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MGP003014

UniProt Annotations

Entry Information
Gene Nameserine/threonine kinase 11
Protein EntrySTK11_HUMAN
UniProt IDQ15831
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; Synonyms=LKB1(L); IsoId=Q15831-1; Sequence=Displayed; Name=2; Synonyms=LKB1(S); IsoId=Q15831-2; Sequence=VSP_041746; Note=Phosphorylated by PKC/PRKCZ on Ser-399.;
Catalytic ActivityATP + a protein = ADP + a phosphoprotein. {ECO:0000269|PubMed:14976552}.
CofactorName=Mg(2+); Xref=ChEBI:CHEBI:18420; Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
DiseaseNote=Defects in STK11 are associated with some sporadic cancers, especially lung cancers. Frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Defects promote lung cancerigenesis process, especially lung cancer progression and metastasis. Confers lung adenocarcinoma the ability to trans- differentiate into squamous cell carcinoma. Also able to promotes lung cancer metastasis, via both cancer-cell autonomous and non- cancer-cell autonomous mechanisms.
DiseasePeutz-Jeghers syndrome (PJS) [MIM:175200]: An autosomal dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer. {ECO:0000269|PubMed:10408777, ECO:0000269|PubMed:12372054, ECO:0000269|PubMed:21411391, ECO:0000269|PubMed:9425897, ECO:0000269|PubMed:9428765, ECO:0000269|PubMed:9760200, ECO:0000269|PubMed:9837816}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseTesticular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:9605748}. Note=The gene represented in this entry may be involved in disease pathogenesis.
Enzyme RegulationActivated 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. {ECO:0000269|PubMed:19892943, ECO:0000269|PubMed:22983157}.
FunctionIsoform 2: Has a role in spermiogenesis. {ECO:0000250}.
FunctionTumor 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 (in vitro). 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). {ECO:0000269|PubMed:11430832, ECO:0000269|PubMed:12805220, ECO:0000269|PubMed:14517248, ECO:0000269|PubMed:14976552, ECO:0000269|PubMed:15016379, ECO:0000269|PubMed:15733851, ECO:0000269|PubMed:15987703, ECO:0000269|PubMed:17108107, ECO:0000269|PubMed:18321849, ECO:0000269|PubMed:21317932, ECO:0000269|PubMed:25329316}.
InteractionQ9Y376:CAB39; NbExp=5; IntAct=EBI-306838, EBI-306905; Q16543:CDC37; NbExp=3; IntAct=EBI-306838, EBI-295634; Q13451:FKBP5; NbExp=3; IntAct=EBI-306838, EBI-306914; P07900:HSP90AA1; NbExp=2; IntAct=EBI-306838, EBI-296047; P08238:HSP90AB1; NbExp=3; IntAct=EBI-306838, EBI-352572; Q96L34:MARK4; NbExp=2; IntAct=EBI-306838, EBI-302319; Q7RTN6:STRADA; NbExp=10; IntAct=EBI-306838, EBI-1109114; Q9C0K7:STRADB; NbExp=6; IntAct=EBI-306838, EBI-306893; Q8NFZ5:TNIP2; NbExp=5; IntAct=EBI-306838, EBI-359372; Q9NNW5:WDR6; NbExp=3; IntAct=EBI-306838, EBI-1568315; P63104:YWHAZ; NbExp=6; IntAct=EBI-306838, EBI-347088;
PtmAcetylated. Deacetylation at Lys-48 enhances cytoplasmic localization and kinase activity in vitro. {ECO:0000269|PubMed:18687677}.
PtmPhosphorylated by ATM at Thr-363 following ionizing radiation (IR). Phosphorylation at Ser-428 by RPS6KA1 and/or some PKA is required to inhibit cell growth. Phosphorylation at Ser-428 is also required during neuronal polarization to mediate phosphorylation of BRSK1 and BRSK2 (By similarity). 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-363 mediates CDKN1A degradation (By similarity). {ECO:0000250|UniProtKB:Q9WTK7, ECO:0000269|PubMed:11430832, ECO:0000269|PubMed:12805220, ECO:0000269|PubMed:18321849, ECO:0000269|PubMed:18854309}.
SimilarityBelongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. LKB1 subfamily. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationIsoform 2: Nucleus {ECO:0000269|PubMed:23612973}. Cytoplasm {ECO:0000269|PubMed:23612973}. Note=Predominantly nuclear, but translocates to the cytoplasm in response to metformin or peroxynitrite treatment.
Subcellular LocationNucleus. Cytoplasm. Membrane {ECO:0000250}. Mitochondrion. Note=A small fraction localizes at membranes (By similarity). Relocates to the cytoplasm when bound to STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta). Translocates to the mitochondrion during apoptosis. Translocates to the cytoplasm in response to metformin or peroxynitrite treatment. PTEN promotes cytoplasmic localization. {ECO:0000250}.
SubunitCatalytic 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. Interacts with NISCH; this interaction may increase STK11 activity. Interacts with PTEN; leading to PTEN phosphorylation. Interacts with SIRT1; the interaction deacetylates STK11. Interacts with CDKN1A. {ECO:0000269|PubMed:11741830, ECO:0000269|PubMed:12805220, ECO:0000269|PubMed:14517248, ECO:0000269|PubMed:15987703, ECO:0000269|PubMed:17108107, ECO:0000269|PubMed:17216128, ECO:0000269|PubMed:18687677, ECO:0000269|PubMed:19892943, ECO:0000269|PubMed:22983157, ECO:0000269|PubMed:23572524, ECO:0000269|PubMed:25329316}.
Tissue SpecificityUbiquitously expressed. Strongest expression in testis and fetal liver.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/STK11ID292.html";
Web ResourceName=Wikipedia; Note=PJS entry; URL="http://en.wikipedia.org/wiki/PJS";
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