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serine/threonine kinase 4

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2225

Nomenclature: serine/threonine kinase 4

Abbreviated Name: MST1

Family: MST subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 487 20q13.12 STK4 serine/threonine kinase 4
Mouse - 487 2 H3 Stk4 serine/threonine kinase 4
Rat - 487 3 q42 Stk4 serine/threonine kinase 4
Previous and Unofficial Names Click here for help
Kas-2 | kinase responsive to stress 2 | KRS2 | YSK3
Database Links Click here for help
Alphafold Q13043 (Hs), Q9JI11 (Mm)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL4598 (Hs)
Ensembl Gene ENSG00000101109 (Hs), ENSMUSG00000018209 (Mm), ENSRNOG00000013529 (Rn)
Entrez Gene 6789 (Hs), 58231 (Mm), 311622 (Rn)
Human Protein Atlas ENSG00000101109 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:6789 (Hs), mmu:58231 (Mm), rno:311622 (Rn)
OMIM 604965 (Hs)
Orphanet ORPHA317798 (Hs)
Pharos Q13043 (Hs)
RefSeq Nucleotide NM_006282 (Hs), NM_021420 (Mm), NM_001107800 (Rn)
RefSeq Protein NP_006273 (Hs), NP_067395 (Mm), NP_001101270 (Rn)
UniProtKB Q13043 (Hs), Q9JI11 (Mm)
Wikipedia STK4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of Mst1 kinase.
PDB Id:  3COM
Resolution:  2.2Å
Species:  Human
References: 
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
cerdulatinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.4 pIC50 8
⤷ pIC50 8.4 (IC50 4x10-9 M) [8]
IHMT-MST1-58 Small molecule or natural product Hs Inhibition 7.6 pIC50 22
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [22]
SBP-3264 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 6
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [6]
bosutinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.7 pIC50 17
⤷ pIC50 6.7 (IC50 1.91x10-7 M) [17]
compound 38 [PMID: 20817473] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.4 pIC50 7
⤷ pIC50 6.4 (IC50 4.12x10-7 M) [7]
XMU-MP-1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.3 pIC50 6
⤷ pIC50 6.3 (IC50 4.93x10-7 M) [6]
DiscoveRx KINOMEscan® screen Click here for help
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: 11,21
Key to terms and symbols Click column headers to sort
Target used in screen: MST1
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.7 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.5 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.7 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.4 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 7.3 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.9 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 6.6 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
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: 2,14
Key to terms and symbols Click column headers to sort
Target used in screen: MST1/MST1(STK4)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition -0.2 -0.5 1.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.2 0.0 -3.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 2.7 5.0 1.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.0 12.0 5.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 3.6 19.0 -1.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.7 1.0 2.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 4.2 2.0 4.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.5 1.0 3.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.6 1.0 2.0
SU9516 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.7 9.0 -2.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
The kinases MST1 and MST2 are key components of the Hippo signalling pathway. MST1/2 function has been identified as a signal-dependent amplifier of IL-2−STAT5 signalling in Treg cells that maintains immune tolerance, and to be essential for prevention of tumour resistance and autoimmunity [20]. Mst1 is required for long-lived humoral immunity [5]. The Hippo pathway also appears to couple the cellular metabolic state and immune function of CD8α+ dendritic cells, in a mechanism that progammes this dendritic cell subset to present antigens to, and selectively prime CD8+ T cells [12]. In this way, output from the Hippo signalling pathway is able to induce cytotoxic T cell responses to viruses, bacteria and tumours. Manipulating this selective dendritic cell process has implications for cancer immunotherapy, and for treating immune disorders. It can be envisioned that pharmacological agents could be developed which are able to activate CD8α+ dendritic cells, shape the adaptive immune response, and prime anti-tumour T cells.
Immuno Process Associations
Immuno Process:  Immune system development
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  T-cell immunodeficiency, recurrent infections, and autoimmunity with or without cardiac malformations
Synonyms: Combined immunodeficiency due to STK4 deficiency [Orphanet: ORPHA314689]
OMIM: 614868
Orphanet: ORPHA314689
Role:  Several STK4 mutations have been characterised in patients of different ethnic origins, with this autosomal recessive combined immunodeficiency.
References:  1,9-10,15-16,18-19
General Comments
STK4 (MST1) is a key regulator of pancreatic β cell function and is a proapoptotic kinase in diabetogenic conditions [4]. It promotes β cell apoptosis via upregulation of the BCL-2 homology-3 (BH3)-only protein BIM. Small molecule STK4 inhbitors are being explored for potential to treat types 1 and 2 diabetes [3,13,22].

