Top ▲

serine/threonine kinase 11

Click here for help

Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2212

Nomenclature: serine/threonine kinase 11

Abbreviated Name: LKB1

Family: LKB subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 433 19p13.3 STK11 serine/threonine kinase 11
Mouse - 436 10 C1 Stk11 serine/threonine kinase 11
Rat - 438 7q11 Stk11 serine/threonine kinase 11
Previous and Unofficial Names Click here for help
liver kinase B1 homolog | Par-4 | PJS | polarization-related protein LKB1 | serine/threonine kinase 11 (Peutz-Jeghers syndrome)
Database Links Click here for help
Alphafold Q15831 (Hs), Q9WTK7 (Mm), D4AE59 (Rn)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL5606 (Hs), CHEMBL3734644 (Mm)
Ensembl Gene ENSG00000118046 (Hs), ENSMUSG00000003068 (Mm), ENSRNOG00000014287 (Rn)
Entrez Gene 6794 (Hs), 20869 (Mm), 314621 (Rn)
Human Protein Atlas ENSG00000118046 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:6794 (Hs), mmu:20869 (Mm), rno:314621 (Rn)
OMIM 602216 (Hs)
Orphanet ORPHA119884 (Hs)
Pharos Q15831 (Hs)
RefSeq Nucleotide NM_000455 (Hs), NM_011492 (Mm), NM_001108069 (Rn)
RefSeq Protein NP_000446 (Hs), NP_035622 (Mm), NP_001101539 (Rn)
UniProtKB Q15831 (Hs), Q9WTK7 (Mm), D4AE59 (Rn)
Wikipedia STK11 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the heterotrimeric IKB1-STRADalpha-MO25alpha complex.
PDB Id:  2WTK
Resolution:  2.65Å
Species:  Human
References:  9
Enzyme Reaction Click here for help
EC Number: 2.7.11.1
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: 3,7
Key to terms and symbols Click column headers to sort
Target used in screen: LKB1
Ligand Sp. Type Action Value Parameter
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.2 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.4 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.9 pKd
PHA-665752 Small molecule or natural product Hs Inhibitor Inhibition 5.6 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 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: 1,4
Key to terms and symbols Click column headers to sort
Target used in screen: LKB1/LKB1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 5.8 30.0 3.0
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 12.4 67.0 11.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 13.5 21.0 1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 18.7 77.0 20.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 23.5 87.0 41.0
indirubin-3'-monoxime Small molecule or natural product Hs Inhibitor Inhibition 25.6 83.0 44.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 31.8 82.0 96.0
aloisine A Small molecule or natural product Hs Inhibitor Inhibition 33.5 97.0 73.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 34.8 90.0 55.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 41.4 97.0 74.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Development of fatal TH2-dominant inflammatory symptoms in mice with a specific Stk11 knockout in their Treg cells, and experiments showing Stk11's role in the coordination of metabolic and functional fitness of Treg cells, suggest that this kinase acts as a crucial checkpoint that actively maintains Treg cell survival and homeostatic function [5,8]. Stk11 was found to control Treg expression of the T cell co-receptors PD-1, GITR and OX40 (expression elevated in the absence of Stk11). Conditional knockout of Stk11 in dendritic cells (DCs) leads to excessive Treg expansion and blunted antigen-specific T cell immunity, which highlights DC-derived Stk11 as a regulatory switch that is crucial for regulating Treg homeostasis, immune response and tolerance [2].
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Melanoma, cutaneous malignant, susceptibility to, 1; CMM1
OMIM: 155600
Disease:  Pancreatic cancer
Disease Ontology: DOID:1793
OMIM: 260350
Disease:  Peutz-Jeghers syndrome
Disease Ontology: DOID:3852
OMIM: 175200
Orphanet: ORPHA2869
Disease:  Testicular germ cell tumor
Synonyms: Seminoma [Disease Ontology: DOID:4440]
Testicular pure germ cell tumor [Disease Ontology: DOID:4087]
Disease Ontology: DOID:4440, DOID:4087
OMIM: 273300
General Comments
LKB1 (encoded by STK11), via direct phosphorylation of AMPK, functions as a bioenergetic sensor that controls cell metabolism and growth, and acts as a tumour suppressor [6].

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. Chen S, Fang L, Guo W, Zhou Y, Yu G, Li W, Dong K, Liu J, Luo Y, Wang B et al.. (2018) Control of Treg cell homeostasis and immune equilibrium by Lkb1 in dendritic cells. Nat Commun, 9 (1): 5298. [PMID:30546010]

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. He N, Fan W, Henriquez B, Yu RT, Atkins AR, Liddle C, Zheng Y, Downes M, Evans RM. (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci USA, 114 (47): 12542-12547. [PMID:29109251]

6. Shackelford DB, Shaw RJ. (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer, 9 (8): 563-75. [PMID:19629071]

7. 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]

8. Yang K, Blanco DB, Neale G, Vogel P, Avila J, Clish CB, Wu C, Shrestha S, Rankin S, Long L et al.. (2017) Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature, 548 (7669): 602-606. [PMID:28847007]

9. Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM. (2009) Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science, 326 (5960): 1707-11. [PMID:19892943]

How to cite this page

LKB subfamily: serine/threonine kinase 11. Last modified on 17/12/2018. Accessed on 06/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2212.