serine/threonine kinase 4 | MST subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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serine/threonine kinase 4

  Target has curated data in GtoImmuPdb

Target id: 2225

Nomenclature: serine/threonine kinase 4

Abbreviated Name: MST1

Family: MST subfamily

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 - 487 20q11.2-q13.2 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
Kas-2 | kinase responsive to stress 2 | KRS2 | YSK3
Database Links
BRENDA
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 Mst1 kinase.
PDB Id:  3COM
Resolution:  2.2Å
Species:  Human
References: 
Enzyme Reaction
EC Number: 2.7.11.1

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
cerdulatinib Hs Inhibition 8.4 pIC50 5
pIC50 8.4 (IC50 4x10-9 M) [5]
bosutinib Hs Inhibition 6.7 pIC50 13
pIC50 6.7 (IC50 1.91x10-7 M) [13]
compound 38 [PMID: 20817473] Hs Inhibition 6.4 pIC50 4
pIC50 6.4 (IC50 4.12x10-7 M) [4]
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: 8,17

Key to terms and symbols Click column headers to sort
Target used in screen: MST1
Ligand Sp. Type Action Value Parameter
staurosporine Hs Inhibitor Inhibition 9.7 pKd
lestaurtinib Hs Inhibitor Inhibition 8.5 pKd
sunitinib Hs Inhibitor Inhibition 7.7 pKd
midostaurin Hs Inhibitor Inhibition 7.4 pKd
JNJ-28312141 Hs Inhibitor Inhibition 7.3 pKd
SU-14813 Hs Inhibitor Inhibition 6.9 pKd
bosutinib Hs Inhibitor Inhibition 6.7 pKd
dovitinib Hs Inhibitor Inhibition 6.7 pKd
tozasertib Hs Inhibitor Inhibition 6.7 pKd
neratinib 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
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: 2,10

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 Hs Inhibitor Inhibition -0.2 -0.5 1.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 2.2 0.0 -3.0
K-252a Hs Inhibitor Inhibition 2.7 5.0 1.0
SU11652 Hs Inhibitor Inhibition 3.0 12.0 5.0
SB 218078 Hs Inhibitor Inhibition 3.6 19.0 -1.0
Gö 6976 Hs Inhibitor Inhibition 3.7 1.0 2.0
JAK3 inhibitor VI Hs Inhibitor Inhibition 4.2 2.0 4.0
PKR inhibitor Hs Inhibitor Inhibition 5.5 1.0 3.0
midostaurin Hs Inhibitor Inhibition 5.6 1.0 2.0
SU9516 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 [16]. Mst1 is required for long-lived humoral immunity [3]. 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 [9]. 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
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0060215 primitive hemopoiesis IEA
Clinically-Relevant Mutations and Pathophysiology
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: 
References:  1,6-7,11-12,14-15

References

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1. Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schaffer AA et al.. (2012) The phenotype of human STK4 deficiency. Blood, 119 (15): 3450–7. DOI: 10.1182/blood-2011-09-378158

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. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. Nehme NT, Schmid JP, Debeurme F, Andre-Schmutz I, Lim A, Nitschke P, 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

13. 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]

14. 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]

15. 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]

16. 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]

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]

How to cite this page

MST subfamily: serine/threonine kinase 4. Last modified on 14/05/2019. Accessed on 23/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2225.