Platelet MAPKs—a 20+ year history: What do we really know?

Abstract

The existence of mitogen activated protein kinases (MAPKs) in platelets has been known for more than 20 years. Since that time hundreds of reports have been published describing the conditions that cause MAPK activation in platelets and their role in regulating diverse platelet functions from the molecular to physiological level. However, this cacophony of reports, with inconsistent and sometimes contradictory findings, has muddied the waters leading to great confusion. Since the last review of platelet MAPKs was published more than a decade ago, there have been more than 50 reports, including the description of novel knockout mouse models, that have furthered our knowledge. Therefore, we undertook an extensive literature review to delineate what is known about platelet MAPKs. We specifically discuss what is currently known about how MAPKs are activated and what signaling cascades they regulate in platelets incorporating recent findings from knockout mouse models. In addition, we will discuss the role each MAPK plays in regulating distinct platelet functions. In doing so, we hope to clarify the role for MAPKs and identify knowledge gaps in this field that await future researchers. In addition, we discuss the limitations of current studies with a particular focus on the off‐target effects of commonly used MAPK inhibitors. We conclude with a look at the clinical utility of MAPK inhibitors as potential antithrombotic therapies with an analysis of current clinical trial data.

Sulfenylome analysis of pathogen‐inactivated platelets reveals the presence of cysteine oxidation in integrin signaling pathway and cytoskeleton regulation

“…Of interest, integrin signaling, Rho‐GTPase, and p38MAPK pathways share common proteins and play a role in platelet activation, secretion, shape change, and clot retraction 2,3,44 . They involve phosphorylation events following surface receptors activation.…”

“…One well-known waterfall is the mitogen-activated protein kinases (MAPK) pathway that is triggered by the activation of surface receptors. 2 The phosphorylation is required in the inside-out signaling for platelet aggregation and granule secretion as well for the outside-in signaling and clot retraction through RhoGTPases pathway. 3 Protein oxidation related to reactive oxygen species (ROS, an important second messenger in platelet function 4 ) is another PTM that follows activation of receptors and initiates platelet activation.…”

“…The cascades of events are regulated by post‐translational modifications (PTMs) such as phosphorylation. One well‐known waterfall is the mitogen‐activated protein kinases (MAPK) pathway that is triggered by the activation of surface receptors 2 . The phosphorylation is required in the inside‐out signaling for platelet aggregation and granule secretion as well for the outside‐in signaling and clot retraction through RhoGTPases pathway 3 .…”

“…The sulfenylated set of proteins fits with the literature on PITs' impact over PC proteome (Figure 6B, red proteins). Pathway analysis with Panther GO revealed the implication of cysteine sulfenylation in various pathways involved in metabolism regulation, cell signaling, shape change, blood coagulation, and so on.Of interest, integrin signaling, Rho-GTPase, and p38MAPK pathways share common proteins and play a role in platelet activation, secretion, shape change, and clot retraction 2,3,44. They involve phosphorylation events following surface receptors activation.…”

SARS-CoV-2 and Plasma Hypercoagulability

“…provided evidence that this involves the mitogen-activated protein kinase (MAPK) pathway. 106 In platelets, activation of the MAPK pathway has been shown to lead to αII b β 3 activation, thromboxane A2 and α-granule release, phosphatidylserine exposure, and increased aggregation 66 (Fig. 1 ).…”