ASK1 facilitates tumor metastasis through phosphorylation of an ADP receptor P2Y12 in platelets

Kamiyama, Manabu; Shirai, Toshiaki; Tamura, Shogo; Suzuki‐Inoue, Katsue; Ehata, Shogo; Takahashi, Kei; Miyazono, Kohei; Hayakawa, Yoshihiro; Sato, Takehiro; Takeda, Kohsuke; Naguro, Isao; Ichijo, Hidenori

doi:10.1038/cdd.2017.114

Cited by 36 publications

(45 citation statements)

References 43 publications

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“…ASK1 inhibition slows the growth of gastric cancer xenografts in mice and Ask1 −/− mice have fewer and smaller tumours than wild-type controls in the N-methyl-N-nitrosourea chemically induced gastric tumourigenesis model [72,113]. Moreover, plateletspecific deletion of ASK1 prevents tumour metastasis in mice that have established lung cancer, induced by the injection of either melanoma or Lewis lung carcinoma cells [69,114]. Thus, it is apparent that ASK1 can function as both a tumour suppressor or tumour promoter, depending on the cellular responses induced by ASK1 modulation.…”

Section: Discussionmentioning

confidence: 99%

ASK1 inhibition: a therapeutic strategy with multi-system benefits

2020

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p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species-induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, central nervous system, and cardiopulmonary systems. These responses are associated with many human diseases, including arthritis, dementia, and multiple organ dysfunctions. Attempts to prevent P38-and JNK-mediated disease using small molecule inhibitors of P38 or JNK have generally been unsuccessful. However, apoptosis signal-regulating kinase 1 (ASK1), an upstream regulator of P38 and JNK, has emerged as an alternative drug target for limiting P38-and JNK-mediated disease. Within this review, we compile the evidence that ASK1 mediates damaging cellular responses via prolonged P38 or JNK activation. We discuss the potential benefits of ASK1 inhibition as a therapeutic and summarise the studies that have tested the effects of ASK1 inhibition in cell and animal disease models, in addition to human clinical trials for a variety of disorders. Keywords Apoptosis signal-regulating kinase 1. MAP3K5. Clinical trial. ROS. MAPK. p38. JNK Mitogen-activated protein kinase kinase kinase 5 (MAP3K5), commonly known as apoptosis signal-regulating kinase 1 (ASK1), has emerged as a target for preventing p38 mitogen-activated protein kinase (MAPK14, 11, and 12/ P38α, β, and γ) and c-Jun N-terminal kinase (MAPK8, 9, and 10/JNK1, 2, and 3)-mediated cell death and disease. Both P38 and JNK are associated with reactive oxygen species (ROS)-induced disease 1 , and numerous studies have demonstrated that P38 and JNK inhibition ameliorates cell death [3-7]. However, complete inhibition of P38 or JNK in vivo is problematic, given that these ubiquitously expressed proteins are also critical for cell survival and homeostatic and/ or metabolic functions [8-11]. This is highlighted by the embryonic lethality of homozygous P38α and Jnk1/2 knockout mice [12, 13]. In addition, homozygous P38β knockout mice exhibit defective skeletal development [14] and homozygous Jnk1 knockout mice spontaneously develop intestinal tumours [15]. Negative outcomes have also been reported due to partial P38 or Jnk expression, with heterozygous P38α knockout mice developing progressive renal dysfunction [16] and heterozygous Jnk1 knockout mice exhibiting altered weight gain, hyperinsulinaemia, insulin resistance, inflammatory cytokine disruption, and reduced viability [17]. Serious side effects have also been observed when pharmacological inhibition of P38 or JNK is pursued in vivo [14, 18, 19]. For example, pamapimod, a P38 (α and β) inhibitor, did not significantly reduce joint swelling or improve mobility in individuals with rheumatoid arthritis in a phase II clinical trial. However, 35% of the participants receiving daily pamapimod (300 mg) experienced infection, 20% developed a skin rash, 15% became dizzy, and 13% had e...

