Details of Drug Off-Target (DOT)

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

• DOT Name: cGMP-dependent protein kinase 2 (PRKG2)
• Synonyms: cGK 2; cGK2; EC 2.7.11.12; cGMP-dependent protein kinase II; cGKII
• Gene Name: PRKG2
• Related Disease: Acromesomelic dysplasia 4
• UniProt ID: KGP2_HUMAN
• PDB ID: 5BV6; 5C6C; 5C8W; 5JIX; 5JIZ; 6BQ8
• EC Number: 2.7.11.12
• Pfam ID: PF00027 ; PF00069
• Sequence:
  MGNGSVKPKHSKHPDGHSGNLTTDALRNKVTELERELRRKDAEIQEREYHLKELREQLSK
  QTVAIAELTEELQNKCIQLNKLQDVVHMQGGSPLQASPDKVPLEVHRKTSGLVSLHSRRG
  AKAGVSAEPTTRTYDLNKPPEFSFEKARVRKDSSEKKLITDALNKNQFLKRLDPQQIKDM
  VECMYGRNYQQGSYIIKQGEPGNHIFVLAEGRLEVFQGEKLLSSIPMWTTFGELAILYNC
  TRTASVKAITNVKTWALDREVFQNIMRRTAQARDEQYRNFLRSVSLLKNLPEDKLTKIID
  CLEVEYYDKGDYIIREGEEGSTFFILAKGKVKVTQSTEGHDQPQLIKTLQKGEYFGEKAL
  ISDDVRSANIIAEENDVACLVIDRETFNQTVGTFEELQKYLEGYVANLNRDDEKRHAKRS
  MSNWKLSKALSLEMIQLKEKVARFSSSSPFQNLEIIATLGVGGFGRVELVKVKNENVAFA
  MKCIRKKHIVDTKQQEHVYSEKRILEELCSPFIVKLYRTFKDNKYVYMLLEACLGGELWS
  ILRDRGSFDEPTSKFCVACVTEAFDYLHRLGIIYRDLKPENLILDAEGYLKLVDFGFAKK
  IGSGQKTWTFCGTPEYVAPEVILNKGHDFSVDFWSLGILVYELLTGNPPFSGVDQMMTYN
  LILKGIEKMDFPRKITRRPEDLIRRLCRQNPTERLGNLKNGINDIKKHRWLNGFNWEGLK
  ARSLPSPLQRELKGPIDHSYFDKYPPEKGMPPDELSGWDKDF
• Function: Crucial regulator of intestinal secretion and bone growth. Phosphorylates and activates CFTR on the plasma membrane. Plays a key role in intestinal secretion by regulating cGMP-dependent translocation of CFTR in jejunum. Acts downstream of NMDAR to activate the plasma membrane accumulation of GRIA1/GLUR1 in synapse and increase synaptic plasticity. Phosphorylates GRIA1/GLUR1 at Ser-863. Acts as a regulator of gene expression and activator of the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2 in mechanically stimulated osteoblasts. Under fluid shear stress, mediates ERK activation and subsequent induction of FOS, FOSL1/FRA1, FOSL2/FRA2 and FOSB that play a key role in the osteoblast anabolic response to mechanical stimulation.
• Tissue Specificity: Highly concentrated in brain, lung and intestinal mucosa.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Circadian entrainment (hsa04713)
  Thermogenesis (hsa04714)
  Long-term depression (hsa04730)
  Olfactory transduction (hsa04740)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Salivary secretion (hsa04970)
• Reactome Pathway:
  Ca2+ pathway (R-HSA-4086398)
  cGMP effects (R-HSA-418457)
  RAS processing (R-HSA-9648002)
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acromesomelic dysplasia 4	DISJY5E9	Strong	Autosomal recessive	[1]

5 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 cGMP-dependent protein kinase 2 (PRKG2).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of cGMP-dependent protein kinase 2 (PRKG2).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of cGMP-dependent protein kinase 2 (PRKG2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of cGMP-dependent protein kinase 2 (PRKG2).	[6]
Uric acid	DMA1MKT	Investigative	Uric acid decreases the expression of cGMP-dependent protein kinase 2 (PRKG2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of cGMP-dependent protein kinase 2 (PRKG2).	[4]

References

• [1] Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia. J Med Genet. 2022 Jan;59(1):28-38. doi: 10.1136/jmedgenet-2020-107177. Epub 2020 Oct 26.
• [2] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [5] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [6] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [7] Enhanced alpha-kinase 1 accelerates multiple early nephropathies in streptozotocin-induced hyperglycemic mice. Biochim Biophys Acta. 2016 Nov;1862(11):2034-2042. doi: 10.1016/j.bbadis.2016.08.010. Epub 2016 Aug 16.