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PMID:16308421

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Citation

Shaw, RJ, Lamia, KA, Vasquez, D, Koo, SH, Bardeesy, N, Depinho, RA, Montminy, M and Cantley, LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642-6

Abstract

The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)-activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element-binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1alpha expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 in the liver to lower blood glucose levels.

Links

PubMed PMC3074427 Online version:10.1126/science.1120781

Keywords

AMP-Activated Protein Kinases; Animals; Blood Glucose/analysis; Diabetes Mellitus, Type 2/drug therapy; Diabetes Mellitus, Type 2/metabolism; Enzyme Activation; Female; Gene Expression Regulation; Gluconeogenesis/genetics; Glucose/metabolism; HeLa Cells; Homeostasis; Humans; Hyperglycemia/drug therapy; Hyperglycemia/metabolism; Hypoglycemic Agents/pharmacology; Hypoglycemic Agents/therapeutic use; Lipogenesis/genetics; Liver/enzymology; Liver/metabolism; Male; Metformin/pharmacology; Metformin/therapeutic use; Mice; Mice, Obese; Multienzyme Complexes/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Signal Transduction; Trans-Activators/genetics; Trans-Activators/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:STK11

enables

GO:0030295: protein kinase activator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:STK11

involved_in

GO:0042593: glucose homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:STK11

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CRTC2

involved_in

GO:0042593: glucose homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CRTC2

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CRTC2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AAPK2

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:AAPK2

enables

GO:0004679: AMP-activated protein kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:AAPK2

involved_in

GO:0042593: glucose homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AAPK1

involved_in

GO:0042593: glucose homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AAPK1

enables

GO:0004679: AMP-activated protein kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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