Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0KMIYQ)

• DOT Name: Receptor-interacting serine/threonine-protein kinase 2 (RIPK2)
• Synonyms: EC 2.7.11.1; CARD-containing interleukin-1 beta-converting enzyme-associated kinase; CARD-containing IL-1 beta ICE-kinase; RIP-like-interacting CLARP kinase; Receptor-interacting protein 2; RIP-2; Tyrosine-protein kinase RIPK2; EC 2.7.10.2
• Gene Name: RIPK2
• UniProt ID: RIPK2_HUMAN
• PDB ID: 2N7Z; 2N83; 4C8B; 5AR2; 5AR3; 5AR4; 5AR5; 5AR7; 5AR8; 5J79; 5J7B; 5NG0; 5NG2; 5NG3; 5W5J; 5W5O; 5YRN; 6ES0; 6FU5; 6GFJ; 6GGS; 6HMX; 6RN8; 6RNA; 6S1F; 6SZE; 6SZJ; 6UL8; 7OBS; 7OBT; 8AZA
• EC Number: 2.7.10.2; 2.7.11.1
• Pfam ID: PF00619 ; PF07714
• Sequence:
  MNGEAICSALPTIPYHKLADLRYLSRGASGTVSSARHADWRVQVAVKHLHIHTPLLDSER
  KDVLREAEILHKARFSYILPILGICNEPEFLGIVTEYMPNGSLNELLHRKTEYPDVAWPL
  RFRILHEIALGVNYLHNMTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRS
  SKSAPEGGTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMY
  SVSQGHRPVINEESLPYDIPHRARMISLIESGWAQNPDERPSFLKCLIELEPVLRTFEEI
  TFLEAVIQLKKTKLQSVSSAIHLCDKKKMELSLNIPVNHGPQEESCGSSQLHENSGSPET
  SRSLPAPQDNDFLSRKAQDCYFMKLHHCPGNHSWDSTISGSQRAAFCDHKTTPCSSAIIN
  PLSTAGNSERLQPGIAQQWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTK
  PTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGLQPYPEILVVSRSPSLNLLQNKSM
• Function: Serine/threonine/tyrosine-protein kinase that plays an essential role in modulation of innate and adaptive immune responses. Acts as a key effector of NOD1 and NOD2 signaling pathways: upon activation by bacterial peptidoglycans, NOD1 and NOD2 oligomerize and recruit RIPK2 via CARD-CARD domains, leading to the formation of RIPK2 filaments. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3, as well as 'Met-1'-linked (linear) polyubiquitination by the LUBAC complex, becoming a scaffolding protein for downstream effectors. 'Met-1'-linked polyubiquitin chains attached to RIPK2 recruit IKBKG/NEMO, which undergoes 'Lys-63'-linked polyubiquitination in a RIPK2-dependent process. 'Lys-63'-linked polyubiquitin chains attached to RIPK2 serve as docking sites for TAB2 and TAB3 and mediate the recruitment of MAP3K7/TAK1 to IKBKG/NEMO, inducing subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. The protein kinase activity is dispensable for the NOD1 and NOD2 signaling pathways. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappa-B activation by NOD2. Also involved in adaptive immunity: plays a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. Plays a role in the inactivation of RHOA in response to NGFR signaling.
• Tissue Specificity: Detected in heart, brain, placenta, lung, peripheral blood leukocytes, spleen, kidney, testis, prostate, pancreas and lymph node.
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Neurotrophin sig.ling pathway (hsa04722)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  Downstream TCR signaling (R-HSA-202424)
  p75NTR recruits signalling complexes (R-HSA-209543)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  Ovarian tumor domain proteases (R-HSA-5689896)
  Interleukin-1 signaling (R-HSA-9020702)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  NOD1/2 Signaling Pathway (R-HSA-168638)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) affects the response to substance of Topotecan.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[1]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[10]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[10]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[15]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[16]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[10]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[18]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[22]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[24]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Receptor-interacting serine/threonine-protein kinase 2 (RIPK2).	[25]

References

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• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [22] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [23] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.
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