PMC 1300093. PMID 9929493. doi:10.1016/S0006-3495(99)77255-3. 
  3. ^ a b c Torrecillas A, Corbalán-García S, Gómez-Fernández JC (March 2004). "An infrared spectroscopic study of the secondary structure of protein kinase C alpha and its thermal denaturation". Biochemistry 43 (8): 2332–44. PMID 14979730. doi:10.1021/bi035128i. 
  4. ^ Mullin JM, Laughlin KV, Ginanni N, Marano CW, Clarke HM, Peralta Soler A (2000). "Increased tight junction permeability can result from protein kinase C activation/translocation and act as a tumor promotional event in epithelial cancers". Ann. N. Y. Acad. Sci. 915: 231–6. PMID 11193580. doi:10.1111/j.1749-6632.2000.tb05246.x. 
  5. ^ Rosson D, O'Brien TG, Kampherstein JA, Szallasi Z, Bogi K, Blumberg PM, Mullin JM (June 1997). "Protein kinase C-alpha activity modulates transepithelial permeability and cell junctions in the LLC-PK1 epithelial cell line". J. Biol. Chem. 272 (23): 14950–3. PMID 9169467. doi:10.1074/jbc.272.23.14950. 
  6. ^ Le M, Krilov L, Meng J, Chapin-Kennedy K, Ceryak S, Bouscarel B (August 2006). "Bile acids stimulate PKCalpha autophosphorylation and activation: role in the attenuation of prostaglandin E1-induced cAMP production in human dermal fibroblasts". Am. J. Physiol. Gastrointest. Liver Physiol. 291 (2): G275–87. PMID 16710050. doi:10.1152/ajpgi.00346.2005. 
  7. ^ Ikegami T, Krilov L, Meng J, Patel B, Chapin-Kennedy K, Bouscarel B (November 2006). "Decreased glucagon responsiveness by bile acids: a role for protein kinase Calpha and glucagon receptor phosphorylation". Endocrinology 147 (11): 5294–302. PMID 16916948. doi:10.1210/en.2006-0516. 
  8. ^ a b Dorn GW, Force T (March 2005). "Protein kinase cascades in the regulation of cardiac hypertrophy". J. Clin. Invest. 115 (3): 527–37. PMC 1052008. PMID 15765134. doi:10.1172/JCI24178. 
  9. ^ de Quervain DJ, Kolassa IT, Ackermann S, Aerni A, Boesiger P, Demougin P, Elbert T, Ertl V, Gschwind L, Hadziselimovic N, Hanser E, Heck A, Hieber P, Huynh KD, Klarhöfer M, Luechinger R, Rasch B, Scheffler K, Spalek K, Stippich C, Vogler C, Vukojevic V, Stetak A, Papassotiropoulos A (May 2012). "PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors". Proc. Natl. Acad. Sci. U.S.A. 109 (22): 8746–51. PMC 3365172. PMID 22586106. doi:10.1073/pnas.1200857109. Lay summaryScience News (May 14, 2012). 
  10. ^ Hu T, Exton JH (August 2005). "A point mutation at phenylalanine 663 abolishes protein kinase C alpha's ability to translocate to the perinuclear region and activate phospholipase D1". Biochem. Biophys. Res. Commun. 333 (3): 750–3. PMID 15963950. doi:10.1016/j.bbrc.2005.05.184. 
  11. ^ a b Myklebust JH, Smeland EB, Josefsen D, Sioud M (January 2000). "Protein kinase C-alpha isoform is involved in erythropoietin-induced erythroid differentiation of CD34(+) progenitor cells from human bone marrow". Blood 95 (2): 510–8. PMID 10627456. 
