Q9WTK7 · STK11_MOUSE
- ProteinSerine/threonine-protein kinase STK11
- GeneStk11
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids436 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, thus promoting their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA, PTEN and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2 and thereby regulates processes including: inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, and B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neuron polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1. Also acts as a mediator of p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to the mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with NUAK1, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair (PubMed:25329316).
Isoform 2
Has a role in spermiogenesis.
Catalytic activity
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]
Cofactor
Mn2+ (UniProtKB | Rhea| CHEBI:29035 )
Activity regulation
Activated by forming a complex with STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): STRADA (or STRADB)-binding promotes a conformational change of STK11/LKB1 in an active conformation, which is stabilized by CAB39/MO25alpha (or CAB39L/MO25beta) interacting with the STK11/LKB1 activation loop. Sequestration in the nucleus by NR4A1 prevents it from phosphorylating and activating cytoplasmic AMPK (By similarity).
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameSerine/threonine-protein kinase STK11
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ9WTK7
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Translocates to mitochondrion during apoptosis (By similarity).
A small fraction localizes at membranes. Relocates to the cytoplasm when bound to STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta). PTEN promotes cytoplasmic localization (By similarity).
A small fraction localizes at membranes. Relocates to the cytoplasm when bound to STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta). PTEN promotes cytoplasmic localization (By similarity).
Isoform 2
Note: Relocates to the cytoplasm when bound to STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta).
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Mice die in utero 8.5 to 9.5 dpc due to severe defects in their vasculature: embryos show neural tube defects, mesenchymal cell death, and vascular abnormalities. Extraembryonic development is also severely affected; the mutant placentas exhibit defective labyrinth layer development and the fetal vessels fail to invade the placenta. Male mice specifically lacking isoform 2 are sterile (PubMed:18774945).
A specifically deletion in liver results in hyperglycemia with increased gluconeogenic and lipogenic gene expression due to loss of AMPK phosphorylation and subsequent dephosphorylation of CRTC2/TORC2 (PubMed:16308421).
Use of a conditional allele, leads to defects in defects in axon formation with a thinner cortical wall and larger lateral ventricles in the brain cortex (PubMed:17482548).
Heterozygous mice develop multiple gastric adenomatous polyps, with polyps remarkably similar to hamartomas of PJS patients both macroscopically and histologically. Polyps in the heterozygous mice are detected at 5 months, and cause premature lethality progressively from 8 months onwards. Polyps are most frequently observed in the stomach where they typically concentrate close to the pylorus. Polyps in the small and large intestine are significantly less frequent. The histology of the polyps in the heterozygous mice is remarkably similar to PJS polyps including the relative contribution of well-differentiated epithelium, and a prominent smooth muscle component. Ptgs2/Cox2 is highly up-regulated in heterozygous mice polyps concomitantly with activation of the extracellular signal-regulated kinases Mapk1/Erk2 and Mapk3/Erk1: treatment with celecoxib Ptgs2/Cox2 inhibitor significantly reduces the total polyp burden
A specifically deletion in liver results in hyperglycemia with increased gluconeogenic and lipogenic gene expression due to loss of AMPK phosphorylation and subsequent dephosphorylation of CRTC2/TORC2 (PubMed:16308421).
Use of a conditional allele, leads to defects in defects in axon formation with a thinner cortical wall and larger lateral ventricles in the brain cortex (PubMed:17482548).
Heterozygous mice develop multiple gastric adenomatous polyps, with polyps remarkably similar to hamartomas of PJS patients both macroscopically and histologically. Polyps in the heterozygous mice are detected at 5 months, and cause premature lethality progressively from 8 months onwards. Polyps are most frequently observed in the stomach where they typically concentrate close to the pylorus. Polyps in the small and large intestine are significantly less frequent. The histology of the polyps in the heterozygous mice is remarkably similar to PJS polyps including the relative contribution of well-differentiated epithelium, and a prominent smooth muscle component. Ptgs2/Cox2 is highly up-regulated in heterozygous mice polyps concomitantly with activation of the extracellular signal-regulated kinases Mapk1/Erk2 and Mapk3/Erk1: treatment with celecoxib Ptgs2/Cox2 inhibitor significantly reduces the total polyp burden
