Target General Infomation
Target ID
T12808
Former ID
TTDC00182
Target Name
Protein kinase C, alpha type
Gene Name
PRKCA
Synonyms
PKC-A; PKC-alpha; PKCalpha; Protein Kinase C alpha; PRKCA
Target Type
Clinical Trial
Disease Human immunodeficiency virus infection [ICD9: 279.3; ICD10: B20-B26]
Renal transplantation [ICD9: 279.5; ICD10: D89.8]
Function
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation,migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activating signaling cascade involving MAPK1/3 (ERK1/2) and RAP1GAP. Involved in cell proliferation and cell growth arrest by positive and negative regulation of the cell cycle. Can promote cell growth by phosphorylating and activating RAF1, which mediates the activation of the MAPK/ERK signaling cascade, and/or by up-regulating CDKN1A, which facilitates active cyclin-dependent kinase (CDK) complex formationin glioma cells. In intestinal cells stimulated by the phorbol ester PMA, can trigger a cell cycle arrest program which is associated with the accumulation of the hyper-phosphorylated growth-suppressive form of RB1 and induction of the CDK inhibitors CDKN1A and CDKN1B. Exhibits anti-apoptotic function in glioma cells and protects them from apoptosis by suppressing the p53/TP53-mediated activationof IGFBP3, and in leukemia cells mediates anti-apoptotic action by phosphorylating BCL2. During macrophage differentiation induced by macrophage colony-stimulating factor (CSF1), is translocated to the nucleus and is associated with macrophage development. After wounding, translocates from focal contacts to lamellipodia and participates in the modulation of desmosomal adhesion. Plays a role in cell motility by phosphorylating CSPG4, which induces association of CSPG4 with extensive lamellipodia at the cell periphery and polarization of the cell accompanied by increases in cell motility. Is highly expressed in a number of cancer cells where it can act as a tumor promoter and is implicated in malignant phenotypes of several tumors such as gliomas and breast cancers. Negatively regulates myocardial contractility and positively regulates angiogenesis, platelet aggregation and thrombus formation in arteries. Mediates hypertrophic growth of neonatal cardiomyocytes, in part through a MAPK1/3(ERK1/2)- dependent signaling pathway, and upon PMA treatment, is required to induce cardiomyocyte hypertrophy up to heart failure and death, by increasing protein synthesis, protein-DNA ratio and cell surface area. Regulates cardiomyocyte function by phosphorylating cardiac troponin T (TNNT2/CTNT), which induces significant reduction in actomyosin ATPase activity, myofilament calcium sensitivityand myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation ofkinase activation and vascular tube formation. Involved in the stabilization of VEGFA mRNA at post-transcriptional level and mediates VEGFA-induced cell proliferation. In the regulation of calcium-induced platelet aggregation, mediates signals from the CD36/GP4 receptor for granule release, and activates the integrin heterodimer ITGA2B- ITGB3 through the RAP1GAP pathway for adhesion. During response to lipopolysaccharides (LPS), may regulate selective LPS-induced macrophage functions involved in host defense and inflammation. But in some inflammatory responses, may negatively regulate NF- kappa-B-induced genes, through IL1A-dependent induction of NF- kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O- tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which modulates EIF4G1 binding to MKNK1 and may be involved in the regulation of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of KIT activity. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription.
