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Protein

Serine/threonine-protein kinase STK11

Gene

Stk11

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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. In vein endothelial cells, inhibits PI3K/Akt signaling activity and thus induces apoptosis in response to the oxidant peroxynitrite. 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 (By similarity).By similarity1 Publication
Isoform 2: Has a role in spermiogenesis.1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity, Mn2+By similarity

Enzyme regulationi

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).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei78 – 781ATPPROSITE-ProRule annotation
Active sitei178 – 1781Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi55 – 639ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • metal ion binding Source: UniProtKB-KW
  • p53 binding Source: UniProtKB
  • protein complex binding Source: RGD
  • protein kinase activator activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: RGD

GO - Biological processi

  • autophagy Source: UniProtKB-KW
  • axonogenesis Source: RGD
  • cell cycle Source: UniProtKB-KW
  • cellular response to DNA damage stimulus Source: UniProtKB-KW
  • establishment of cell polarity Source: UniProtKB
  • glucose homeostasis Source: UniProtKB
  • intrinsic apoptotic signaling pathway by p53 class mediator Source: UniProtKB
  • negative regulation of cell growth Source: UniProtKB
  • positive regulation of gluconeogenesis Source: RGD
  • protein autophosphorylation Source: UniProtKB
  • protein heterooligomerization Source: RGD
  • regulation of cell growth Source: UniProtKB
  • response to glucagon Source: RGD
  • response to ionizing radiation Source: UniProtKB
  • response to lipid Source: RGD
  • response to peptide hormone Source: RGD
  • spermatogenesis Source: UniProtKB-KW
  • vasculature development Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Apoptosis, Autophagy, Cell cycle, Differentiation, DNA damage, Spermatogenesis

Keywords - Ligandi

ATP-binding, Magnesium, Manganese, Metal-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase STK11 (EC:2.7.11.1)
Alternative name(s):
Liver kinase B1 homolog
Short name:
LKB1
Gene namesi
Name:Stk11
Synonyms:Lkb1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi1308653. Stk11.

Subcellular locationi

Isoform 2 :
  • Nucleus
  • Cytoplasm

  • Note: Relocates to the cytoplasm when bound to STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta).

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: UniProtKB
  • membrane Source: UniProtKB
  • mitochondrion Source: UniProtKB
  • nucleus Source: RGD
  • protein complex Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Mitochondrion, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 435435Serine/threonine-protein kinase STK11PRO_0000412651Add
BLAST
Propeptidei436 – 4383Removed in mature formBy similarityPRO_0000422302

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei31 – 311PhosphoserineCombined sources
Modified residuei44 – 441N6-acetyllysineBy similarity
Modified residuei48 – 481N6-acetyllysineBy similarity
Modified residuei96 – 961N6-acetyllysineBy similarity
Modified residuei97 – 971N6-acetyllysineBy similarity
Modified residuei191 – 1911Phosphothreonine; by autocatalysisBy similarity
Modified residuei298 – 2981N6-acetyllysineBy similarity
Modified residuei313 – 3131N6-acetyllysineBy similarity
Modified residuei327 – 3271PhosphoserineBy similarity
Modified residuei338 – 3381Phosphothreonine; by autocatalysisBy similarity
Modified residuei368 – 3681Phosphothreonine; by ATM and autocatalysisBy similarity
Modified residuei405 – 4051PhosphoserineBy similarity
Modified residuei422 – 4221N6-acetyllysineBy similarity
Lipidationi424 – 4241S-palmitoyl cysteineBy similarity
Modified residuei428 – 4281N6-acetyllysineBy similarity
Modified residuei433 – 4331Phosphoserine; by autocatalysis, PKA, PKC/PRKCZ and RPS6KA1By similarity
Modified residuei435 – 4351Cysteine methyl esterBy similarity
Lipidationi435 – 4351S-farnesyl cysteineBy similarity
Modified residuei436 – 4361N6-acetyllysineBy similarity

Post-translational modificationi

Phosphorylated by ATM at Thr-368 following ionizing radiation (IR). Phosphorylation at Ser-433 by RPS6KA1 and/or some PKA is required to inhibit cell growth. Phosphorylation at Ser-433 is also required during neuronal polarization to mediate phosphorylation of BRSK1 and BRSK2. Phosphorylation by PKC/PRKCZ at Ser-428 promotes peroxynitrite-induced nuclear export of STK11, leading to PTEN activation and subsequent inhibition of AKT signaling. 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-368 mediates CDKN1A degradation.By similarity
Acetylated. Deacetylation at Lys-48 enhances cytoplasmic localization and kinase activity in vitro.1 Publication

Keywords - PTMi

Acetylation, Lipoprotein, Methylation, Palmitate, Phosphoprotein, Prenylation

Proteomic databases

PaxDbiD4AE59.
PeptideAtlasiD4AE59.

PTM databases

iPTMnetiD4AE59.

