Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis

Miller, Shyra J.; Lan, Zheng D.; Hardiman, Atira; Wu, Jianqiang; Kordich, Jennifer J.; Patmore, Deanna M.; Hegde, Rashmi S.; Cripe, Timothy P.; Cancelas, José A.; Collins, Margaret H.; Ratner, Nancy

doi:10.1038/onc.2009.360

Cited by 76 publications

(80 citation statements)

References 61 publications

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“…33,34 The tyrosine phosphatase activity not only contributes to EYA's role in DDR but also promotes motility of tumor and ECs. 11,12,28,35 Attenuation of EC proliferation by EYA PTP inhibitors under hypoxia demonstrates that this catalytic activity contributes to cell proliferation in DNA damagee inducing conditions. It remains possible that the transactivation activity of the EYAs also plays a role.…”

Section: Discussionmentioning

confidence: 99%

The Eyes Absent Proteins in Developmental and Pathological Angiogenesis

Wang

Tadjuidje

Pandey

et al. 2016

The American Journal of Pathology

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Management of neoangiogenesis remains a high-value therapeutic goal. A recently uncovered association between the DNA damage repair pathway and pathological angiogenesis could open previously unexplored possibilities for intervention. An attractive and novel target is the Eyes absent (EYA) tyrosine phosphatase, which plays a critical role in the repair versus apoptosis decision after DNA damage. This study examines the role of EYA in the postnatal development of the retinal vasculature and under conditions of ischemia-reperfusion encountered in proliferative retinopathies. We find that the ability of the EYA proteins to promote endothelial cell (EC) migration contributes to a delay in postnatal development of the retinal vasculature when Eya3 is deleted specifically in ECs. By using genetic and chemical biology tools, we show that EYA contributes to pathological angiogenesis in a model of oxygen-induced retinopathy. Both in vivo and in vitro, loss of EYA tyrosine phosphatase activity leads to defective assembly of g-H2AX foci and thus to DNA damage repair in ECs under oxidative stress. These data reveal the potential utility of EYA tyrosine phosphatase inhibitors as therapeutic agents in inhibiting pathological neovascularization with a range of clinical applications. (Am J Pathol 2016, 186: 568e578; http:// dx

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Section: Discussionmentioning

confidence: 99%

The Eyes Absent Proteins in Developmental and Pathological Angiogenesis

Wang

Tadjuidje

Pandey

et al. 2016

The American Journal of Pathology

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“…Stimulation with recombinant PDGF-BB induced epicardial cell migration into the myocardium; however, adenoviral transduction of the Nf1 GAP-related domain (Nf1-GRD) (Hiatt et al, 2001;Miller et al, 2010) significantly reduced PDGF-BB-induced EMT (Fig. 6C,D).…”

Section: Nf1 Regulation Of Ras Signaling Plays a Role In Pdgf-inducedmentioning

confidence: 99%

“…E12.5 hearts were isolated and incubated with adenovirus expressing GFP or Nf1 GAP-related domain (Miller et al, 2010), kindly provided by Dr Robert Gerard or Dr Nancy Ratner (Cincinnati Children's Hospital, OH, USA), respectively. PDGF-BB (R&D Systems), imatinib mesylate (Sigma), AG1296 (Sigma) and U0126 (Sigma) were added to the cultures as indicated.…”

Section: Ex Vivo Migration Assaymentioning

confidence: 99%

Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation

Baek

Tallquist

2012

Development

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The epicardium is the primary source of coronary vascular smooth muscle cells (cVSMCs) and fibroblasts that reside in the compact myocardium. To form these epicardial-derived cells (EPDCs), the epicardium undergoes the process of epithelial to mesenchymal transition (EMT). Although several signaling pathways have been identified that disrupt EMT, no pathway has been reported that restricts this developmental process. Here, we identify neurofibromin 1 (Nf1) as a key mediator of epicardial EMT. To determine the function of Nf1 during epicardial EMT and the formation of epicardial derivatives, cardiac fibroblasts and cVSMCs, we generated mice with a tissue-specific deletion of Nf1 in the epicardium. We found that mutant epicardial cells transitioned more readily to mesenchymal cells in vitro and in vivo. The mesothelial epicardium lost epithelial gene expression and became more invasive. Using lineage tracing of EPDCs, we found that the process of EMT occurred earlier in Nf1 mutant hearts, with an increase in epicardial cells entering the compact myocardium. Moreover, loss of Nf1 caused increased EPDC proliferation and resulted in more cardiac fibroblasts and cVSMCs. Finally, we were able to partially reverse the excessive EMT caused by loss of Nf1 by disrupting Pdgfrα expression in the epicardium. Conversely, Nf1 activation was able to inhibit PDGF-induced epicardial EMT. Our results demonstrate a regulatory role for Nf1 during epicardial EMT and provide insights into the susceptibility of patients with disrupted NF1 signaling to cardiovascular disease.

