Fyn-Dependent Regulation of Energy Expenditure and Body Weight Is Mediated by Tyrosine Phosphorylation of LKB1

Eijiro Yamada, Jeffrey E. Pessin, Irwin J. Kurland, Gary J. Schwartz, Claire C. Bastie

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Fyn null mice display reduced adiposity associated with increased fatty acid oxidation, energy expenditure, and activation of the AMP-dependent protein kinase (AMPK) in skeletal muscle and adipose tissue. The acute pharmacological inhibition of Fyn kinase activity with SU6656 in wild-type mice reproduces these metabolic effects and induced a specific reduction in fat mass with no change in lean mass. LKB1, the main upstream AMPK kinase (AMPKK) in peripheral tissues, was redistributed from the nucleus into the cytoplasm of cells treated with SU6656 and in cells expressing a kinase-deficient, but not a constitutively kinase-active, Fyn mutant. Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues, and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation. These data demonstrate a crosstalk between Fyn tyrosine kinase and the AMPK energy-sensing pathway, through Fyn-dependent regulation of the AMPK upstream activator LKB1.

Original languageEnglish (US)
Pages (from-to)113-124
Number of pages12
JournalCell Metabolism
Volume11
Issue number2
DOIs
StatePublished - Feb 3 2010

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Adenosine Monophosphate
Protein Kinases
Energy Metabolism
Tyrosine
Phosphotransferases
Body Weight
Phosphorylation
Cytoplasm
Proto-Oncogene Proteins c-fyn
Adiposity
Adipose Tissue
Skeletal Muscle
Fatty Acids
Fats
Pharmacology
Muscles
Mutation
SU 6656

Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Fyn-Dependent Regulation of Energy Expenditure and Body Weight Is Mediated by Tyrosine Phosphorylation of LKB1. / Yamada, Eijiro; Pessin, Jeffrey E.; Kurland, Irwin J.; Schwartz, Gary J.; Bastie, Claire C.

In: Cell Metabolism, Vol. 11, No. 2, 03.02.2010, p. 113-124.

Research output: Contribution to journalArticle

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AB - Fyn null mice display reduced adiposity associated with increased fatty acid oxidation, energy expenditure, and activation of the AMP-dependent protein kinase (AMPK) in skeletal muscle and adipose tissue. The acute pharmacological inhibition of Fyn kinase activity with SU6656 in wild-type mice reproduces these metabolic effects and induced a specific reduction in fat mass with no change in lean mass. LKB1, the main upstream AMPK kinase (AMPKK) in peripheral tissues, was redistributed from the nucleus into the cytoplasm of cells treated with SU6656 and in cells expressing a kinase-deficient, but not a constitutively kinase-active, Fyn mutant. Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues, and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation. These data demonstrate a crosstalk between Fyn tyrosine kinase and the AMPK energy-sensing pathway, through Fyn-dependent regulation of the AMPK upstream activator LKB1.

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