Expressioni

Tissue specificityi

Expressed in brain, heart, testis, skeletal muscle and spleen, and weakly in liver and kidney. Isoform 1 is expressed at highest levels in the brain. Isoform 2 is expressed at highest levels in the testis, primarily in postmitotic developing germ cells (at protein level).1 Publication

Developmental stagei

Isoform 2 is expressed in testis from 30 days of age, with significantly increased levels by 60 days; this corresponds to the stage when haploid spermatids appear.1 Publication

Gene expression databases

BgeeiENSRNOG00000014287.
GenevisibleiD4AE59. RN.

Interactioni

Subunit structurei

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 (By similarity). Interacts with NR4A1, p53/TP53, SMAD4, STK11IP and WDR6 (By similarity). Interacts with NISCH; this interaction may increase STK11 activity (By similarity). Interacts with SIRT1; the interaction deacetylates STK11 (By similarity). Interacts with CDKN1A (By similarity).By similarity2 Publications

GO - Molecular functioni

  • p53 binding Source: UniProtKB
  • protein complex binding Source: RGD

Protein-protein interaction databases

IntActiD4AE59. 1 interaction.
STRINGi10116.ENSRNOP00000057414.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini49 – 311263Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni45 – 9046Sufficient for interaction with SIRT1By similarityAdd
BLAST

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0583. Eukaryota.
COG0515. LUCA.
InParanoidiD4AE59.
OrthoDBiEOG091G0BNP.
PhylomeDBiD4AE59.
TreeFamiTF105322.

Family and domain databases

InterProiIPR020636. Ca/CaM-dep_Ca-dep_prot_Kinase.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERiPTHR24347. PTHR24347. 1 hit.
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: D4AE59-1) [UniParc]FASTAAdd to basket
Also known as: LKB1(L)

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.

« Hide

        10         20         30         40         50
MDVADPQPLG LFPEGELMSV GMDTFIHRID STEVIYQPRR KRAKLIGKYL
60 70 80 90 100
MGDLLGEGSY GKVKEVLDSE TLCRRAVKIL KKKKLRRIPN GEANVKKEIQ
110 120 130 140 150
LLRRLRHRNV IQLVDVLYNE EKQKRPTYMV MEYCVCGMQE MLDSVPEKRF
160 170 180 190 200
PVCQAHGYFR QLIDGLEYLH SQGIVHKDIK PGNLLLTTNG TLKISDLGVA
210 220 230 240 250
EALHPFAVDD TCRTSQGSPA FQPPEIANGL DTFSGFKVDI WSAGVTLYNI
260 270 280 290 300
TTGLYPFEGD NIYKLFENIG RGDFTIPCDC APPLSDLLRG MLEYEPAKRF
310 320 330 340 350
SIRQIRQHSW FRKKHPLAEA LVPIPPSPDT KDRWRSMTVV PYLEDLHGRA
360 370 380 390 400
EEEEDEDLFD IEDGIIYTQD FTVPGQVLEE EVGQNGQSHS LPKAVCVNGT
410 420 430
EPQLSSKVKP EGRPGAANPA RKVCSSNKIR RLSACKQQ
Length:438
Mass (Da):49,469
Last modified:April 20, 2010 - v1
Checksum:i25F0FFF43342C8FD
GO
Isoform 2 (identifier: D4AE59-2) [UniParc]FASTAAdd to basket
Also known as: LKB1(S)

The sequence of this isoform differs from the canonical sequence as follows:
     376-438: QVLEEEVGQN...IRRLSACKQQ → VEETAESGLS...EPEEGFGAVV

Show »
Length:414
Mass (Da):46,758
Checksum:iF8137B1E00CAC44D
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei376 – 43863QVLEE…ACKQQ → VEETAESGLSEDACDTCMWK SQGAGLPGEEPEEGFGAVV in isoform 2. CuratedVSP_055418Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AABR06047719 Genomic DNA. No translation available.
UniGeneiRn.12052.

Genome annotation databases

UCSCiRGD:1308653. rat. [D4AE59-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AABR06047719 Genomic DNA. No translation available.
UniGeneiRn.12052.

3D structure databases

ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiD4AE59. 1 interaction.
STRINGi10116.ENSRNOP00000057414.

PTM databases

iPTMnetiD4AE59.

Proteomic databases

PaxDbiD4AE59.
PeptideAtlasiD4AE59.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

UCSCiRGD:1308653. rat. [D4AE59-1]

Organism-specific databases

RGDi1308653. Stk11.

Phylogenomic databases

eggNOGiKOG0583. Eukaryota.
COG0515. LUCA.
InParanoidiD4AE59.
OrthoDBiEOG091G0BNP.
PhylomeDBiD4AE59.
TreeFamiTF105322.

Miscellaneous databases

PROiD4AE59.

Gene expression databases

BgeeiENSRNOG00000014287.
GenevisibleiD4AE59. RN.

Family and domain databases

InterProiIPR020636. Ca/CaM-dep_Ca-dep_prot_Kinase.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERiPTHR24347. PTHR24347. 1 hit.
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSTK11_RAT
AccessioniPrimary (citable) accession number: D4AE59
Secondary accession number(s): D4A179
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 21, 2011
Last sequence update: April 20, 2010
Last modified: September 7, 2016
This is version 54 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.