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“…PP2A is functionally inactivated in many cancers, and it is considered a tumor suppressor (32). In contrast, EYA has cancer-promoting activity, including sustained proliferative signaling, resistance to cell death, angiogenesis, metastasis, and replicative immortality, and is overexpressed in many cancers (19,(33)(34)(35). Our observation that depletion of Eya1 by shRNAs (ϳ80% loss) in human MDA-MB-231 breast cancer cells results in destabilization of Myc (ϳ40% of that in control cells) and accumulation of pT58-Myc (ϳ194% of that in control cells) suggests a novel mechanism regulating Myc stability and pT58 levels.…”

Section: Deregulation Of Myc By Eya1 In Human Breast Cancermentioning

confidence: 99%

EYA1's Conformation Specificity in Dephosphorylating Phosphothreonine in Myc and Its Activity on Myc Stabilization in Breast Cancer

Rodrı́guez

Cheng

et al. 2017

Molecular and Cellular Biology

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EYA1 is known to be overexpressed in human breast cancer, in which the Myc protein is also accumulated in association with decreased phospho-T58 (pT58) levels. We have recently reported that EYA1 functions as a unique protein phosphatase to dephosphorylate Myc at pT58 to regulate Myc levels. However, it remains unclear whether EYA1-mediated Myc dephosphorylation on T58 is a critical function in regulating Myc protein stability in breast cancer. Furthermore, EYA1's substrate specificity has remained elusive. In this study, we have investigated these questions, and here, we report that depletion of EYA1 using short hairpin RNA (shRNA) in breast cancer cells destabilizes the Myc protein and increases pT58 levels, leading to an increase in the doubling time and impairment of cell cycle progression. In correlation with EYA1-mediated stabilization of cMyc and reduced levels of pT58, EYA1 greatly reduced cMyc-FBW7 binding and cMyc ubiquitination, thus providing novel insight into how EYA1 acts to regulate the FBW7-mediated Myc degradation machinery. We found that the conserved C-terminal haloacid dehalogenase domain of EYA1, which has been reported to have only tyrosine phosphatase activity, has dual phosphatase activities, and both the N-and C-terminal domains interact with substrates to increase the catalytic activity of EYA1. Enzymatic assay and nuclear magnetic resonance (NMR) analysis demonstrated that EYA1 has a striking conformation preference for phospho-T58 of Myc. Together, our results not only provide novel structural evidence about the conformation specificity of EYA1 in dephosphorylating phosphothreonine in Myc but also reveal an important mechanism contributing to Myc deregulation in human breast cancer. KEYWORDS EYA1, threonine phosphatase, Myc, degradation, FBW7, cell proliferation, breast cancer, deregulation T he transcription factor Eyes absent (EYA) represents the prototype of a novel class of eukaryotic aspartyl protein tyrosine phosphatases (1-3) that play important roles in development and disease (4-6). While the conserved C-terminal haloacid dehalogenase domain of EYA (ED), which contains the signature motif for the aspartate-based serine/threonine (Ser/Thr) phosphatase family (1-3, 7), has been reported to have only tyrosine phosphatase activity (8), a recent study reported that the N terminus of EYA (NT), which bears no sequence similarity to any known Ser/Thr phosphatase families, has Thr phosphatase activity (8). Therefore, it remains unclear which domain of EYA contains residues for substrate binding and catalytic activity and how EYA achieves

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Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis

Cited by 76 publications

References 61 publications

The Eyes Absent Proteins in Developmental and Pathological Angiogenesis

The Eyes Absent Proteins in Developmental and Pathological Angiogenesis

Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation

EYA1's Conformation Specificity in Dephosphorylating Phosphothreonine in Myc and Its Activity on Myc Stabilization in Breast Cancer

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