BioChemical Class
Kinase
Target Validation
T12808
UniProt ID
EC Number
EC 2.7.11.13
Sequence
MADVFPGNDSTASQDVANRFARKGALRQKNVHEVKDHKFIARFFKQPTFCSHCTDFIWGF
GKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPDTDDPRSKHKFKIHTYGSPTFCDHCGS
LLYGLIHQGMKCDTCDMNVHKQCVINVPSLCGMDHTEKRGRIYLKAEVADEKLHVTVRDA
KNLIPMDPNGLSDPYVKLKLIPDPKNESKQKTKTIRSTLNPQWNESFTFKLKPSDKDRRL
SVEIWDWDRTTRNDFMGSLSFGVSELMKMPASGWYKLLNQEEGEYYNVPIPEGDEEGNME
LRQKFEKAKLGPAGNKVISPSEDRKQPSNNLDRVKLTDFNFLMVLGKGSFGKVMLADRKG
TEELYAIKILKKDVVIQDDDVECTMVEKRVLALLDKPPFLTQLHSCFQTVDRLYFVMEYV
NGGDLMYHIQQVGKFKEPQAVFYAAEISIGLFFLHKRGIIYRDLKLDNVMLDSEGHIKIA
DFGMCKEHMMDGVTTRTFCGTPDYIAPEIIAYQPYGKSVDWWAYGVLLYEMLAGQPPFDG
EDEDELFQSIMEHNVSYPKSLSKEAVSVCKGLMTKHPAKRLGCGPEGERDVREHAFFRRI
DWEKLENREIQPPFKPKVCGKGAENFDKFFTRGQPVLTPPDQLVIANIDQSDFEGFSYVN
PQFVHPILQSAV
Drugs and Mode of Action
Drug(s) CI-1040 Drug Info Phase 2 Discovery agent [521505], [541019]
Sotrastaurin acetate Drug Info Phase 2 Renal transplantation [537117]
ISIS 3521 Drug Info Discontinued in Phase 2 Discovery agent [546108]
BALANOL Drug Info Terminated Discovery agent [542983], [545589]
LY-317644 Drug Info Terminated Discovery agent [546513]
RO-320432 Drug Info Terminated Discovery agent [541291], [545975]
Inhibitor (-)-Cercosporamide Drug Info [529887]
1,2-dioctanoyl-sn-glycerol Drug Info [530134]
2,3,3-Triphenyl-acrylonitrile Drug Info [528755]
2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile Drug Info [528755]
3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile Drug Info [528755]
3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile Drug Info [528755]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione Drug Info [528032]
3,4-diphenyl-1H-pyrrole-2,5-dione Drug Info [528032]
3-(1H-Indol-3-yl)-4-phenylamino-pyrrole-2,5-dione Drug Info [527221]
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile Drug Info [528755]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione Drug Info [528032]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione Drug Info [528032]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole Drug Info [527308]
4-cycloheptyliden(4-hydroxyphenyl)methylphenol Drug Info [528755]
4-cyclohexyliden(4-hydroxyphenyl)methylphenol Drug Info [528755]
4-cyclopentyliden(4-hydroxyphenyl)methylphenol Drug Info [528755]
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol Drug Info [528755]
ACETOSIDE Drug Info [534763]
BALANOL Drug Info [551285]
BISINDOLYLMALEIMIDE IX Drug Info [525872]
CALCEOLARIOSIDE A Drug Info [534763]
CALCEOLARIOSIDE B Drug Info [534763]
CI-1040 Drug Info [525872]
Diheptan-3-yl 5-(hydroxymethyl)isophthalate Drug Info [530134]
Dihexan-3-yl 5-(hydroxymethyl)isophthalate Drug Info [530134]
FORSYTHIASIDE Drug Info [534763]
Go 6983 Drug Info [534191]
Indolocarbazole analogue Drug Info [526234]
KN-62 Drug Info [525872]
KT-5720 Drug Info [525872]
LEUCOSCEPTOSIDE A Drug Info [534763]
LY-317644 Drug Info [551283]
LY-326449 Drug Info [534154]
Plantainoside D Drug Info [534763]
PROSTRATIN Drug Info [527606]
PUNICAFOLIN Drug Info [551233]
RO-316233 Drug Info [528701]
Ro-32-0557 Drug Info [551264]
RO-320432 Drug Info [551264]
Sotrastaurin acetate Drug Info [537117]
STAUROSPORINONE Drug Info [525872]
TANNIN Drug Info [551233]
[2,2':5',2'']Terthiophen-4-yl-methanol Drug Info [525575]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde Drug Info [525575]
[2,2':5',2'']Terthiophene-4-carbaldehyde Drug Info [525575]
Modulator ISIS 3521 Drug Info
Pathways
KEGG Pathway MAPK signaling pathway
ErbB signaling pathway
Ras signaling pathway
Rap1 signaling pathway
Calcium signaling pathway
HIF-1 signaling pathway
Phosphatidylinositol signaling system
Sphingolipid signaling pathway
mTOR signaling pathway
PI3K-Akt signaling pathway
Adrenergic signaling in cardiomyocytes
Vascular smooth muscle contraction
Wnt signaling pathway
VEGF signaling pathway
Focal adhesion
Tight junction
Gap junction
Natural killer cell mediated cytotoxicity
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
Leukocyte transendothelial migration
Circadian entrainment
Long-term potentiation
Retrograde endocannabinoid signaling
Glutamatergic synapse
Cholinergic synapse
Serotonergic synapse
GABAergic synapse
Dopaminergic synapse
Long-term depression
Inflammatory mediator regulation of TRP channels
Insulin secretion
GnRH signaling pathway
Melanogenesis
Thyroid hormone synthesis
Thyroid hormone signaling pathway
Oxytocin signaling pathway
Aldosterone-regulated sodium reabsorption
Endocrine and other factor-regulated calcium reabsorption
Salivary secretion
Gastric acid secretion
Pancreatic secretion
Amphetamine addiction
Morphine addiction
Vibrio cholerae infection
Pathogenic Escherichia coli infection
African trypanosomiasis
Amoebiasis
Hepatitis B
Influenza A
Pathways in cancer
Proteoglycans in cancer
MicroRNAs in cancer
Glioma
Non-small cell lung cancer
Choline metabolism in cancer
NetPath Pathway IL2 Signaling Pathway
PANTHER Pathway Alpha adrenergic receptor signaling pathway
Alzheimer disease-amyloid secretase pathway
Angiogenesis
Apoptosis signaling pathway
EGF receptor signaling pathway
Endothelin signaling pathway
FGF signaling pathway
Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway
Muscarinic acetylcholine receptor 1 and 3 signaling pathway
PDGF signaling pathway
VEGF signaling pathway
Wnt signaling pathway
5HT2 type receptor mediated signaling pathway
Histamine H1 receptor mediated signaling pathway
Oxytocin receptor mediated signaling pathway
Thyrotropin-releasing hormone receptor signaling pathway
Angiotensin II-stimulated signaling through G proteins and beta-arrestin
CCKR signaling map ST
Pathway Interaction Database Endothelins
TCR signaling in na&amp
#xef
ve CD4+ T cells
Canonical NF-kappaB pathway
Signaling events regulated by Ret tyrosine kinase
TCR signaling in na&amp
ve CD8+ T cells
Thromboxane A2 receptor signaling
Role of Calcineurin-dependent NFAT signaling in lymphocytes
mTOR signaling pathway
Ras signaling in the CD4+ TCR pathway
ErbB1 downstream signaling
Syndecan-4-mediated signaling events
ATF-2 transcription factor network
PDGFR-beta signaling pathway
Retinoic acid receptors-mediated signaling
IL8- and CXCR2-mediated signaling events
VEGFR1 specific signals
Signaling events mediated by VEGFR1 and VEGFR2
PAR1-mediated thrombin signaling events
a6b1 and a6b4 Integrin signaling
IL8- and CXCR1-mediated signaling events
Regulation of Ras family activation
Downstream signaling in na&amp
PathWhiz Pathway Fc Epsilon Receptor I Signaling in Mast Cells
Activation of PKC through G protein coupled receptor
Reactome Calmodulin induced events
Disinhibition of SNARE formation
Regulation of KIT signaling
EGFR Transactivation by Gastrin
Inactivation, recovery and regulation of the phototransduction cascade
Syndecan interactions
Acetylcholine regulates insulin secretion
Ca2+ pathway
Trafficking of GluR2-containing AMPA receptors
G alpha (z) signalling events
Depolymerisation of the Nuclear Lamina
HuR (ELAVL1) binds and stabilizes mRNA
WNT5A-dependent internalization of FZD4
VEGFR2 mediated cell proliferation
Response to elevated platelet cytosolic Ca2+
WikiPathways ErbB Signaling Pathway
Calcium Regulation in the Cardiac Cell
Insulin Signaling
EGF/EGFR Signaling Pathway
Wnt Signaling Pathway
Wnt Signaling Pathway and Pluripotency
Wnt Signaling Pathway Netpath
G Protein Signaling Pathways
Kit receptor signaling pathway
Transcriptional activation by NRF2
