Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSEH90E)

• DOT Name: Protein kinase C delta type (PRKCD)
• Synonyms: EC 2.7.11.13; Tyrosine-protein kinase PRKCD; EC 2.7.10.2; nPKC-delta
• Gene Name: PRKCD
• Related Disease:
  Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD
  Autoimmune lymphoproliferative syndrome
  Autosomal systemic lupus erythematosus type 16
  Common variable immunodeficiency
• UniProt ID: KPCD_HUMAN
• PDB ID: 1YRK; 2YUU
• EC Number: 2.7.10.2; 2.7.11.13
• Pfam ID: PF00130 ; PF21494 ; PF00069 ; PF00433
• Sequence:
  MAPFLRIAFNSYELGSLQAEDEANQPFCAVKMKEALSTERGKTLVQKKPTMYPEWKSTFD
  AHIYEGRVIQIVLMRAAEEPVSEVTVGVSVLAERCKKNNGKAEFWLDLQPQAKVLMSVQY
  FLEDVDCKQSMRSEDEAKFPTMNRRGAIKQAKIHYIKNHEFIATFFGQPTFCSVCKDFVW
  GLNKQGYKCRQCNAAIHKKCIDKIIGRCTGTAANSRDTIFQKERFNIDMPHRFKVHNYMS
  PTFCDHCGSLLWGLVKQGLKCEDCGMNVHHKCREKVANLCGINQKLLAEALNQVTQRASR
  RSDSASSEPVGIYQGFEKKTGVAGEDMQDNSGTYGKIWEGSSKCNINNFIFHKVLGKGSF
  GKVLLGELKGRGEYFAIKALKKDVVLIDDDVECTMVEKRVLTLAAENPFLTHLICTFQTK
  DHLFFVMEFLNGGDLMYHIQDKGRFELYRATFYAAEIMCGLQFLHSKGIIYRDLKLDNVL
  LDRDGHIKIADFGMCKENIFGESRASTFCGTPDYIAPEILQGLKYTFSVDWWSFGVLLYE
  MLIGQSPFHGDDEDELFESIRVDTPHYPRWITKESKDILEKLFEREPTKRLGVTGNIKIH
  PFFKTINWTLLEKRRLEPPFRPKVKSPRDYSNFDQEFLNEKARLSYSDKNLIDSMDQSAF
  AGFSFVNPKFEHLLED
• Function: Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor-initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Negatively regulates B cell proliferation and also has an important function in self-antigen induced B cell tolerance induction. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53. In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)-induced inhibition of cell cycle progression at G1/S phase by up-regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1. Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro-survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Involved in antifungal immunity by mediating phosphorylation and activation of CARD9 downstream of C-type lectin receptors activation, promoting interaction between CARD9 and BCL10, followed by activation of NF-kappa-B and MAP kinase p38 pathways. Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl-phenylalanine (fMLP)-treated cells, is required for NCF1 (p47-phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways. May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation. Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release. Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1 and beta-catenin. The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion. Phosphorylates ELAVL1 in response to angiotensin-2 treatment. Phosphorylates mitochondrial phospholipid scramblase 3 (PLSCR3), resulting in increased cardiolipin expression on the mitochondrial outer membrane which facilitates apoptosis. Phosphorylates SMPD1 which induces SMPD1 secretion.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Autophagy - animal (hsa04140)
  Vascular smooth muscle contraction (hsa04270)
  NOD-like receptor sig.ling pathway (hsa04621)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Neurotrophin sig.ling pathway (hsa04722)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Type II diabetes mellitus (hsa04930)
  Insulin resistance (hsa04931)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Prion disease (hsa05020)
  Shigellosis (hsa05131)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Calmodulin induced events (R-HSA-111933)
  Effects of PIP2 hydrolysis (R-HSA-114508)
  SHC1 events in ERBB2 signaling (R-HSA-1250196)
  DAG and IP3 signaling (R-HSA-1489509)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  G alpha (z) signalling events (R-HSA-418597)
  HuR (ELAVL1) binds and stabilizes mRNA (R-HSA-450520)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  Neutrophil degranulation (R-HSA-6798695)
  Interferon gamma signaling (R-HSA-877300)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD	DISTRA44	Strong	Autosomal recessive	[1]
Autoimmune lymphoproliferative syndrome	DISUG5ES	Supportive	Autosomal dominant	[2]
Autosomal systemic lupus erythematosus type 16	DIS9RKY9	Supportive	Autosomal dominant	[3]
Common variable immunodeficiency	DISHE7JQ	Supportive	Autosomal dominant	[4]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Protein kinase C delta type (PRKCD) increases the response to substance of Doxorubicin.	[46]
Methotrexate	DM2TEOL	Approved	Protein kinase C delta type (PRKCD) affects the response to substance of Methotrexate.	[47]
Afimoxifene	DMFORDT	Phase 2	Protein kinase C delta type (PRKCD) decreases the response to substance of Afimoxifene.	[48]
