Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWBRAJ6)

• DOT Name: Tyrosine-protein kinase Mer (MERTK)
• Synonyms: EC 2.7.10.1; Proto-oncogene c-Mer; Receptor tyrosine kinase MerTK
• Gene Name: MERTK
• Related Disease:
  MERTK-related retinopathy
  Retinitis pigmentosa 38
  Retinitis pigmentosa
• UniProt ID: MERTK_HUMAN
• PDB ID: 2DBJ ; 2P0C ; 3BPR ; 3BRB ; 3TCP ; 4M3Q ; 4MH7 ; 4MHA ; 5K0K ; 5K0X ; 5TC0 ; 5TD2 ; 5U6C ; 6MEP ; 7AAX ; 7AAY ; 7AAZ ; 7AB0 ; 7AB1 ; 7AB2 ; 7AVX ; 7AVY ; 7AVZ ; 7AW0 ; 7AW1 ; 7AW2 ; 7AW3 ; 7AW4 ; 7CQE ; 7DXL ; 7M5Z ; 7OAM ; 7OLS ; 7OLV ; 7OLX ; 7XHY
• EC Number: 2.7.10.1
• Pfam ID: PF00041 ; PF00047 ; PF13927 ; PF07714
• Sequence:
  MGPAPLPLLLGLFLPALWRRAITEAREEAKPYPLFPGPFPGSLQTDHTPLLSLPHASGYQ
  PALMFSPTQPGRPHTGNVAIPQVTSVESKPLPPLAFKHTVGHIILSEHKGVKFNCSISVP
  NIYQDTTISWWKDGKELLGAHHAITQFYPDDEVTAIIASFSITSVQRSDNGSYICKMKIN
  NEEIVSDPIYIEVQGLPHFTKQPESMNVTRNTAFNLTCQAVGPPEPVNIFWVQNSSRVNE
  QPEKSPSVLTVPGLTEMAVFSCEAHNDKGLTVSKGVQINIKAIPSPPTEVSIRNSTAHSI
  LISWVPGFDGYSPFRNCSIQVKEADPLSNGSVMIFNTSALPHLYQIKQLQALANYSIGVS
  CMNEIGWSAVSPWILASTTEGAPSVAPLNVTVFLNESSDNVDIRWMKPPTKQQDGELVGY
  RISHVWQSAGISKELLEEVGQNGSRARISVQVHNATCTVRIAAVTRGGVGPFSDPVKIFI
  PAHGWVDYAPSSTPAPGNADPVLIIFGCFCGFILIGLILYISLAIRKRVQETKFGNAFTE
  EDSELVVNYIAKKSFCRRAIELTLHSLGVSEELQNKLEDVVIDRNLLILGKILGEGEFGS
  VMEGNLKQEDGTSLKVAVKTMKLDNSSQREIEEFLSEAACMKDFSHPNVIRLLGVCIEMS
  SQGIPKPMVILPFMKYGDLHTYLLYSRLETGPKHIPLQTLLKFMVDIALGMEYLSNRNFL
  HRDLAARNCMLRDDMTVCVADFGLSKKIYSGDYYRQGRIAKMPVKWIAIESLADRVYTSK
  SDVWAFGVTMWEIATRGMTPYPGVQNHEMYDYLLHGHRLKQPEDCLDELYEIMYSCWRTD
  PLDRPTFSVLRLQLEKLLESLPDVRNQADVIYVNTQLLESSEGLAQGSTLAPLDLNIDPD
  SIIASCTPRAAISVVTAEVHDSKPHEGRYILNGGSEEWEDLTSAPSAAVTAEKNSVLPGE
  RLVRNGVSWSHSSMLPLGSSLPDELLFADDSSEGSEVLM
• Function: Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Also plays an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3.
• Tissue Specificity: Not expressed in normal B- and T-lymphocytes but is expressed in numerous neoplastic B- and T-cell lines. Highly expressed in testis, ovary, prostate, lung, and kidney, with lower expression in spleen, small intestine, colon, and liver.
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway: Cell surface interactions at the vascular wall (R-HSA-202733)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
MERTK-related retinopathy	DISG7EC5	Definitive	Autosomal recessive	[1]
Retinitis pigmentosa 38	DISEMXBI	Definitive	Autosomal recessive	[2]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
adenosine diphosphate	DMFUHKP	Investigative	Tyrosine-protein kinase Mer (MERTK) increases the response to substance of adenosine diphosphate.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tyrosine-protein kinase Mer (MERTK).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein kinase Mer (MERTK).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tyrosine-protein kinase Mer (MERTK).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tyrosine-protein kinase Mer (MERTK).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tyrosine-protein kinase Mer (MERTK).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tyrosine-protein kinase Mer (MERTK).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tyrosine-protein kinase Mer (MERTK).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tyrosine-protein kinase Mer (MERTK).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Tyrosine-protein kinase Mer (MERTK).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tyrosine-protein kinase Mer (MERTK).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Tyrosine-protein kinase Mer (MERTK).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Tyrosine-protein kinase Mer (MERTK).	[14]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Tyrosine-protein kinase Mer (MERTK).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tyrosine-protein kinase Mer (MERTK).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tyrosine-protein kinase Mer (MERTK).	[17]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Tyrosine-protein kinase Mer (MERTK).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Tyrosine-protein kinase Mer (MERTK).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Tyrosine-protein kinase Mer (MERTK).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tyrosine-protein kinase Mer (MERTK).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tyrosine-protein kinase Mer (MERTK).	[24]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Tyrosine-protein kinase Mer (MERTK).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the cleavage of Tyrosine-protein kinase Mer (MERTK).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tyrosine-protein kinase Mer (MERTK).	[23]

References

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• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
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• [19] A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Blood. 2007 Feb 1;109(3):1026-33. doi: 10.1182/blood-2006-05-021634. Epub 2006 Oct 17.
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• [26] Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses. J Thromb Haemost. 2005 Apr;3(4):733-41. doi: 10.1111/j.1538-7836.2005.01186.x. Epub 2005 Feb 23.