MER proto-oncogene, tyrosine kinase | Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family | IUPHAR Guide to IMMUNOPHARMACOLOGY

Top ▲

MER proto-oncogene, tyrosine kinase

  Target has curated data in GtoImmuPdb

Target id: 1837

Nomenclature: MER proto-oncogene, tyrosine kinase

Abbreviated Name: Mer

Family: Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 999 2q14.1 MERTK MER proto-oncogene, tyrosine kinase
Mouse 1 994 2 Mertk MER proto-oncogene tyrosine kinase
Rat 1 994 3q36 Mertk MER proto-oncogene
Previous and Unofficial Names
RP38 | Rdy | retinal dystrophy | tyrosine-protein kinase Mer | Eyk | Nyk | Tyro 12 | c-mer proto-oncogene tyrosine kinase | MER proto-oncogene
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with ADP
PDB Id:  3BRB
Ligand:  ADP   This ligand is endogenous
Resolution:  1.9Å
Species:  Human
References:  6
Enzyme Reaction
EC Number: 2.7.10.1
Natural/Endogenous Ligands
growth arrest specific protein 6 {Sp: Human}

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
merestinib Hs Inhibition 9.1 pKd 18
pKd 9.1 (Kd 8x10-10 M) [18]
Description: Binding constant determined by KINOMEScan assay.
UNC4203 Hs Inhibition 9.4 pKi 19
pKi 9.4 (Ki 4.3x10-10 M) [19]
G749 Hs Inhibition 9.0 pIC50 7
pIC50 9.0 (IC50 1x10-9 M) [7]
sitravatinib Hs Inhibition 8.7 pIC50 12
pIC50 8.7 (IC50 2x10-9 M) [12]
Description: In a biochemical enzyme activity assay.
gilteritinib Hs Inhibition ~8.5 pIC50 8
pIC50 ~8.5 (IC50 ~3x10-9 M) [8]
LDC1267 Hs Inhibition 8.3 pIC50 11
pIC50 8.3 (IC50 5x10-9 M) [11]
BMS-777607 Hs Inhibition 7.8 pIC50 14
pIC50 7.8 (IC50 1.4x10-8 M) [14]
MK-2461 Hs Inhibition 7.6 pIC50 10
pIC50 7.6 (IC50 2.4x10-8 M) [10]
RIPK1 inhibitor 22b Hs Inhibition 7.5 pIC50 9
pIC50 7.5 (IC50 2.9x10-8 M) [9]
pIC50 7.5 (IC50 2.9x10-8 M) [9]
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 3,17

Key to terms and symbols Click column headers to sort
Target used in screen: MERTK
Ligand Sp. Type Action Value Parameter
foretinib Hs Inhibitor Inhibition 9.6 pKd
crizotinib Hs Inhibitor Inhibition 8.4 pKd
staurosporine Hs Inhibitor Inhibition 8.2 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.7 pKd
sunitinib Hs Inhibitor Inhibition 7.6 pKd
lestaurtinib Hs Inhibitor Inhibition 7.5 pKd
SU-14813 Hs Inhibitor Inhibition 7.2 pKd
JNJ-28312141 Hs Inhibitor Inhibition 7.1 pKd
bosutinib Hs Inhibitor Inhibition 7.0 pKd
tamatinib Hs Inhibitor Inhibition 6.8 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,4

