Regulation of c-Jun-NH2 Terminal Kinase and Extracellular-Signal Regulated Kinase in Human Platelets

Abstract

Platelets are an interesting model for studying the relationship betwen adhesion and mitogen-activated protein (MAP) kinase activation. We have recently shown that in platelets, ERK2 was activated by thrombin and downregulated by IIbβ3integrin engagement. Here we focused our attention on the c-Jun NH2-terminal kinases (JNKs) and their activation in conditions of platelet aggregation. We found that JNK1 was present in human platelets and was activated after thrombin induction. JNK1 phosphorylation was detected with low concentrations of thrombin (0.02 U/mL) and after 1 minute of thrombin-induced platelet aggregation. JNK1 activation was increased (fivefold) when fibrinogen binding to IIbβ3 integrin was inhibited by the Arg-Gly-Asp-Ser (RGDS) peptide or (Fab′)2 fragments of a monoclonal antibody specific for IIbβ3, demonstrating that, like ERK2, IIbβ3 integrin engagement negatively regulates JNK1 activation. Comparison of JNK1 activation by thrombin in stirred and unstirred platelets in the presence of RGDS peptide showed a positive regulation by stirring itself, independently of IIbβ3 integrin engagement, which was confirmed in a thrombasthenic patient lacking platelet IIbβ3. The same positive regulation by stirring was found for ERK2. These results suggest that MAP kinases (JNK1 and ERK2) are activated positively by thrombin and stirring. In conclusion, we found that JNK1 is present in platelets and can be activated after thrombin induction. Moreover, this is the first report showing that two different MAP kinases (ERK2 and JNK1) are regulated negatively by IIbβ3 engagement and positively by mechanical forces in platelets.

Inhibitory mechanisms of resveratrol in platelet activation: pivotal roles of p38 MAPK and NO/cyclic GMP

“…The MAPKs consist of three major subgroups. The ERKs (p44 ERK1 and p42 ERK2) are involved in proliferation, adhesion and cell progression (Bugaud et al , 1999). p38 MAPK and JNKs, or stress‐activated protein kinases, which include the 46‐kDa JNK1 and 55‐kDa JNK2 isoforms, appear to be involved in apoptosis (Bugaud et al , 1999).…”

“…The ERKs (p44 ERK1 and p42 ERK2) are involved in proliferation, adhesion and cell progression (Bugaud et al , 1999). p38 MAPK and JNKs, or stress‐activated protein kinases, which include the 46‐kDa JNK1 and 55‐kDa JNK2 isoforms, appear to be involved in apoptosis (Bugaud et al , 1999). In platelets, ERKs (especially ERK2), JNK, and p38 MAPK, have been identified (Bugaud et al , 1999).…”

“…p38 MAPK and JNKs, or stress‐activated protein kinases, which include the 46‐kDa JNK1 and 55‐kDa JNK2 isoforms, appear to be involved in apoptosis (Bugaud et al , 1999). In platelets, ERKs (especially ERK2), JNK, and p38 MAPK, have been identified (Bugaud et al , 1999). JNK is present and active in platelets and is regulated similarly to ERK2 (Bugaud et al , 1999).…”

“…In platelets, ERKs (especially ERK2), JNK, and p38 MAPK, have been identified (Bugaud et al , 1999). JNK is present and active in platelets and is regulated similarly to ERK2 (Bugaud et al , 1999). The roles of JNK and ERK2 in physiopathology are unclear, but they have been suggested to be suppressors of α IIb β 3 activation or negative regulators of platelet activation (Hughes et al , 1997).…”

Costimulation of the Gi‐coupled ADP receptor and the Gq‐coupled TXA2 receptor is required for ERK2 activation in collagen‐induced platelet aggregation

“…Collagen induces mitogen‐activated protein kinase (MAPK) activation [16]. Platelet MAPKs include the extracellular signal‐regulated kinase (ERKs), the c‐Jun N‐terminal kinase (JNK) and p38 MAPK [17–19]. ERKs are activated by various agonists, including thrombin, collagen, and TXA 2 [17].…”