Myometrial Relaxation and Contraction Pathways
Human Complement System
Cardiac Hypertrophic Response
Syndecan interactions
Regulation of mRNA Stability by Proteins that Bind AU-rich Elements
Signaling by SCF-KIT
DAG and IP3 signaling
Gastrin-CREB signalling pathway via PKC and MAPK
T-Cell Receptor and Co-stimulatory Signaling
Alpha 6 Beta 4 signaling pathway
Spinal Cord Injury
Integrated Pancreatic Cancer Pathway
Oncostatin M Signaling Pathway
Corticotropin-releasing hormone
AGE/RAGE pathway
Pathogenic Escherichia coli infection
Signaling Pathways in Glioblastoma
Endothelin Pathways
Regulation of Microtubule Cytoskeleton
FSH signaling pathway
miRs in Muscle Cell Differentiation
Opioid Signalling
Response to elevated platelet cytosolic Ca2+
Integration of energy metabolism
TOR Signaling
References
Ref 521505ClinicalTrials.gov (NCT00033384) CI-1040 in Treating Patients With Advanced Breast, Colon, Pancreatic, or Non-Small Cell Lung Cancer. U.S. National Institutes of Health.
Ref 537117Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
Ref 541019(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5676).
Ref 541291(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6034).
Ref 542983(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8142).
Ref 545589Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003814)
Ref 545975Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005586)
Ref 546108Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006393)
Ref 546513Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008685)
Ref 525575Bioorg Med Chem Lett. 1999 Aug 2;9(15):2279-82.Novel protein kinase C inhibitors: synthesis and PKC inhibition of beta-substituted polythiophene derivatives.
Ref 525872Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors.
Ref 526234Bioorg Med Chem Lett. 2002 Jan 21;12(2):147-50.Mixed lineage kinase activity of indolocarbazole analogues.
Ref 527221Bioorg Med Chem Lett. 2004 Oct 18;14(20):5171-4.Synthesis of anilino-monoindolylmaleimides as potent and selective PKCbeta inhibitors.
Ref 527308J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole.
Ref 527606J Med Chem. 1992 May 29;35(11):1978-86.A nonpromoting phorbol from the samoan medicinal plant Homalanthus nutans inhibits cell killing by HIV-1.
Ref 528032J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors.
Ref 528701J Med Chem. 1992 Jan;35(1):177-84.Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides.
Ref 528755J Med Chem. 1992 Feb 7;35(3):573-83.Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation.
Ref 529887Bioorg Med Chem Lett. 2009 Feb 1;19(3):724-6. Epub 2008 Dec 11.(-)-Cercosporamide derivatives as novel antihyperglycemic agents.
Ref 530134J Med Chem. 2009 Jul 9;52(13):3969-81.Design, synthesis, and biological activity of isophthalic acid derivatives targeted to the C1 domain of protein kinase C.
Ref 534154J Med Chem. 1996 Jul 5;39(14):2664-71.(S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta.
Ref 534191Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80.
Ref 534763J Nat Prod. 1998 Nov;61(11):1410-2.Phenylethanoid glycosides from Digitalis purpurea and Penstemon linarioides with PKCalpha-inhibitory activity.
Ref 537117Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
Ref 551233Tannins as selective inhibitors of protein kinase C, Bioorg. Med. Chem. Lett. 2(3):239-244 (1992).
Ref 551264Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994).
Ref 551283Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995).
Ref 551285Evaluation of differential hypoxic cytotoxicity and electrochemical studies of nitro 5-deazaflavins, Bioorg. Med. Chem. Lett. 5(18):2155-2160 (1995).
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Wang and Dr. Li.