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 31 | No change in kinase activity; when associated with A-325; A-336 and A-366. | ||||
Sequence: S → A | ||||||
Mutagenesis | 78 | Loss of kinase activity. | ||||
Sequence: K → I | ||||||
Mutagenesis | 194 | Loss of kinase activity and descreased phosphorylation. | ||||
Sequence: D → A | ||||||
Mutagenesis | 325 | No change in kinase activity; when associated with A-31; A-336 and A-366. | ||||
Sequence: S → A | ||||||
Mutagenesis | 336 | Abolishes ability to suppress cell growth. Decreased phosphorylation; when associated with A-366. No change in kinase activity; when associated with A-31; A-325 and A-366. | ||||
Sequence: T → A | ||||||
Mutagenesis | 366 | Diminished interaction with CDKN1A and impaired ability to repair UV-induced DNA damage by affecting CDKN1AUV-induced degradation. Decreased phosphorylation; when associated with A-336. No change in kinase activity; when associated with A-31; A-325 and A-336. | ||||
Sequence: T → A | ||||||
Mutagenesis | 431 | Does not prevent S-farnesylation. Defects in neuron polarization. | ||||
Sequence: S → A | ||||||
Mutagenesis | 433 | Does not affect nuclear localization. Does not prevent phosphorylation at S-431. | ||||
Sequence: C → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 12 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Chemistry
PTM/Processing
Features
Showing features for chain, modified residue, lipidation, propeptide.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000260032 | 1-433 | Serine/threonine-protein kinase STK11 | |||
Sequence: MDVADPEPLGLFSEGELMSVGMDTFIHRIDSTEVIYQPRRKRAKLIGKYLMGDLLGEGSYGKVKEVLDSETLCRRAVKILKKKKLRRIPNGEANVKKEIQLLRRLRHRNVIQLVDVLYNEEKQKMYMVMEYCVCGMQEMLDSVPEKRFPVCQAHGYFRQLIDGLEYLHSQGIVHKDIKPGNLLLTTNGTLKISDLGVAEALHPFAVDDTCRTSQGSPAFQPPEIANGLDTFSGFKVDIWSAGVTLYNITTGLYPFEGDNIYKLFENIGRGDFTIPCDCGPPLSDLLRGMLEYEPAKRFSIRQIRQHSWFRKKHPLAEALVPIPPSPDTKDRWRSMTVVPYLEDLHGRAEEEEEEDLFDIEDGIIYTQDFTVPGQVLEEEVGQNGQSHSLPKAVCVNGTEPQLSSKVKPEGRPGTANPARKVCSSNKIRRLSAC | ||||||
Modified residue | 31 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 44 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 48 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 96 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 97 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 189 | Phosphothreonine; by autocatalysis | ||||
Sequence: T | ||||||
Modified residue | 296 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 311 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 325 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 336 | Phosphothreonine; by autocatalysis | ||||
Sequence: T | ||||||
Modified residue | 366 | Phosphothreonine; by ATM and autocatalysis | ||||
Sequence: T | ||||||
Modified residue | 403 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 420 | N6-acetyllysine | ||||
Sequence: K | ||||||
Lipidation | 422 | S-palmitoyl cysteine | ||||
Sequence: C | ||||||
Modified residue | 426 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 431 | Phosphoserine; by autocatalysis, PKA, PKC/PRKCZ and RPS6KA1 | ||||
Sequence: S | ||||||
Modified residue | 433 | Cysteine methyl ester | ||||
Sequence: C | ||||||
Lipidation | 433 | S-farnesyl cysteine | ||||
Sequence: C | ||||||
Modified residue | 434 | N6-acetyllysine | ||||
Sequence: K | ||||||
Propeptide | PRO_0000422301 | 434-436 | Removed in mature form | |||
Sequence: KQQ |
Post-translational modification
Phosphorylated by ATM at Thr-366 following ionizing radiation (IR). Phosphorylation at Ser-431 by RPS6KA1 and/or some PKA is required to inhibit cell growth. Phosphorylation at Ser-431 is also required during neuronal polarization to mediate phosphorylation of BRSK1 and BRSK2. Phosphorylation by PKC/PRKCZ at Ser-399 in isoform 2 promotes metformin (or peroxynitrite)-induced nuclear export of STK11 and activation of AMPK. UV radiation-induced phosphorylation at Thr-366 mediates CDKN1A degradation.
Acetylated. Deacetylation at Lys-48 enhances cytoplasmic localization and kinase activity in vitro.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Isoform 1
Widely expressed.
Isoform 2
Predominantly expressed in testis (at protein level).
Isoform 3
Expressed in adult brain and liver and absent from tissues derived from postnatal day 7.
Developmental stage
Ubiquitously expressed 7-11 dpc. Present in nucleated embryonic blood cells from 9 dpc. Restricted to gastrointestinal tract, testis and lung from days 15-19 dpc.
Gene expression databases
Interaction
Subunit
Catalytic component of a trimeric complex composed of STK11/LKB1, STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): the complex tethers STK11/LKB1 in the cytoplasm and stimulates its catalytic activity. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with p53/TP53, SMAD4, STK11IP and WDR6. Interacts with NR4A1 (By similarity).
Interacts with NISCH; this interaction may increase STK11 activity (By similarity).
Interacts with PTEN, leading to PTEN phosphorylation (By similarity).
Interacts with SIRT1; the interaction deacetylates STK11 (By similarity).
Interacts with CDKN1A
Interacts with NISCH; this interaction may increase STK11 activity (By similarity).
