Target Information
Target General Infomation | |||||
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Target ID |
T12808
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Former ID |
TTDC00182
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Target Name |
Protein kinase C, alpha type
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Gene Name |
PRKCA
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Synonyms |
PKC-A; PKC-alpha; PKCalpha; Protein Kinase C alpha; PRKCA
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Target Type |
Clinical Trial
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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.
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BioChemical Class |
Kinase
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Target Validation |
T12808
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UniProt ID | |||||
EC Number |
EC 2.7.11.13
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Sequence |
MADVFPGNDSTASQDVANRFARKGALRQKNVHEVKDHKFIARFFKQPTFCSHCTDFIWGF
GKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPDTDDPRSKHKFKIHTYGSPTFCDHCGS LLYGLIHQGMKCDTCDMNVHKQCVINVPSLCGMDHTEKRGRIYLKAEVADEKLHVTVRDA KNLIPMDPNGLSDPYVKLKLIPDPKNESKQKTKTIRSTLNPQWNESFTFKLKPSDKDRRL SVEIWDWDRTTRNDFMGSLSFGVSELMKMPASGWYKLLNQEEGEYYNVPIPEGDEEGNME LRQKFEKAKLGPAGNKVISPSEDRKQPSNNLDRVKLTDFNFLMVLGKGSFGKVMLADRKG TEELYAIKILKKDVVIQDDDVECTMVEKRVLALLDKPPFLTQLHSCFQTVDRLYFVMEYV NGGDLMYHIQQVGKFKEPQAVFYAAEISIGLFFLHKRGIIYRDLKLDNVMLDSEGHIKIA DFGMCKEHMMDGVTTRTFCGTPDYIAPEIIAYQPYGKSVDWWAYGVLLYEMLAGQPPFDG EDEDELFQSIMEHNVSYPKSLSKEAVSVCKGLMTKHPAKRLGCGPEGERDVREHAFFRRI DWEKLENREIQPPFKPKVCGKGAENFDKFFTRGQPVLTPPDQLVIANIDQSDFEGFSYVN PQFVHPILQSAV |
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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& | |||||
#xef | |||||
ve CD4+ T cells | |||||
Canonical NF-kappaB pathway | |||||
Signaling events regulated by Ret tyrosine kinase | |||||
TCR signaling in na& | |||||
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& | |||||
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 521505 | ClinicalTrials.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 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 545589 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003814) | ||||
Ref 545975 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005586) | ||||
Ref 525575 | Bioorg 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 525872 | Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors. | ||||
Ref 526234 | Bioorg Med Chem Lett. 2002 Jan 21;12(2):147-50.Mixed lineage kinase activity of indolocarbazole analogues. | ||||
Ref 527221 | Bioorg Med Chem Lett. 2004 Oct 18;14(20):5171-4.Synthesis of anilino-monoindolylmaleimides as potent and selective PKCbeta inhibitors. | ||||
Ref 527308 | J Med Chem. 2004 Dec 2;47(25):6239-47.Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. | ||||
Ref 527606 | J 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 528032 | J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. | ||||
Ref 528701 | J Med Chem. 1992 Jan;35(1):177-84.Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. | ||||
Ref 528755 | J 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 529887 | Bioorg Med Chem Lett. 2009 Feb 1;19(3):724-6. Epub 2008 Dec 11.(-)-Cercosporamide derivatives as novel antihyperglycemic agents. | ||||
Ref 530134 | J 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 534154 | J 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 534191 | Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80. | ||||
Ref 534763 | J Nat Prod. 1998 Nov;61(11):1410-2.Phenylethanoid glycosides from Digitalis purpurea and Penstemon linarioides with PKCalpha-inhibitory activity. | ||||
Ref 551233 | Tannins as selective inhibitors of protein kinase C, Bioorg. Med. Chem. Lett. 2(3):239-244 (1992). | ||||
Ref 551264 | Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994). | ||||
Ref 551283 | Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995). |
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