Details of Drug Off-Target (DOT)

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

• DOT Name: Ribosomal protein S6 kinase alpha-3 (RPS6KA3)
• Synonyms: S6K-alpha-3; EC 2.7.11.1; 90 kDa ribosomal protein S6 kinase 3; p90-RSK 3; p90RSK3; Insulin-stimulated protein kinase 1; ISPK-1; MAP kinase-activated protein kinase 1b; MAPK-activated protein kinase 1b; MAPKAP kinase 1b; MAPKAPK-1b; Ribosomal S6 kinase 2; RSK-2; pp90RSK2
• Gene Name: RPS6KA3
• Related Disease:
  Coffin-Lowry syndrome
  Intellectual disability, X-linked 19
  Non-syndromic X-linked intellectual disability
  Symptomatic form of Coffin-Lowry syndrome in female carriers
• UniProt ID: KS6A3_HUMAN
• PDB ID: 4D9T; 4D9U; 4JG6; 4JG7; 4JG8; 4NUS; 4NW5; 4NW6; 5D9K; 5D9L; 7OPO; 8EQ5
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00433
• Sequence:
  MPLAQLADPWQKMAVESPSDSAENGQQIMDEPMGEEEINPQTEEVSIKEIAITHHVKEGH
  EKADPSQFELLKVLGQGSFGKVFLVKKISGSDARQLYAMKVLKKATLKVRDRVRTKMERD
  ILVEVNHPFIVKLHYAFQTEGKLYLILDFLRGGDLFTRLSKEVMFTEEDVKFYLAELALA
  LDHLHSLGIIYRDLKPENILLDEEGHIKLTDFGLSKESIDHEKKAYSFCGTVEYMAPEVV
  NRRGHTQSADWWSFGVLMFEMLTGTLPFQGKDRKETMTMILKAKLGMPQFLSPEAQSLLR
  MLFKRNPANRLGAGPDGVEEIKRHSFFSTIDWNKLYRREIHPPFKPATGRPEDTFYFDPE
  FTAKTPKDSPGIPPSANAHQLFRGFSFVAITSDDESQAMQTVGVHSIVQQLHRNSIQFTD
  GYEVKEDIGVGSYSVCKRCIHKATNMEFAVKIIDKSKRDPTEEIEILLRYGQHPNIITLK
  DVYDDGKYVYVVTELMKGGELLDKILRQKFFSEREASAVLFTITKTVEYLHAQGVVHRDL
  KPSNILYVDESGNPESIRICDFGFAKQLRAENGLLMTPCYTANFVAPEVLKRQGYDAACD
  IWSLGVLLYTMLTGYTPFANGPDDTPEEILARIGSGKFSLSGGYWNSVSDTAKDLVSKML
  HVDPHQRLTAALVLRHPWIVHWDQLPQYQLNRQDAPHLVKGAMAATYSALNRNQSPVLEP
  VGRSTLAQRRGIKKITSTAL
• Function: Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Negatively regulates EGF-induced MAPK1/3 phosphorylation via phosphorylation of SOS1. Phosphorylates SOS1 at 'Ser-1134' and 'Ser-1161' that create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK1/3 phosphorylation. Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2 signaling pathway controls cell migration. Acts as a regulator of osteoblast differentiation by mediating phosphorylation of ATF4, thereby promoting ATF4 transactivation activity.
• Tissue Specificity: Expressed in many tissues, highest levels in skeletal muscle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Oocyte meiosis (hsa04114)
  mTOR sig.ling pathway (hsa04150)
  Thermogenesis (hsa04714)
  Long-term potentiation (hsa04720)
  Neurotrophin sig.ling pathway (hsa04722)
  Progesterone-mediated oocyte maturation (hsa04914)
  Insulin resistance (hsa04931)
  Yersinia infection (hsa05135)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  CREB phosphorylation (R-HSA-199920)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Recycling pathway of L1 (R-HSA-437239)
  CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling (R-HSA-442742)
  RSK activation (R-HSA-444257)
  Gastrin-CREB signalling pathway via PKC and MAPK (R-HSA-881907)
  ERK/MAPK targets (R-HSA-198753)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coffin-Lowry syndrome	DISMTBDA	Definitive	X-linked	[1]
Intellectual disability, X-linked 19	DIS240KZ	Strong	X-linked	[2]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[3]
Symptomatic form of Coffin-Lowry syndrome in female carriers	DISMIAI3	Supportive	Autosomal dominant	[4]

3 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 Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[5]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[27]
Sulfate	DMW0ZBF	Investigative	Sulfate affects the methylation of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[17]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[18]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[19]
Ximelegatran	DMU8ANS	Approved	Ximelegatran decreases the activity of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[22]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[12]
UCN-01	DMUNJZB	Phase 2	UCN-01 decreases the activity of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the activity of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[26]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[28]
Daidzein	DMRFTJX	Investigative	Daidzein increases the expression of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[12]
H-89	DM4RVGO	Investigative	H-89 decreases the activity of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Ribosomal protein S6 kinase alpha-3 (RPS6KA3).	[23]

References

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