Interacts with PTEN, leading to PTEN phosphorylation (By similarity).
Interacts with SIRT1; the interaction deacetylates STK11 (By similarity).
Interacts with CDKN1A
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q9WTK7 | Pard3b Q9CSB4 | 2 | EBI-8627450, EBI-16107395 | |
XENO | Q9WTK7 | PRKAA2 P54646 | 2 | EBI-8627450, EBI-1383852 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 45-90 | Sufficient for interaction with SIRT1 | ||||
Sequence: LIGKYLMGDLLGEGSYGKVKEVLDSETLCRRAVKILKKKKLRRIPN | ||||||
Domain | 49-309 | Protein kinase | ||||
Sequence: YLMGDLLGEGSYGKVKEVLDSETLCRRAVKILKKKKLRRIPNGEANVKKEIQLLRRLRHRNVIQLVDVLYNEEKQKMYMVMEYCVCGMQEMLDSVPEKRFPVCQAHGYFRQLIDGLEYLHSQGIVHKDIKPGNLLLTTNGTLKISDLGVAEALHPFAVDDTCRTSQGSPAFQPPEIANGLDTFSGFKVDIWSAGVTLYNITTGLYPFEGDNIYKLFENIGRGDFTIPCDCGPPLSDLLRGMLEYEPAKRFSIRQIRQHSWF | ||||||
Region | 397-421 | Disordered | ||||
Sequence: GTEPQLSSKVKPEGRPGTANPARKV |
Sequence similarities
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
This entry describes 3 isoforms produced by Alternative splicing.
Q9WTK7-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- SynonymsLKB1(L), STK11C
- Length436
- Mass (Da)49,267
- Last updated1999-11-01 v1
- ChecksumCCD9BCF94CF5CC9C
Q9WTK7-2
- Name2
- SynonymsLKB1(S)
Q9WTK7-3
- Name3
- SynonymsSTK11N
- Differences from canonical
Computationally mapped potential isoform sequences
There are 3 potential isoforms mapped to this entry
Features
Showing features for sequence conflict, alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 95 | in Ref. 2; BAE42728 | ||||
Sequence: V → L | ||||||
Alternative sequence | VSP_060609 | 98-232 | in isoform 3 | |||
Sequence: EIQLLRRLRHRNVIQLVDVLYNEEKQKMYMVMEYCVCGMQEMLDSVPEKRFPVCQAHGYFRQLIDGLEYLHSQGIVHKDIKPGNLLLTTNGTLKISDLGVAEALHPFAVDDTCRTSQGSPAFQPPEIANGLDTFS → PCTLSLWMTPAGQARAPRPSSLLRLPMDWTPFQVSRWTSGQLGSHFTTSPRACTHLRGTISTSSLRTLGEETSPSLVTAAHHSLTYSEGCWSMSRPRGSPSDRLGSTAGSGRNTLWLRRSYLSHQAQTLRTAGAV | ||||||
Alternative sequence | VSP_060610 | 233-436 | in isoform 3 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_052222 | 374-415 | in isoform 2 | |||
Sequence: QVLEEEVGQNGQSHSLPKAVCVNGTEPQLSSKVKPEGRPGTA → VEEAAEAGLSEDACDTCMWKSQGAGLPGEEPEEGFGALV | ||||||
Alternative sequence | VSP_052223 | 416-436 | in isoform 2 | |||
Sequence: Missing |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF129870 EMBL· GenBank· DDBJ | AAD22100.1 EMBL· GenBank· DDBJ | mRNA | ||
AF145287 EMBL· GenBank· DDBJ | AAD31044.1 EMBL· GenBank· DDBJ | mRNA | ||
EU730638 EMBL· GenBank· DDBJ | ACE73833.1 EMBL· GenBank· DDBJ | mRNA | ||
AF145296 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF145288 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF145289 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF145290 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF145291 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF145292 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF145293 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF145294 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF145295 EMBL· GenBank· DDBJ | AAD55368.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF151711 EMBL· GenBank· DDBJ | AAF21370.1 EMBL· GenBank· DDBJ | mRNA | ||
AB015801 EMBL· GenBank· DDBJ | BAA76749.1 EMBL· GenBank· DDBJ | mRNA | ||
KY779728 EMBL· GenBank· DDBJ | AVC68843.1 EMBL· GenBank· DDBJ | mRNA | ||
AK171909 EMBL· GenBank· DDBJ | BAE42728.1 EMBL· GenBank· DDBJ | mRNA | ||
AK172528 EMBL· GenBank· DDBJ | BAE43050.1 EMBL· GenBank· DDBJ | mRNA | ||
AK172385 EMBL· GenBank· DDBJ | BAE42977.1 EMBL· GenBank· DDBJ | mRNA | ||
BC052379 EMBL· GenBank· DDBJ | AAH52379.1 EMBL· GenBank· DDBJ | mRNA |