MAPK1 regulates platelet function and thrombus formation.

Abstract

Background: Mitogen activated protein kinase 1 (MAPK1 or ERK2) is a Ser/Thr kinase and its inhibition by pharmacological inhibitors attenuated platelet function. However, conflicting results for different inhibitors were obtained due to off-target effects. Moreover, whether MAPK1 affects platelet function is unknown.

Objectives: This study intends to evaluate the role of MAPK1 in platelet activity and thrombus formation.

Methods: Megakaryocyte/platelet-specific MAPK1 knockout mice were generated and utilized to assess platelet aggregation, activation, procoagulant activity, spreading and clot retraction. In addition, tail bleeding time and arterial and venous thrombus formation assays were performed to evaluate the in vivo hemostatic function and thrombus formation.

Results: MAPK1 deficiency impaired hemostasis, both arterial and venous thrombosis. Consistently, MAPK1-deficient platelets presented reduced platelet aggregation, granules release, αIIbβ3 activation, calcium mobilization, procoagulant activity, spreading and clot retraction. Additionally, MAPK1 deficiency inhibited phosphorylation of p38, ERK5, JNK and ASK1 as well as the release of arachidonic acid and thromboxane B2. Moreover, MAPK1 interacts with talin1 and phosphorylates it at Ser425 in activated platelets and its deletion impaired the phosphorylation of talin1 and β3. Furthermore, inhibition of platelet feedback signaling by apyrase abolished the difference of platelet aggregation compared to control platelets and inhibited the phosphorylation of ASK1 and talin1 in activated control platelets. Finally, inhibition of MAPK1 decreased human platelet function and reduced the phosphorylation of talin1 and β3.

Conclusion: Our study identifies a novel mechanism for MAPK1 in the regulation of platelet function and thrombosis, implying its potential as a target to treat thrombotic disorders.