References

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1. Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schäffer AA, Gertz EM, Schambach A, Kreipe HH, Pfeifer D et al.. (2012) The phenotype of human STK4 deficiency. Blood, 119 (15): 3450-7. DOI: 10.1182/blood-2011-09-378158 [PMID:22294732]

2. 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]

3. Ardestani A, Li S, Annamalai K, Lupse B, Geravandi S, Dobrowolski A, Yu S, Zhu S, Baguley TD, Surakattula M et al.. (2019) Neratinib protects pancreatic beta cells in diabetes. Nat Commun, 10 (1): 5015. [PMID:31676778]

4. Ardestani A, Paroni F, Azizi Z, Kaur S, Khobragade V, Yuan T, Frogne T, Tao W, Oberholzer J, Pattou F et al.. (2014) MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nat Med, 20 (4): 385-397. [PMID:24633305]

5. Bagherzadeh Yazdchi S, Witalis M, Meli AP, Leung J, Li X, Panneton V, Chang J, Li J, Nutt SL, Johnson RL et al.. (2019) Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity. J Immunol, 202 (1): 69-78. [PMID:30478091]

6. Bata N, Chaikuad A, Bakas NA, Limpert AS, Lambert LJ, Sheffler DJ, Berger LM, Liu G, Yuan C, Wang L et al.. (2022) Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia. J Med Chem, 65 (2): 1352-1369. [PMID:34807584]

7. Bindi S, Fancelli D, Alli C, Berta D, Bertrand JA, Cameron AD, Cappella P, Carpinelli P, Cervi G, Croci V et al.. (2010) Thieno[3,2-c]pyrazoles: a novel class of Aurora inhibitors with favorable antitumor activity. Bioorg Med Chem, 18 (19): 7113-20. [PMID:20817473]

8. Coffey G, Betz A, DeGuzman F, Pak Y, Inagaki M, Baker DC, Hollenbach SJ, Pandey A, Sinha U. (2014) The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther, 351 (3): 538-48. [PMID:25253883]

9. Crequer A, Picard C, Patin E, D'Amico A, Abhyankar A, Munzer M, Debré M, Zhang SY, de Saint-Basile G, Fischer A et al.. (2012) Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. PLoS ONE, 7 (8): e44010. [PMID:22952854]

10. Dang TS, Willet JD, Griffin HR, Morgan NV, O'Boyle G, Arkwright PD, Hughes SM, Abinun M, Tee LJ, Barge D et al.. (2016) Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency. J Clin Immunol, 36 (2): 117-22. [PMID:26801501]

11. 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]

12. Du X, Wen J, Wang Y, Karmaus PWF, Khatamian A, Tan H, Li Y, Guy C, Nguyen TM, Dhungana Y et al.. (2018) Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells. Nature, 558 (7708): 141-145. [PMID:29849151]

13. Faizah Z, Amanda B, Ashari FY, Triastuti E, Oxtoby R, Rahaju AS, Aziz MA, Lusida MI, Oceandy D. (2020) Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice. Molecules, 25 (19). DOI: 10.3390/molecules25194381 [PMID:32987643]

14. 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]

15. Halacli SO, Ayvaz DC, Sun-Tan C, Erman B, Uz E, Yilmaz DY, Ozgul K, Tezcan İ, Sanal O. (2015) STK4 (MST1) deficiency in two siblings with autoimmune cytopenias: A novel mutation. Clin Immunol, 161 (2): 316-23. [PMID:26117625]

16. Nehme NT, Schmid JP, Debeurme F, André-Schmutz I, Lim A, Nitschke P, Rieux-Laucat F, Lutz P, Picard C, Mahlaoui N et al.. (2012) MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood, 119 (15): 3458-68. DOI: 10.1182/blood-2011-09-378364 [PMID:22174160]

17. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M et al.. (2009) Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia, 23 (3): 477-85. [PMID:19039322]

18. Sharafian S, Ziaee V, Shahrooei M, Ahadi M, Parvaneh N. (2019) A Novel STK4 Mutation Presenting with Juvenile Idiopathic Arthritis and Epidermodysplasia Verruciformis. J Clin Immunol, 39 (1): 11-14. [PMID:30612220]

19. Sherkat R, Sabri MR, Dehghan B, Bigdelian H, Reisi N, Afsharmoghadam N, Rahimi H, Rahmanian N, Klein C. (2017) EBV lymphoproliferative-associated disease and primary cardiac T-cell lymphoma in a STK4 deficient patient: A case report. Medicine (Baltimore), 96 (48): e8852. [PMID:29310365]

20. Shi H, Liu C, Tan H, Li Y, Nguyen TM, Dhungana Y, Guy C, Vogel P, Neale G, Rankin S et al.. (2018) Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity. Immunity, 49 (5): 899-914.e6. [PMID:30413360]

21. 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]

22. Wu Y, Qi Z, Wang B, Wang J, Liu Q, Wang A, Shi C, Zhou B, Liang Q, Wang W et al.. (2022) Discovery of IHMT-MST1-58 as a Novel, Potent, and Selective MST1 Inhibitor for the Treatment of Type 1/2 Diabetes. J Med Chem, 65 (17): 11818-11839. [PMID:36037148]

How to cite this page

MST subfamily: serine/threonine kinase 4. Last modified on 30/08/2022. Accessed on 12/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2225.