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Section: Discussionmentioning

confidence: 99%

ASK1 inhibition: a therapeutic strategy with multi-system benefits

2020

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“…21 Also, Kamiyama et al further reported that MEKK5/p38 facilitates tumor metastasis through phosphorylation of the ADP receptor P2Y12 in platelets. 30 Although these 2 studies clearly showed the roles of MEKK5 in platelet activation and thrombus formation, MEKK5-deficient mice with prolonged bleeding times limited its application as a viable antiplatelet target. In this study, we found that another MAP3K family member (MEKK3) is highly expressed in human and mouse platelets.…”

Section: Discussionmentioning

confidence: 99%

Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice

et al. 2018

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Key Points• MEKK3 regulates platelet activation through ERK1/2 and JNK2.• MEKK3 2/2 mice are protected from microthrombosis and myocardial infarct expansion post-MI.MAPKs play important roles in platelet activation. However, the molecular mechanisms by which MAPKs are regulated in platelets remain largely unknown. Real-time polymerase chain reaction and western blot data showed that MEKK3, a key MAP3K family member, was expressed in human and mouse platelets. Then, megakaryocyte/platelet-specific MEKK3-deletion (MEKK3 2/2 ) mice were developed to elucidate the platelet-related function(s) of MEKK3. We found that agonist-induced aggregation and degranulation were reduced in MEKK3 2/2 platelets in vitro. MEKK3 deficiency significantly impaired integrin aIIbb3-mediated inside-out signaling but did not affect the outside-in signaling.At the molecular level, MEKK3 deficiency led to severely impaired activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun NH 2 -terminal kinase 2 but not p38 or ERK5. In vivo, MEKK3 2/2 mice showed delayed thrombus formation following FeCl 3 -induced carotid artery injury. Interestingly, the tail bleeding time was normal in MEKK3 2/2 mice. Moreover, MEKK3 2/2 mice had fewer microthrombi, reduced myocardial infarction (MI) size, and improved post-MI heart function in a mouse model of MI.These results suggest that MEKK3 plays important roles in platelet MAPK activation and may be used as a new effective target for antithrombosis and prevention of MI expansion.

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“…Specifically, several platelet agonists trigger the phosphorylation of ASK1 in platelets, correlated with platelet aggregation; the aggregation of platelets from ASK1 −/− mice is defective in response to agonists stimuli. Besides, the platelet ASK1 activates MKKs 3/6 and 4, leading to p38 activation, subsequently phosphorylates the key enzyme cytoplasmic phospholipase A2 (cPLA2) in thromboxane A2 (TxA2) generation, resulting in platelet granule release and thrombus formation(Naik et al, 2017) (Kamiyama et al, 2017). …”

Section: Ask1 In Cardiovascular Diseasesmentioning

confidence: 99%

ASK family in cardiovascular biology and medicine

Liu

Zhou

Wang

2017

Advances in Biological Regulation

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Cardiovascular disease is a major cause of death worldwide. Mitogen-activated protein kinase (MAPK) signal cascades signaling pathways play crucial roles in cardiovascular pathophysiology. Apoptosis signal-regulating kinase (ASK) family members ASK1, ASK2 and ASK3 are the key molecules in MAPK signal cascades and are activated by various stresses. ASK1 is the most extensively studied MAPKKK and is involved in regulation of the cellular functions such as cell survival, proliferation, inflammation and apoptosis. The current review focuses on the relationship between ASK1 and cardiovascular disease, while exploring the novel therapeutic strategies for cardiovascular disease involved in the ASK1 signal pathway.

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ASK1 facilitates tumor metastasis through phosphorylation of an ADP receptor P2Y12 in platelets

Cited by 36 publications

References 43 publications

ASK1 inhibition: a therapeutic strategy with multi-system benefits

ASK1 inhibition: a therapeutic strategy with multi-system benefits

Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice

ASK family in cardiovascular biology and medicine

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