AMPK α2 subunit is involved in platelet signaling, clot retraction, and thrombus stability.
The adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a regulator of energy balance at the cellular and whole-body levels, but little is known about the role of AMPK in platelet activation. We report that both the α1 and α2 AMPK isoforms are expressed by human and murine platelets and that thrombin elicits the phosphorylation of AMPKα as well as the upstream kinase, liver kinase B1 (LKB1). In human platelets, the kinase inhibitors iodotubercidin and compound C significantly inhibited thrombin-induced platelet aggregation and clot retraction without affecting the initial increase in [Ca(2+)](i). Clot retraction was also impaired in platelets from AMPKα2(-/-) mice but not from wild-type littermates or AMPKα1(-/-) mice. Moreover, rebleeding was more frequent in AMPKα2(-/-) mice, and the FeCl(3)-induced thrombi formed in AMPKα2(-/-) mice were unstable. Mechanistically, AMPKα2 was found to phosphorylate in vitro the Src-family kinase, Fyn, and isoform deletion resulted in the attenuated threonine phosphorylation of Fyn as well as the subsequent tyrosine phosphorylation of its substrate, β3 integrin. These data indicate that AMPKα2-by affecting Fyn phosphorylation and activity-plays a key role in platelet αIIbβ3 integrin signaling, leading to clot retraction and thrombus stability.
Randriamboavonjy
Voahanginirina
V
Institute for Vascular Signalling, Centre for Molecular Medicine, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
Isaak
Johann
J
Frömel
Timo
T
Viollet
Benoit
B
Fisslthaler
Beate
B
Preissner
Klaus T
KT
Fleming
Ingrid
I
D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D001792:Blood Platelets / Q000473:pathology* / Q000502:physiology; D002712:Chlorides; D003018:Clot Retraction; D005290:Ferric Compounds; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D015398:Signal Transduction; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology*
D002712:Chlorides; D005290:Ferric Compounds; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D055372:AMP-Activated Protein Kinases; C024555:ferric chloride