ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition

Maruyama, Takeshi; Sasaki, Ayana; Iijima, Sayuri; Ayukawa, Shiyu; Goda, Nobuhito; Tazuru, Keisuke; Hashimoto, Norikazu; Hayashi, Takashi; Kozawa, Kei; Sato, Narumichi; Ishikawa, Susumu; Morita, Tomoko; Fujita, Yasuyuki

doi:10.1016/j.isci.2020.101327

Cited by 9 publications

(3 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, this inhibition is dependent on the kinase activity of ZAK. Thus, the ZAK inhibitor PLX4720 ( 22 ) abolishes the ZAK inhibitory effect on COBL and formation of ruffles is again observed in these cotransfected cells ( Fig. 3C and D ).…”

Section: Resultsmentioning

confidence: 63%

Myofibrillar myopathy hallmarks associated with ZAK deficiency

Stonadge

Genzor

Russell

et al. 2023

Human Molecular Genetics

View full text Add to dashboard Cite

The ZAK gene encodes two functionally distinct kinases, ZAKɑ and ZAKβ. Homozygous loss of function mutations affecting both isoforms cause a congenital muscle disease. ZAKβ is the only isoform expressed in skeletal muscle and is activated by muscle contraction and cellular compression. The ZAKβ substrates in skeletal muscle or the mechanism whereby ZAKβ senses mechanical stress remain to be determined. To gain insights into the pathogenic mechanism, we exploited ZAK-deficient cell lines, zebrafish, mice and a human biopsy. ZAK-deficient mice and zebrafish show a mild phenotype. In mice, comparative histopathology data from regeneration, overloading, ageing and sex conditions indicate that while age and activity are drivers of the pathology, ZAKβ appears to have a marginal role in myoblast fusion in vitro or muscle regeneration in vivo. The presence of SYNPO2, BAG3 and FLNC in a phosphoproteomics assay and extended analyses suggested a role for ZAKβ in the turnover of FLNC. Immunofluorescence analysis of muscle sections from mice and a human biopsy showed evidence of FLNC and BAG3 accumulations as well as other myofibrillar myopathy markers. Moreover, endogenous overloading of skeletal muscle exacerbated the presence of fibres with FLNC accumulations in mice, indicating that ZAKβ signalling is necessary for an adaptive turnover of FLNC that allows for the normal physiological response to sustained mechanical stress. We suggest that accumulation of mislocalized FLNC and BAG3 in highly immunoreactive fibres contributes to the pathogenic mechanism of ZAK-deficiency.

show abstract

Section: Resultsmentioning

confidence: 63%

Myofibrillar myopathy hallmarks associated with ZAK deficiency

Stonadge

Genzor

Russell

et al. 2023

Human Molecular Genetics

View full text Add to dashboard Cite

show abstract

“…Given that p38-MAPK activation and nucleic acid damage are known features of the UVB NLRP1 inflammasome, we tested whether poly(dA:dT) and poly(I:C) activate ZAKα, the MAP3K that controls NLRP1 inflammasome responses due to ribosomal RNA damage. Intriguingly, the ZAK kinase inhibitors sorafenib ( 46 ) and PLX-4720 ( 47 ) could suppress poly(dA:dT), poly(I:C), and ANS-induced IL-1β release ( SI Appendix , Fig. S4 C and D ) but had no effect on VbP-induced IL-1β release.…”

Section: Resultsmentioning

confidence: 99%

Activation of the NLRP1 inflammasome in human keratinocytes by the dsDNA mimetic poly(dA:dT)

Zhou

Sarkar

Okamura

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The accrual of cytosolic DNA leads to transcription of type I IFNs, proteolytic maturation of the IL-1 family of cytokines, and pyroptotic cell death. Caspase-1 cleaves pro-IL1β to generate mature bioactive cytokine and gasdermin D which facilitates IL-1 release and pyroptotic cell death. Absent in melanoma-2 ( AIM2 ) is a sensor of dsDNA leading to caspase-1 activation, although in human monocytes, cGAS-STING acting upstream of NLRP3 mediates the dsDNA-activated inflammasome response. In healthy human keratinocytes, AIM2 is not expressed yet caspase-1 is activated by the synthetic dsDNA mimetic poly(dA:dT). Here, we show that this response is not mediated by either AIM2 or the cGAS-STING-NLRP3 pathway and is instead dependent on NLRP1. Poly(dA:dT) is unique in its ability to activate NLRP1, as conventional linear dsDNAs fail to elicit NLRP1 activation. DsRNA was recently shown to activate NLRP1 and prior work has shown that poly(dA:dT) is transcribed into an RNA intermediate that stimulates the RNA sensor RIG-I. However, poly(dA:dT)-dependent RNA intermediates are insufficient to activate NLRP1. Instead, poly(dA:dT) results in oxidative nucleic acid damage and cellular stress, events which activate MAP3 kinases including ZAKα that converge on p38 to activate NLRP1. Collectively, this work defines a new activator of NLRP1, broadening our understanding of sensors that recognize poly(dA:dT) and advances the understanding of the immunostimulatory potential of this potent adjuvant.

show abstract

“…The superior ability of young progenitors to utilize IL-7 induces the decreased expression of Bcl2, the IL-7 downstream anti-apoptotic regulator, in old progenitors, thereby eliminating the thymus-resident loser cells. (Martins et al 2014 ). It is noteworthy that the disrupted ability of bone-marrow progenitors to synthetic IL-7 receptor reversed the result of competition, which associate points between cell anabolism and cell competition.…”

Section: Different Modes Of Cell Competition Between Cancer Cells And...mentioning

confidence: 98%

Pleiotropic effects of cell competition between normal and transformed cells in mammalian cancers

Zhang

Zhu

2022

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition

Cited by 9 publications

References 30 publications

Myofibrillar myopathy hallmarks associated with ZAK deficiency

Myofibrillar myopathy hallmarks associated with ZAK deficiency

Activation of the NLRP1 inflammasome in human keratinocytes by the dsDNA mimetic poly(dA:dT)

Pleiotropic effects of cell competition between normal and transformed cells in mammalian cancers

Contact Info

Product

Resources

About