RGD Reference Report - Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. - Rat Genome Database

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Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade.

Authors: Hawley, SA  Boudeau, J  Reid, JL  Mustard, KJ  Udd, L  Makela, TP  Alessi, DR  Hardie, DG 
Citation: Hawley SA, etal., J Biol. 2003;2(4):28. Epub 2003 Sep 24.
RGD ID: 1600691
Pubmed: PMID:14511394   (View Abstract at PubMed)
PMCID: PMC333410   (View Article at PubMed Central)
DOI: DOI:10.1186/1475-4924-2-28   (Journal Full-text)

BACKGROUND: The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as a 'metabolic master switch' and inhibits cell proliferation. Activation requires phosphorylation of Thr172 of AMPK within the activation loop by upstream kinases (AMPKKs) that have not been identified. Recently, we identified three related protein kinases acting upstream of the yeast homolog of AMPK. Although they do not have obvious mammalian homologs, they are related to LKB1, a tumor suppressor that is mutated in the human Peutz-Jeghers cancer syndrome. We recently showed that LKB1 exists as a complex with two accessory subunits, STRAD alpha/beta and MO25 alpha/beta. RESULTS: We report the following observations. First, two AMPKK activities purified from rat liver contain LKB1, STRAD alpha and MO25 alpha, and can be immunoprecipitated using anti-LKB1 antibodies. Second, both endogenous and recombinant complexes of LKB1, STRAD alpha/beta and MO25 alpha/beta activate AMPK via phosphorylation of Thr172. Third, catalytically active LKB1, STRAD alpha or STRAD beta and MO25 alpha or MO25 beta are required for full activity. Fourth, the AMPK-activating drugs AICA riboside and phenformin do not activate AMPK in HeLa cells (which lack LKB1), but activation can be restored by stably expressing wild-type, but not catalytically inactive, LKB1. Fifth, AICA riboside and phenformin fail to activate AMPK in immortalized fibroblasts from LKB1-knockout mouse embryos. CONCLUSIONS: These results provide the first description of a physiological substrate for the LKB1 tumor suppressor and suggest that it functions as an upstream regulator of AMPK. Our findings indicate that the tumors in Peutz-Jeghers syndrome could result from deficient activation of AMPK as a consequence of LKB1 inactivation.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
STK11HumanPeutz-Jeghers syndrome  TAS  RGD 
Stk11RatPeutz-Jeghers syndrome  ISOSTK11 (Homo sapiens) RGD 
Stk11MousePeutz-Jeghers syndrome  ISOSTK11 (Homo sapiens) RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
StradaRatactivation of protein kinase activity involved_inIDA PMID:14511394UniProt 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cab39Ratprotein-containing complex  IDA  RGD 
Prkaa1Ratprotein-containing complex  IDA  RGD 
Prkaa2Ratprotein-containing complex  IDA  RGD 
Prkab1Ratprotein-containing complex  IDA  RGD 
Prkag1Ratprotein-containing complex  IDA  RGD 
Stk11Ratprotein-containing complex  IDA  RGD 
StradaRatprotein-containing complex  IDA  RGD 

Molecular Function

  

Molecular Pathway Annotations    Click to see Annotation Detail View
Objects Annotated

Genes (Rattus norvegicus)
Cab39  (calcium binding protein 39)
Prkaa1  (protein kinase AMP-activated catalytic subunit alpha 1)
Prkaa2  (protein kinase AMP-activated catalytic subunit alpha 2)
Prkab1  (protein kinase AMP-activated non-catalytic subunit beta 1)
Prkag1  (protein kinase AMP-activated non-catalytic subunit gamma 1)
Stk11  (serine/threonine kinase 11)
Strada  (STE20 related adaptor alpha)

Genes (Mus musculus)
Stk11  (serine/threonine kinase 11)

Genes (Homo sapiens)
STK11  (serine/threonine kinase 11)


Additional Information