Redundant role of ASK1-mediated p38MAPK activation in human platelet function

Śledź, Kamila M.; Moore, Samantha; Vijayaragavan, Vijayasameerah; Mallah, Shahida; Goudswaard, Lucy J; Williams, Christopher M.; Hunter, Roger W.; Hers, Ingeborg

doi:10.1016/j.cellsig.2020.109528

Cited by 12 publications

(23 citation statements)

References 44 publications

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“…The only known substrate of ERK1/2 expressed in platelets is cPLA 2 ‐Ser505 31 . The MEK1/2 inhibitors PD184352 and U0126 attenuated agonist‐induced cPLA 2 ‐Ser505 phosphorylation and TxA 2 generation, 17,32 suggesting that ERK1/2 regulates cPLA 2 activity. But this is controversial as cPla 2 ‐Ser505 phosphorylation was unaffected in Map3k3 −/− mouse platelets, despite a clear reduction in Erk1/2 activity 26 .…”

Section: Erk1/2 Signaling and Platelet Functionmentioning

confidence: 99%

“…MK2 (MAPKAPK2) is also a substrate of p38 and may constitute a link between p38 activity and regulation of δ‐granule secretion and the actin cytoskeleton 32,47,66 . In addition to these canonical p38 substrates, P2Y 12 ‐Thr345 may be a novel target of p38 and/or JNK1/2 signaling as knockout of Ask1 attenuated P2Y 12 ‐Thr345 phosphorylation 29 .…”

Section: P38 Mapk Signaling and Platelet Functionmentioning

confidence: 99%

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

Patel

Naik

2020

Journal of Thrombosis and Haemostasis

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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.

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Section: Erk1/2 Signaling and Platelet Functionmentioning

confidence: 99%

Section: P38 Mapk Signaling and Platelet Functionmentioning

confidence: 99%

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

Patel

Naik

2020

Journal of Thrombosis and Haemostasis

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“…Platelet stimulation increases cPLA 2 phosphorylation at Ser‐505, which increases cPLA 2 activity 47‐50 . In platelets, both ERK1/2 and p38 are activated by anti‐CD9, 51 are known kinases for cPLA 2 Ser‐505, 19,34,52‐55 and are needed for cPLA 2 phosphorylation downstream of FcγRIIA 56 . Because ASK1 is a known regulator of p38 in platelets, we examined anti‐mCD9‐induced cPla 2 phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

“…phosphorylation and TxA 2 generation is due to the activity of ERK1/2, a cPLA 2 kinase. [52][53][54] This hypothesis is consistent with previous findings that: (1) both ERK1/2 and p38 are activated downstream of FcγRIIA and mediate IV.3-induced cPLA 2 phosphorylation in human platelets, 51,56 (2) that inhibition of both ERK1/2 and p38 is needed to block CRP-induced TxA 2 generation in murine platelets, 54 (3) that ERK1/2 is hyperactivated in Ask1 -/platelets, and (4) that ASK1 regulates early, but not late (likely ERK1/2 dependent), cPLA 2 phosphorylation in platelets. 19,34 Together, these observations suggest that although ASK1/p38 are needed for cPLA 2 phosphorylation and TxA 2 generation immediately after agonist addition, ASK1/p38 are not absolutely required for cPLA 2 phosphorylation and TxA 2 generation in platelets.…”

Section: Discussionmentioning

confidence: 99%

“…Ser-505,19,34,[52][53][54][55] and are needed for cPLA 2 phosphorylation downstream of FcγRIIA 56. Because ASK1 is a known regulator of p38 in platelets, we examined anti-mCD9-induced cPla 2 phosphorylation.Although anti-mCD9 induced phosphorylation of both cPla 2 and p38 in hFcR/Ask1 +/+ platelets, activation/phosphorylation of p38 was blocked in hFcR/Ask1 -/platelets.…”

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confidence: 99%

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Apoptosis signal‐regulating kinase 1 regulates immune‐mediated thrombocytopenia, thrombosis, and systemic shock

Patel

Shaik

Zhou

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Immune complexes (ICs) bind to and activate platelets via FcγRIIA, causing patients to experience thrombocytopenia, as well as an increased risk of forming occlusive thrombi. Although platelets have been shown to mediate IC-induced pathologies, the mechanisms involved have yet to be fully elucidated. We identified that apoptosis signal-regulating kinase 1 (ASK1) is present in both human and mouse platelets and potentiates many platelet functions. Objectives: Here we set out to study ASK1's role in regulating IC-mediated platelet functions in vitro and IC-induced pathologies using an in vivo mouse model. Methods: Using human platelets treated with an ASK1-specific inhibitor and platelets from FCGR2A/Ask1-/transgenic mice, we examined various platelet functions induced by model ICs in vitro and in vivo. Results: We found that ASK1 was activated in human platelets following cross-linking of FcγRIIA using either anti-hCD9 or IV.3 + goat-anti-mouse. Although genetic deletion or inhibition of ASK1 significantly attenuated anti-CD9-induced platelet aggregation, activation of the canonical FcγRIIA signaling targets Syk and PLCγ2 was unaffected. We further found that anti-mCD9-induced cPla 2 phosphorylation and TxA 2 generation is delayed in Ask1 null transgenic mouse platelets leading to diminished δ-granule secretion. In vivo, absence of Ask1 protected FCGR2A transgenic mice from thrombocytopenia, thrombosis, and systemic shock following injection of anti-mCD9. In whole blood microfluidics, platelet adhesion and thrombus formation on fibrinogen was enhanced by Ask1. Conclusions: These findings suggest that ASK1 inhibition may be a potential target for the treatment of IC-induced shock and other immune-mediated thrombotic disorders.

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Microplastics induced inflammation in the spleen of developmental Japanese quail (Coturnix japonica) via ROS-mediated p38 MAPK and TNF signaling pathway activation1

Zhang,

Jing

et al. 2024

Environmental Pollution

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Redundant role of ASK1-mediated p38MAPK activation in human platelet function

Cited by 12 publications

References 44 publications

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

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

Apoptosis signal‐regulating kinase 1 regulates immune‐mediated thrombocytopenia, thrombosis, and systemic shock

Microplastics induced inflammation in the spleen of developmental Japanese quail (Coturnix japonica) via ROS-mediated p38 MAPK and TNF signaling pathway activation1

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