Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1.
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.
Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Eijiro
E
Yamada
Jeffrey E
JE
Pessin
Irwin J
IJ
Kurland
Gary J
GJ
Schwartz
Claire C
CC
Bastie
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects; D055786:Gene Knockout Techniques; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism*
D007211:Indoles; C416927:SU 6656; D013449:Sulfonamides; D014443:Tyrosine; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases