Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPI7DAV)

• DOT Name: SRSF protein kinase 1 (SRPK1)
• Synonyms: EC 2.7.11.1; SFRS protein kinase 1; Serine/arginine-rich protein-specific kinase 1; SR-protein-specific kinase 1
• Gene Name: SRPK1
• UniProt ID: SRPK1_HUMAN
• PDB ID: 1WAK; 1WBP; 3BEG; 4WUA; 5MXX; 5MY8; 5NNG; 5XV7; 6FAD; 7DD1; 7PQS; 7ZKS
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MERKVLALQARKKRTKAKKDKAQRKSETQHRGSAPHSESDLPEQEEEILGSDDDEQEDPN
  DYCKGGYHLVKIGDLFNGRYHVIRKLGWGHFSTVWLSWDIQGKKFVAMKVVKSAEHYTET
  ALDEIRLLKSVRNSDPNDPNREMVVQLLDDFKISGVNGTHICMVFEVLGHHLLKWIIKSN
  YQGLPLPCVKKIIQQVLQGLDYLHTKCRIIHTDIKPENILLSVNEQYIRRLAAEATEWQR
  SGAPPPSGSAVSTAPQPKPADKMSKNKKKKLKKKQKRQAELLEKRMQEIEEMEKESGPGQ
  KRPNKQEESESPVERPLKENPPNKMTQEKLEESSTIGQDQTLMERDTEGGAAEINCNGVI
  EVINYTQNSNNETLRHKEDLHNANDCDVQNLNQESSFLSSQNGDSSTSQETDSCTPITSE
  VSDTMVCQSSSTVGQSFSEQHISQLQESIRAEIPCEDEQEQEHNGPLDNKGKSTAGNFLV
  NPLEPKNAEKLKVKIADLGNACWVHKHFTEDIQTRQYRSLEVLIGSGYNTPADIWSTACM
  AFELATGDYLFEPHSGEEYTRDEDHIALIIELLGKVPRKLIVAGKYSKEFFTKKGDLKHI
  TKLKPWGLFEVLVEKYEWSQEEAAGFTDFLLPMLELIPEKRATAAECLRHPWLNS
• Function: Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation.
• Tissue Specificity: Isoform 2 is predominantly expressed in the testis but is also present at lower levels in heart, ovary, small intestine, liver, kidney, pancreas and skeletal muscle. Isoform 1 is only seen in the testis, at lower levels than isoform 2. Highly expressed in different erythroid and lymphoid cell lines, with isoform 2 being far more abundant than isoform 1.
• KEGG Pathway: Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  Replacement of protamines by nucleosomes in the male pronucleus (R-HSA-9821993)
  Maturation of nucleoprotein (R-HSA-9694631)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SRSF protein kinase 1 (SRPK1).	[1]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SRSF protein kinase 1 (SRPK1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SRSF protein kinase 1 (SRPK1).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of SRSF protein kinase 1 (SRPK1).	[1]
Selenium	DM25CGV	Approved	Selenium decreases the expression of SRSF protein kinase 1 (SRPK1).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of SRSF protein kinase 1 (SRPK1).	[6]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of SRSF protein kinase 1 (SRPK1).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of SRSF protein kinase 1 (SRPK1).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of SRSF protein kinase 1 (SRPK1).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of SRSF protein kinase 1 (SRPK1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of SRSF protein kinase 1 (SRPK1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin affects the localization of SRSF protein kinase 1 (SRPK1).	[2]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid affects the localization of SRSF protein kinase 1 (SRPK1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
G1	DMTV42K	Phase 1/2	G1 increases the phosphorylation of SRSF protein kinase 1 (SRPK1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of SRSF protein kinase 1 (SRPK1).	[9]

References

• [1] Comparison of the gene expression profiles of monocytic versus granulocytic lineages of HL-60 leukemia cell differentiation by DNA microarray analysis. Life Sci. 2003 Aug 15;73(13):1705-19. doi: 10.1016/s0024-3205(03)00515-0.
• [2] Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin. EMBO J. 2011 Feb 2;30(3):510-23. doi: 10.1038/emboj.2010.333. Epub 2010 Dec 14.
• [3] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [8] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [9] 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.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] SRSF2 is required for sodium butyrate-mediated p21(WAF1) induction and premature senescence in human lung carcinoma cell lines. Cell Cycle. 2011 Jun 15;10(12):1968-77. doi: 10.4161/cc.10.12.15825. Epub 2011 Jun 15.