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serine/threonine protein kinase STK11; liver kinase B1; LKB1; hLKB1; renal carcinoma antigen NY-REN-19 (STK11, LKB1, PJS)

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 PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 & SNRK - does not phosphorylate MELK - 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: - interacts with p53/TP53 & recruited to the CDKN1A/WAF1 promoter to participate to transcription activation - 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) - 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 - 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) - the complex tethers STK11/LKB1 in the cytoplasm & stimulates its catalytic activity - found in a ternary complex composed of SMAD4, STK11/LKB1 & STK11IP - interacts with p53/TP53, SMAD4, STK11IP & WDR6 Cofactor: Mg+2 or Mn+2 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: a) testicular cancer b) 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

General

nuclear protein prenyl protein serine/threonine kinase

Properties

SIZE: entity length = 433 aa MW = 49 kD COMPARTMENT: mitochondria cytoplasm cell nucleus MOTIF: Ser phosphorylation site {S31} kinase domain SITE: 49-309 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 55-63 ATP-binding site NAME: ATP-binding site SITE: 78-78 aspartate residue {D176} Thr phosphorylation site {T189} Ser phosphorylation site {S325} Thr phosphorylation site {T336} Thr phosphorylation site {T363} Ser phosphorylation site {S428} FOR-PHOSPHORYLATION-BY: protein kinase A CaaX motif SITE: C-TERMINUS QUALITIES: AAX-TRUNCATED CARBOXYMETHYLATED EFFECTOR-BOUND: farnesyl BOUND-VIA: cysteine residue STATE: active state

Database Correlations

OMIM correlations MORBIDMAP 602216 UniProt Q15831 Pfam PF00069 Entrez Gene 6794 Kegg hsa:6794 ENZYME 2.7.11.1

References

  1. UniProt :accession Q15831
  2. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/STK11ID292.html
  3. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/STK11
  4. Wikipedia; Note: PJS entry http://en.wikipedia.org/wiki/PJS