PMID26560530-Compound-35	DMO36RL	Patented	Protein kinase C delta type (PRKCD) decreases the response to substance of PMID26560530-Compound-35.	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein kinase C delta type (PRKCD).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein kinase C delta type (PRKCD).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein kinase C delta type (PRKCD).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein kinase C delta type (PRKCD).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein kinase C delta type (PRKCD).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein kinase C delta type (PRKCD).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein kinase C delta type (PRKCD).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein kinase C delta type (PRKCD).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein kinase C delta type (PRKCD).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Protein kinase C delta type (PRKCD).	[15]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Protein kinase C delta type (PRKCD).	[20]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Protein kinase C delta type (PRKCD).	[23]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Protein kinase C delta type (PRKCD).	[24]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Protein kinase C delta type (PRKCD).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein kinase C delta type (PRKCD).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein kinase C delta type (PRKCD).	[28]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Protein kinase C delta type (PRKCD).	[29]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Protein kinase C delta type (PRKCD).	[9]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Protein kinase C delta type (PRKCD).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein kinase C delta type (PRKCD).	[33]
Metastat	DMTQ4PN	Phase 1	Metastat decreases the activity of Protein kinase C delta type (PRKCD).	[36]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Protein kinase C delta type (PRKCD).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein kinase C delta type (PRKCD).	[40]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Protein kinase C delta type (PRKCD).	[42]
Daidzein	DMRFTJX	Investigative	Daidzein decreases the expression of Protein kinase C delta type (PRKCD).	[9]
NSC-1771	DMNXDGQ	Investigative	NSC-1771 increases the activity of Protein kinase C delta type (PRKCD).	[43]
OXYRESVERATROL	DMN7S4L	Investigative	OXYRESVERATROL increases the expression of Protein kinase C delta type (PRKCD).	[44]
Bisindolylmaleimide-I	DMOQJZC	Investigative	Bisindolylmaleimide-I decreases the expression of Protein kinase C delta type (PRKCD).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Protein kinase C delta type (PRKCD).	[11]
Ethanol	DMDRQZU	Approved	Ethanol increases the phosphorylation of Protein kinase C delta type (PRKCD).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the phosphorylation of Protein kinase C delta type (PRKCD).	[18]
Curcumin	DMQPH29	Phase 3	Curcumin increases the phosphorylation of Protein kinase C delta type (PRKCD).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein kinase C delta type (PRKCD).	[32]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the phosphorylation of Protein kinase C delta type (PRKCD).	[34]
TAK-114	DMTXE19	Phase 1	TAK-114 decreases the phosphorylation of Protein kinase C delta type (PRKCD).	[35]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein kinase C delta type (PRKCD).	[37]
MG-132	DMKA2YS	Preclinical	MG-132 increases the phosphorylation of Protein kinase C delta type (PRKCD).	[38]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Protein kinase C delta type (PRKCD).	[37]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Protein kinase C delta type (PRKCD).	[41]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the phosphorylation of Protein kinase C delta type (PRKCD).	[34]
ISORHAMNETIN	DMQ4Z6E	Investigative	ISORHAMNETIN increases the phosphorylation of Protein kinase C delta type (PRKCD).	[45]

7 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Aspirin increases the cleavage of Protein kinase C delta type (PRKCD).	[17]
Paclitaxel	DMLB81S	Approved	Paclitaxel affects the localization of Protein kinase C delta type (PRKCD).	[19]
Vinblastine	DM5TVS3	Approved	Vinblastine affects the localization of Protein kinase C delta type (PRKCD).	[19]
Methamphetamine	DMPM4SK	Approved	Methamphetamine affects the localization of Protein kinase C delta type (PRKCD).	[21]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the cleavage of Protein kinase C delta type (PRKCD).	[22]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid increases the localization of Protein kinase C delta type (PRKCD).	[25]
Butorphanol	DM5KYPJ	Approved	Butorphanol affects the localization of Protein kinase C delta type (PRKCD).	[26]

References

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