Ask1 regulates murine platelet granule secretion, thromboxane A generation, and thrombus formation.

Mitogen-activated protein kinases (MAPKs) are expressed in platelets and are activated downstream of physiological agonists. Pharmacological and genetic evidence indicate that MAPKs play a significant role in hemostasis and thrombosis, but it is not well understood how MAPKs are activated upon platelet stimulation. Here, we show that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP3K family, is expressed in both human and murine platelets. ASK1 is rapidly and robustly activated upon platelet stimulation by physiological agonists. Disruption of ( ) resulted in a marked functional defect in platelets. platelets showed an impaired agonist-induced integrin αβ activation and platelet aggregation. Although there was no difference in Ca rise, platelet granule secretion and thromboxane A (TxA) generation were significantly attenuated in platelets. The defective granule secretion observed in platelets was a consequence of impaired TxA generation. Biochemical studies showed that platelet agonists failed to activate p38 MAPK in platelets. On the contrary, activation of c-Jun -terminal kinases and extracellular signal-regulated kinase 1/2 MAPKs was augmented in platelets. The defect in p38 MAPK results in failed phosphorylation of cPLA in platelets and impaired platelet aggregate formation under flow. The absence of Ask1 renders mice defective in hemostasis as assessed by prolonged tail-bleeding times. Deletion of also reduces thrombosis as assessed by delayed vessel occlusion of carotid artery after FeCl-induced injury and protects against collagen/epinephrine-induced pulmonary thromboembolism. These results suggest that the platelet Ask1 plays an important role in regulation of hemostasis and thrombosis.