Key to terms and symbols Click column headers to sort
Target used in screen: Mer/c-MER
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 2.6 2.0 0.5
K-252a Hs Inhibitor Inhibition 3.6 2.0 0.0
SU11652 Hs Inhibitor Inhibition 11.5 7.0 0.0
SB 218078 Hs Inhibitor Inhibition 13.6 34.0 11.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 14.8 -1.0 -1.0
EGFR/ErbB-2 inhibitor Hs Inhibitor Inhibition 19.5 64.0 49.0
SU6656 Hs Inhibitor Inhibition 20.9 12.0 13.0
SU11274 Hs Inhibitor Inhibition 21.4 1.0 1.0
bosutinib Hs Inhibitor Inhibition 28.9
PDGF RTK inhibitor Hs Inhibitor Inhibition 32.3 14.0 4.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Mer plays a critical role in regulating self-tolerance mediated between apoptotic cells, dendritic cells, and T cells [2,16].
Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   mature NK T cell (CL:0000814)
References:  2
Immuno Cell Type:  Natural killer cells
Cell Ontology Term:   natural killer cell (CL:0000623)
References:  2,11
Immuno Cell Type:  Macrophages & monocytes
Cell Ontology Term:   macrophage (CL:0000235)
Comment:  Mouse splenic macrophages, marginal zone macrophages, by immunofluorescence staining (Shao et al. 2009); mouse, mature tissue macrophages by mRNA expression (Gautier et al. 2012); mouse dendritic cells (Wallet et al. 2008, Rothlin et al. 2007)
References:  5,15
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
References:  13,16
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 5 GO processes
GO:0006909 phagocytosis IMP
GO:0050766 positive regulation of phagocytosis IDA
GO:0050900 leukocyte migration TAS
click arrow to show/hide IEA associations
GO:0043277 apoptotic cell clearance IEA
GO:0097350 neutrophil clearance IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0050900 leukocyte migration TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0051250 negative regulation of lymphocyte activation IEA
GO:0097350 neutrophil clearance IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0001779 natural killer cell differentiation IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0001818 negative regulation of cytokine production IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0001779 natural killer cell differentiation IEA
GO:0051250 negative regulation of lymphocyte activation IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Retinitis pigmentosa 38; RP38
Synonyms: Retinitis pigmentosa [Orphanet: ORPHA791] [Disease Ontology: DOID:10584]
Disease Ontology: DOID:10584
OMIM: 613862
Orphanet: ORPHA791

References

Show »

1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Behrens EM, Gadue P, Gong SY, Garrett S, Stein PL, Cohen PL. (2003) The mer receptor tyrosine kinase: expression and function suggest a role in innate immunity. Eur. J. Immunol., 33 (8): 2160-7. [PMID:12884290]

3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

4. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

5. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S et al.. (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol., 13 (11): 1118-28. [PMID:23023392]

6. Huang X, Finerty P, Walker JR, Butler-Cole C, Vedadi M, Schapira M, Parker SA, Turk BE, Thompson DA, Dhe-Paganon S. (2009) Structural insights into the inhibited states of the Mer receptor tyrosine kinase. J. Struct. Biol., 165 (2): 88-96. [PMID:19028587]

7. Lee HK, Kim HW, Lee IY, Lee J, Lee J, Jung DS, Lee SY, Park SH, Hwang H, Choi JS et al.. (2014) G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia. Blood, 123 (14): 2209-19. [PMID:24532805]

8. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D, Levis M. (2017) Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood, 129 (2): 257-260. [PMID:27908881]

9. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z, Lin G et al.. (2018) Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J. Med. Chem., 61 (24): 11398-11414. [PMID:30480444]

10. Pan BS, Chan GK, Chenard M, Chi A, Davis LJ, Deshmukh SV, Gibbs JB, Gil S, Hang G, Hatch H et al.. (2010) MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res., 70 (4): 1524-33. [PMID:20145145]

11. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP et al.. (2014) The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature, 507 (7493): 508-12. [PMID:24553136]

12. Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. (2016) Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget, 7 (4): 4093-109. [PMID:26675259]

13. Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G. (2007) TAM receptors are pleiotropic inhibitors of the innate immune response. Cell, 131 (6): 1124-36. [PMID:18083102]

14. Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA, Dai J, Gullo-Brown J, Gupta A, Henley B et al.. (2009) Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem., 52 (5): 1251-4. [PMID:19260711]

15. Shao WH, Zhen Y, Eisenberg RA, Cohen PL. (2009) The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells. Clin. Immunol., 133 (1): 138-44. [PMID:19631584]

16. Wallet MA, Sen P, Flores RR, Wang Y, Yi Z, Huang Y, Mathews CE, Earp HS, Matsushima G, Wang B et al.. (2008) MerTK is required for apoptotic cell-induced T cell tolerance. J. Exp. Med., 205 (1): 219-32. [PMID:18195070]

17. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

18. Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR et al.. (2013) LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs, 31 (4): 833-44. [PMID:23275061]

19. Zhao J, Zhang D, Zhang W, Stashko MA, DeRyckere D, Vasileiadi E, Parker RE, Hunter D, Liu Q, Zhang Y et al.. (2018) Highly Selective MERTK Inhibitors Achieved by a Single Methyl Group. J. Med. Chem., 61 (22): 10242-10254. [PMID:30347155]

How to cite this page

Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family: MER proto-oncogene, tyrosine kinase. Last modified on 11/12/2018. Accessed on 21/07/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1837.