Top ▲
Target has curated data in GtoImmuPdb
Target id: 2225
Nomenclature: serine/threonine kinase 4
Abbreviated Name: MST1
Family: MST subfamily
Gene and Protein Information | ||||||
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 |
Kas-2 | kinase responsive to stress 2 | KRS2 | YSK3 |
Database Links | |
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 | |||||||||||
|
Enzyme Reaction | ||||
|
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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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: 11,21 |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Target used in screen: MST1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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: 2,14 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Target used in screen: MST1/MST1(STK4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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. |
Clinically-Relevant Mutations and Pathophysiology | ||||||||||||||||
|
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]. |
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]
MST subfamily: serine/threonine kinase 4. Last modified on 30/08/2022. Accessed on 04/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2225.