Eph Receptor Signaling and Ephrins

Lisabeth, Erika M.; Falivelli, Giulia; Pasquale, Elena B.

doi:10.1101/cshperspect.a009159

Cited by 361 publications

(394 citation statements)

References 188 publications

(242 reference statements)

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“…The gene expression of positive modulators of cell cycle and proliferation is increased upon loss of EphA2. Our studies are in agreement with previous reports regarding ligand-dependent inhibition of ERK1/2 by EPHA2 (56). Therefore, loss of EPHA2 possibly releases this repression of proliferative signaling, leading to proliferation, which otherwise, through interaction with EFNA1 ligand, contributes to tumor suppression.…”

Section: Discussionsupporting

confidence: 83%

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

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

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Lung adenocarcinoma, a major form of non-small cell lung cancer, is the leading cause of cancer deaths. The Cancer Genome Atlas analysis of lung adenocarcinoma has identified a large number of previously unknown copy number alterations and mutations, requiring experimental validation before use in therapeutics. Here, we describe an shRNA-mediated high-throughput approach to test a set of genes for their ability to function as tumor suppressors in the background of mutant KRas and WT Tp53. We identified several candidate genes from tumors originated from lentiviral delivery of shRNAs along with Cre recombinase into lungs of Loxp-stop-Loxp-KRas mice. Ephrin receptorA2 (EphA2) is among the top candidate genes and was reconfirmed by two distinct shRNAs. By generating knockdown, inducible knockdown and knockout cell lines for loss of EphA2, we showed that negating its expression activates a transcriptional program for cell proliferation. Loss of EPHA2 releases feedback inhibition of KRAS, resulting in activation of ERK1/2 MAP kinase signaling, leading to enhanced cell proliferation. Intriguingly, loss of EPHA2 induces activation of GLI1 transcription factor and hedgehog signaling that further contributes to cell proliferation. Small molecules targeting MEK1/2 and Smoothened hamper proliferation in EphA2-deficient cells. Additionally, in EphA2 WT cells, activation of EPHA2 by its ligand, EFNA1, affects KRAS–RAF interaction, leading to inhibition of the RAS-RAF-MEK-ERK pathway and cell proliferation. Together, our studies have identified that (i) EphA2 acts as a KRas cooperative tumor suppressor by in vivo screen and (ii) reactivation of the EphA2 signal may serve as a potential therapeutic for KRas-induced human lung cancers.

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Section: Discussionsupporting

confidence: 83%

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

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

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“…[1][2][3][4][5][6] The first Eph receptor was cloned from an erythropoietinproducing hepatocellular cancer cell line in 1987, which was named EphA1, and subsequently erythropoietin-producing hepatocellular receptor A2 (EphA2), the most widely characterized member, was identified in 1990 by the screening of the cDNA library of HeLa cells. 7,8) While it is expressed in normal epidermal cells, including the skin, kidney, liver, lung, small intestine, colon, and lens, the expression of EphA2 is inhibited in these differentiated tissues.…”

Section: Introductionmentioning

confidence: 99%

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

Zhou

Sakurai

2017

Biological & Pharmaceutical Bulletin

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Erythropoietin-producing hepatocellular receptor A2 (EphA2) receptor tyrosine kinase controls multiple physiological processes to maintain homeostasis in normal cells. In many types of solid tumors, it has been reported that EphA2 is overexpressed and plays a critical role in oncogenic signaling. However, in recent years, the opposing functions of EphA2 have been explained by the canonical and noncanonical signaling pathways. Ligand-and tyrosine kinase-dependent EphA2 activation (the canonical pathway) inhibits cancer cell proliferation and motility. In contrast, ligand-and tyrosine kinase-independent EphA2 signaling (the noncanonical pathway) promotes tumor survival and metastasis and controls acquired drug resistance and maintenance of cancer stem cell-like properties. Evidence has accumulated showing that the EphA2 noncanonical pathway is mainly regulated by inflammatory cytokines and growth factors via phosphorylation at Ser-897 in the intracellular C-tail region via some serine/threonine kinases, including p90 ribosomal S6 kinase. In this review, we focus on the regulation of Ser-897 phosphorylation and its functional importance in tumor malignancy and discuss future therapeutic targeting.

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“…Detailed discussions of the Eph/ephrin proteins can be found in recent reviews [e.g. 170,191,239]. Briefly, these partners are important in both rostral-caudal and medial-lateral mapping.…”

mentioning

confidence: 99%

In vivo imaging of the zebrafish retinotectal map

Kita¹

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The precise neural connections that form during development support the creation of a functioning nervous system. An accessible experimental model for this process is the retinotectal system in zebrafish, which develops rapidly and can be observed in vivo throughout its establishment using confocal time-lapse imaging. The retinotectal connection is topographic, such that the spatial relationships of the retinal ganglion cell (RGC) somas in the retina are maintained by the arborization locations of their axons on the tectum. However, how axons find their correct arborization location on this topographic map is still debated. While initial studies suggested that zebrafish RGCs were guided directly by a growth cone to their target on the map, recent observations challenge that claim. My work characterizes a novel guidance pattern for RGCs pathfinding on the tectum. Once pathfinding through the tectal neuropil, zebrafish RGCs continually add and remove branches. The directionality of the branches is biased, in that more are pointing towards the eventual arborization zone than away from it. Growth cones, which tip some of the branches, extend mostly in straight lines rather than progressing through turns towards the target. The distance to the target is decreased by the axon branching in many directions, and selecting a branch that decreases the distance to support further rounds of branching. The mechanism of biased branching could be based on known types of input that guide connectivity during development and we focused on the contributions of activity and molecular guidance cue gradients.We hypothesized that silencing neural activity using TTX could alter the navigation methods used, but many of the characteristics of axon pathfinding were similar despite global silencing. The area covered by the branches during pathfinding decreases when the retinotectal system is electrically silent, but the biased branch ratio remains. Several measures of the arbors after the target is reached show differing patterns without activity, supporting previous evidence that activity is an important regulation of arborization dynamics.Molecularly, the retinotectal map is established through gradients of guidance cues that guide axons to their target location, cause them to stop advancing, and elaborate a terminal arbor. Through morpholino knock down we observe the different effects that two of these guidance proteins, ephrin-A5b and ephrin-A2, have on individual axons as they navigate.iii Overall, knockdown of ephrin-A5b tends to increase length, area and number of branches, while the knockdown of ephrin-A2 has the opposite effect on these measures. Additionally, a subset of axons show phenotypes that are masked by the grouped data, where several form loops instead of travelling in rather straight trajectories, or alternatively, grow long and remain relatively branchless as they travel towards the caudal extent of the tectum.The following thesis gives quantitative, detailed insight into some of the ways that activity and molec...

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Eph Receptor Signaling and Ephrins

Cited by 361 publications

References 188 publications

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

In vivo imaging of the zebrafish retinotectal map

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