serine/threonine protein kinase STK11; liver kinase B1; LKB1; hLKB1; renal carcinoma antigen NY-REN-19 (STK11, LKB1, PJS)
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Function
- tumor suppressor serine/threonine protein kinase
- controls activity of AMP-activated protein kinase (AMPK) family members, thus playing a role in various processes such as cell metabolism, cell polarity, apoptosis & DNA damage response
- acts by phosphorylating the T-loop of AMPK family proteins, leading to promote their activity
- phosphorylates non-AMPK family proteins such as STRADA & possibly p53/TP53
- acts as a key upstream regulator of AMPK by mediating phosphorylation & activation of AMPK catalytic subunits PRKAA1 & PRKAA2, thus regulating
- inhibition of signaling pathways that promote cell growth & proliferation when energy levels are low
- glucose homeostasis in liver
- activation of autophagy when cells undergo nutrient deprivation
- 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 neurons polarization by mediating phosphorylation & activation of BRSK1 & BRSK2, leading to axon initiation & specification
- involved in DNA damage response:
- able to promote phosphorylation of p53/TP53
- relevance unclear
- phosphorylation may be indirect & mediated by dowstream STK11/LKB1 kinase NUAK1
- translocates to mitochondrion during apoptosis & regulates p53/TP53-dependent apoptosis pathways
- activated by forming a complex with STRAD (STRADA or STRADB) & CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta)
- phosphorylated by ATM at Thr-363 following ionizing radiation
- phosphorylation at Ser-428 by RPS6KA1 &/or some PKA is required to inhibit cell growth
- phosphorylation at Ser-428 is also required during neuronal polarization to mediate phosphorylation of BRSK1 & BRSK2 (putative)
- catalytic component of a trimeric complex composed of STK11/LKB1, STRAD (STRADA or STRADB) & CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta)
- found in a ternary complex composed of SMAD4, STK11/LKB1 & STK11IP
- interacts with p53/TP53, SMAD4, STK11IP & WDR6
Structure
- belongs to the protein kinase superfamily, CAMK Ser/Thr protein kinase family, LKB1 subfamily
- contains 1 protein kinase domain
Compartment
- nucleus., cytoplasm, membrane, mitochondria
- a small fraction localizes at membranes (putative)
- relocates to the cytoplasm when bound to STRAD (STRADA or STRADB) & CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta)
- translocates to mitochondrion during apoptosis
Alternative splicing
named isoforms=2
Expression
- ubiquitously expressed
- strongest expression in testis & fetal liver
Pathology
- defects in STK11 are a cause of Peutz-Jeghers syndrome
- defects in STK11 are associated with:
- testicular cancer
- some sporadic cancers, especially lung cancer
- frequently mutated & inactivated in non-small cell lung cancer
- defects promote lung cancerigenesis process, especially lung cancer progression & metastasis
- allows lung adenocarcinoma to transform into lung squamous cell carcinoma
- promotes lung cancer metastasis, via both cancer-cell autonomous & non-cancer-cell autonomous mechanisms
More general terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/Q15831.html
- ↑ Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/STK11ID292.html
- ↑ GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/STK11
- ↑ Wikipedia; Note: PJS entry http://en.wikipedia.org/wiki/PJS
Database
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=6794
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:6794
- OMIM: https://mirror.omim.org/entry/175200
- OMIM: https://mirror.omim.org/entry/273300
- OMIM: https://mirror.omim.org/entry/602216
- UniProt: http://www.uniprot.org/uniprot/Q15831.html