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

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.