Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5UWNRD)

• DOT Name: Protein kinase C alpha type (PRKCA)
• Synonyms: PKC-A; PKC-alpha; EC 2.7.11.13
• Gene Name: PRKCA
• UniProt ID: KPCA_HUMAN
• PDB ID: 2ELI; 3IW4; 4DNL; 4RA4
• EC Number: 2.7.11.13
• Pfam ID: PF00130 ; PF00168 ; PF00069 ; PF00433
• Sequence:
  MADVFPGNDSTASQDVANRFARKGALRQKNVHEVKDHKFIARFFKQPTFCSHCTDFIWGF
  GKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPDTDDPRSKHKFKIHTYGSPTFCDHCGS
  LLYGLIHQGMKCDTCDMNVHKQCVINVPSLCGMDHTEKRGRIYLKAEVADEKLHVTVRDA
  KNLIPMDPNGLSDPYVKLKLIPDPKNESKQKTKTIRSTLNPQWNESFTFKLKPSDKDRRL
  SVEIWDWDRTTRNDFMGSLSFGVSELMKMPASGWYKLLNQEEGEYYNVPIPEGDEEGNME
  LRQKFEKAKLGPAGNKVISPSEDRKQPSNNLDRVKLTDFNFLMVLGKGSFGKVMLADRKG
  TEELYAIKILKKDVVIQDDDVECTMVEKRVLALLDKPPFLTQLHSCFQTVDRLYFVMEYV
  NGGDLMYHIQQVGKFKEPQAVFYAAEISIGLFFLHKRGIIYRDLKLDNVMLDSEGHIKIA
  DFGMCKEHMMDGVTTRTFCGTPDYIAPEIIAYQPYGKSVDWWAYGVLLYEMLAGQPPFDG
  EDEDELFQSIMEHNVSYPKSLSKEAVSVCKGLMTKHPAKRLGCGPEGERDVREHAFFRRI
  DWEKLENREIQPPFKPKVCGKGAENFDKFFTRGQPVLTPPDQLVIANIDQSDFEGFSYVN
  PQFVHPILQSAV
• 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 formation in 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 activation of 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. During chemokine-induced CD4(+) T cell migration, phosphorylates CDC42-guanine exchange factor DOCK8 resulting in its dissociation from LRCH1 and the activation of GTPase CDC42. 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 sensitivity and myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation of kinase 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. Phosphorylates SOCS2 at 'Ser-52' facilitating its ubiquitination and proteasomal degradation. Phosphorylates KLHL3 in response to angiotensin II signaling, decreasing the interaction between KLHL3 and WNK4.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  HIF-1 sig.ling pathway (hsa04066)
  Phosphatidylinositol sig.ling system (hsa04070)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  VEGF sig.ling pathway (hsa04370)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  Neutrophil extracellular trap formation (hsa04613)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Leukocyte transendothelial migration (hsa04670)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone sig.ling pathway (hsa04919)
  Oxytocin sig.ling pathway (hsa04921)
  Aldosterone synthesis and secretion (hsa04925)
  Relaxin sig.ling pathway (hsa04926)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  GnRH secretion (hsa04929)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Growth hormone synthesis, secretion and action (hsa04935)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
  Morphine addiction (hsa05032)
  Vibrio cholerae infection (hsa05110)
  African trypanosomiasis (hsa05143)
  Amoebiasis (hsa05146)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroR.s in cancer (hsa05206)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Glioma (hsa05214)
  Non-small cell lung cancer (hsa05223)
  Hepatocellular carcinoma (hsa05225)
  Choline metabolism in cancer (hsa05231)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Disinhibition of SNARE formation (R-HSA-114516)
  SHC1 events in ERBB2 signaling (R-HSA-1250196)
  Signaling by SCF-KIT (R-HSA-1433557)
  Regulation of KIT signaling (R-HSA-1433559)
  EGFR Transactivation by Gastrin (R-HSA-2179392)
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  Syndecan interactions (R-HSA-3000170)
  Acetylcholine regulates insulin secretion (R-HSA-399997)
  Ca2+ pathway (R-HSA-4086398)
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  G alpha (z) signalling events (R-HSA-418597)
  Depolymerization of the Nuclear Lamina (R-HSA-4419969)
  HuR (ELAVL1) binds and stabilizes mRNA (R-HSA-450520)
  WNT5A-dependent internalization of FZD4 (R-HSA-5099900)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  Response to elevated platelet cytosolic Ca2+ (R-HSA-76005)
  RET signaling (R-HSA-8853659)
  ROBO receptors bind AKAP5 (R-HSA-9010642)
  Calmodulin induced events (R-HSA-111933)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Protein kinase C alpha type (PRKCA) affects the response to substance of Arsenic trioxide.	[53]
Methotrexate	DM2TEOL	Approved	Protein kinase C alpha type (PRKCA) decreases the response to substance of Methotrexate.	[54]
Progesterone	DMUY35B	Approved	Protein kinase C alpha type (PRKCA) increases the Reticuloendothelial disorders NEC ADR of Progesterone.	[55]
Morphine	DMRMS0L	Approved	Protein kinase C alpha type (PRKCA) increases the Hyperpathia ADR of Morphine.	[55]
acrolein	DMAMCSR	Investigative	Protein kinase C alpha type (PRKCA) affects the response to substance of acrolein.	[56]