  12. ^ Koivunen, J.; Aaltonen, V.; Peltonen, J. (2006). "Protein kinase C (PKC) family in cancer progression". Cancer Letters 235 (1): 1–10. PMID 15907369. doi:10.1016/j.canlet.2005.03.033.  edit
  13. ^ Haughian, J. M.; Bradford, A. P. (2009). "Protein kinase C alpha (PKCα) regulates growth and invasion of endometrial cancer cells". Journal of Cellular Physiology 220 (1): 112–118. PMID 19235902. doi:10.1002/jcp.21741.  edit
  14. ^ Yazaki, T.; Ahmad, S.; Chahlavi, A.; Zylber-Katz, E.; Dean, N. M.; Rabkin, S. D.; Martuza, R. L.; Glazer, R. I. (1996). "Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide". Molecular pharmacology 50 (2): 236–242. PMID 8700129.  edit
  15. ^ Baltuch, G. H.; Dooley, N. P.; Rostworowski, K. M.; Villemure, J. G.; Yong, V. W. (1995). "Protein kinase C isoform alpha overexpression in C6 glioma cells and its role in cell proliferation". Journal of neuro-oncology 24 (3): 241–250. PMID 7595754. doi:10.1007/BF01052840.  edit
  16. ^[full citation needed]
  17. ^ Storz P, Hausser A, Link G, Dedio J, Ghebrehiwet B, Pfizenmaier K, Johannes FJ (August 2000). "Protein kinase C [micro] is regulated by the multifunctional chaperon protein p32". J. Biol. Chem. 275 (32): 24601–7. PMID 10831594. doi:10.1074/jbc.M002964200. 
  18. ^ Lee HS, Millward-Sadler SJ, Wright MO, Nuki G, Al-Jamal R, Salter DM (November 2002). "Activation of Integrin-RACK1/PKCalpha signalling in human articular chondrocyte mechanotransduction". Osteoarthr. Cartil. 10 (11): 890–7. PMID 12435334. doi:10.1053/joca.2002.0842. 
  19. ^ Parsons M, Keppler MD, Kline A, Messent A, Humphries MJ, Gilchrist R, Hart IR, Quittau-Prevostel C, Hughes WE, Parker PJ, Ng T (August 2002). "Site-directed perturbation of protein kinase C- integrin interaction blocks carcinoma cell chemotaxis". Mol. Cell. Biol. 22 (16): 5897–911. PMC 133968. PMID 12138200. doi:10.1128/MCB.22.16.5897-5911.2002. 
  20. ^ Gauthier ML, Torretto C, Ly J, Francescutti V, O'Day DH (August 2003). "Protein kinase Calpha negatively regulates cell spreading and motility in MDA-MB-231 human breast cancer cells downstream of epidermal growth factor receptor". Biochem. Biophys. Res. Commun. 307 (4): 839–46. PMID 12878187. doi:10.1016/S0006-291X(03)01273-7. 
  21. ^ Anilkumar N, Parsons M, Monk R, Ng T, Adams JC (October 2003). "Interaction of fascin and protein kinase Calpha: a novel intersection in cell adhesion and motility". EMBO J. 22 (20): 5390–402. PMC 213775. PMID 14532112. doi:10.1093/emboj/cdg521. 
  22. ^ Dantzer F, Luna L, Bjørås M, Seeberg E (June 2002). "Human OGG1 undergoes serine phosphorylation and associates with the nuclear matrix and mitotic chromatin in vivo". Nucleic Acids Res. 30 (11): 2349–57. PMC 117190. PMID 12034821. doi:10.1093/nar/30.11.2349. 

Further reading

  • >O'Brian CA (1998). "Protein kinase C-alpha: a novel target for the therapy of androgen-independent prostate cancer? (Review-hypothesis)". Oncol. Rep. 5 (2): 305–9. PMID 9468546. doi:10.3892/or.5.2.305. 
  • Ali A, Hoeflich KP, Woodgett JR (August 2001). "Glycogen synthase kinase-3: properties, functions, and regulation". Chem. Rev. 101 (8): 2527–40. PMID 11749387. doi:10.1021/cr000110o. 
  • Slater SJ, Ho C, Stubbs CD (June 2002). "The use of fluorescent phorbol esters in studies of protein kinase C-membrane interactions". Chem. Phys. Lipids 116 (1-2): 75–91. PMID 12093536. doi:10.1016/S0009-3084(02)00021-X.