Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin‐A1

Frieden, Leslie A.; Townsend, Todd A.; Vaught, David; DeLaughter, Daniel M.; Hwang, Young Sil; Barnett, Joey V.; Chen, Jin

doi:10.1002/dvdy.22458

Cited by 43 publications

(21 citation statements)

References 38 publications

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“…Ephrin-A1 -null mice are viable, fertile, and do not exhibit overt phenotypes in a pathogen-free animal facility (17). Previous experimental data in breast cancer cell lines suggest a model in which the oncogenic role of EPHA2 is largely ligand-independent, whereas ephrin-A1, the prototypic ligand of EPHA2, transduces inhibitory signaling that blocks tumor cell proliferation and invasiveness (3, 6, 18).…”

Section: Resultsmentioning

confidence: 99%

The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer

et al. 2016

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Dysregulation of receptor tyrosine kinases (RTKs) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2+ subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, ephrin-A1. We demonstrate ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo. Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of ephrin-A1 was attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency.

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Section: Resultsmentioning

confidence: 99%

The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer

et al. 2016

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“…EphA3 remains expressed at lower levels in some adult tissues, such as the brain, lung, bladder, prostate and colon (52, 53). The best characterized roles of EphA3 thus far are in epithelial-mesenchymal transition in the developing heart (54, 55) and in axon guidance in the developing nervous system, where this receptor plays a repulsive role that causes axons to avoid regions of high ephrin ligand expression (56–58). EphA3-dependent retraction of cellular processes has also been reported in non-neuronal cells (28).…”

Section: Discussionmentioning

confidence: 99%

Cancer Somatic Mutations Disrupt Functions of the EphA3 Receptor Tyrosine Kinase through Multiple Mechanisms

2012

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The Eph receptor tyrosine kinases are an important family of signal transduction molecules that control many cellular processes, including cell adhesion and movement, cell shape and cell growth. All of these are important aspects of cancer progression, but the relationship between Eph receptors and cancer is complex and not fully understood. Genetic screens of tumor specimens from cancer patients have revealed somatic mutations in many Eph receptors. The most highly mutated Eph receptor is EphA3, but its functional role in cancer is currently not well established. Here we show that many EphA3 mutations identified in lung, colorectal and hepatocellular cancers, melanoma and glioblastoma impair kinase activity or ephrin ligand binding and/or decrease receptor cell surface localization. These results suggest that EphA3 has ephrin- and kinase-dependent tumor suppressing activities, which are disrupted by somatic cancer mutations.

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“…These data represent a cardioprotective role for exogenous ephrinA1-Fc administration in the setting of acute MI and may present a novel therapeutic approach to be used alone or in conjunction with stem/progenitor cells or other biomaterials. Additionally, Frieden et al generated ephrinA1-null mice in which they observed defective valve morphogenesis during development and reduced ejection fraction and fractional shortening in adult mice, not due to changes in blood pressure, but rather due to intrinsic cardiac dysfunction [116]. Collaborative studies are in progress to further explore the adult cardiac phenotype and response to acute and chronic injury.…”

Section: Evaluation Of the Hypothesis: Ephrin–eph Signaling As A Cardmentioning

confidence: 99%

Ephrin–Eph signaling as a potential therapeutic target for the treatment of myocardial infarction

O’Neal¹,

Griffin²,

Dries-Devlin³

et al. 2013

Medical Hypotheses

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Although numerous strategies have been developed to reduce the initial ischemic insult and cellular injury that occurs during myocardial infarction (MI), few have progressed into the clinical arena. The epidemiologic and economic impact of MI necessitates the development of innovative therapies to rapidly and effectively reduce the initial injury and subsequent cardiac dysfunction. The Eph receptors and their cognate ligands, the ephrins, are the largest family of receptor tyrosine kinases, and their signaling has been shown to play a diverse role in various cellular processes. The recent advances in the study of ephrin– Eph signaling have shown promising progress in many fields of medicine. They have been implicated in the pathophysiology of various cancers and in the regulation of inflammation and apoptosis. Recent studies have shown that manipulation of ephrin–Eph cell signaling can favorably influence cardiomyocyte viability and ultimately preserve cardiac function post-MI. In this article, we explore the hypothesis that manipulation of ephrin–Eph signaling may potentially be a novel therapeutic target in the treatment of MI through alteration of the cellular processes that govern injury and wound healing.

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Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin‐A1

Cited by 43 publications

References 38 publications

The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer

The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer

Cancer Somatic Mutations Disrupt Functions of the EphA3 Receptor Tyrosine Kinase through Multiple Mechanisms

Ephrin–Eph signaling as a potential therapeutic target for the treatment of myocardial infarction

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