11 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein kinase C alpha type (PRKCA).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein kinase C alpha type (PRKCA).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the phosphorylation of Protein kinase C alpha type (PRKCA).	[10]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the phosphorylation of Protein kinase C alpha type (PRKCA).	[15]
Miltefosine	DMND304	Approved	Miltefosine decreases the phosphorylation of Protein kinase C alpha type (PRKCA).	[25]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN decreases the phosphorylation of Protein kinase C alpha type (PRKCA).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein kinase C alpha type (PRKCA).	[34]
TAK-114	DMTXE19	Phase 1	TAK-114 decreases the phosphorylation of Protein kinase C alpha type (PRKCA).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein kinase C alpha type (PRKCA).	[40]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protein kinase C alpha type (PRKCA).	[42]
D-glucose	DMMG2TO	Investigative	D-glucose increases the phosphorylation of Protein kinase C alpha type (PRKCA).	[46]

45 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein kinase C alpha type (PRKCA).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein kinase C alpha type (PRKCA).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein kinase C alpha type (PRKCA).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein kinase C alpha type (PRKCA).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein kinase C alpha type (PRKCA).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein kinase C alpha type (PRKCA).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein kinase C alpha type (PRKCA).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein kinase C alpha type (PRKCA).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein kinase C alpha type (PRKCA).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein kinase C alpha type (PRKCA).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein kinase C alpha type (PRKCA).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Protein kinase C alpha type (PRKCA).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Protein kinase C alpha type (PRKCA).	[12]
Nicotine	DMWX5CO	Approved	Nicotine increases the activity of Protein kinase C alpha type (PRKCA).	[16]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Protein kinase C alpha type (PRKCA).	[17]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Protein kinase C alpha type (PRKCA).	[18]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Protein kinase C alpha type (PRKCA).	[19]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Protein kinase C alpha type (PRKCA).	[20]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Protein kinase C alpha type (PRKCA).	[21]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Protein kinase C alpha type (PRKCA).	[22]
Sodium chloride	DMM3950	Approved	Sodium chloride increases the expression of Protein kinase C alpha type (PRKCA).	[23]
Fluticasone propionate	DMRWLB2	Approved	Fluticasone propionate decreases the expression of Protein kinase C alpha type (PRKCA).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein kinase C alpha type (PRKCA).	[26]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein kinase C alpha type (PRKCA).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein kinase C alpha type (PRKCA).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of Protein kinase C alpha type (PRKCA).	[28]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Protein kinase C alpha type (PRKCA).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein kinase C alpha type (PRKCA).	[29]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Protein kinase C alpha type (PRKCA).	[30]
UCN-01	DMUNJZB	Phase 2	UCN-01 decreases the activity of Protein kinase C alpha type (PRKCA).	[32]
Bryostatin-1	DM1JOXY	Phase 2	Bryostatin-1 decreases the expression of Protein kinase C alpha type (PRKCA).	[33]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein kinase C alpha type (PRKCA).	[35]
Metastat	DMTQ4PN	Phase 1	Metastat decreases the activity of Protein kinase C alpha type (PRKCA).	[37]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Protein kinase C alpha type (PRKCA).	[38]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein kinase C alpha type (PRKCA).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein kinase C alpha type (PRKCA).	[41]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Protein kinase C alpha type (PRKCA).	[43]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the activity of Protein kinase C alpha type (PRKCA).	[44]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Protein kinase C alpha type (PRKCA).	[45]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Protein kinase C alpha type (PRKCA).	[47]
Lead acetate	DML0GZ2	Investigative	Lead acetate decreases the expression of Protein kinase C alpha type (PRKCA).	[48]
NSC-1771	DMNXDGQ	Investigative	NSC-1771 decreases the activity of Protein kinase C alpha type (PRKCA).	[49]
H-89	DM4RVGO	Investigative	H-89 decreases the activity of Protein kinase C alpha type (PRKCA).	[50]
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate decreases the expression of Protein kinase C alpha type (PRKCA).	[51]
G6976	DMEZO4M	Investigative	G6976 decreases the expression of Protein kinase C alpha type (PRKCA).	[52]

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