Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor–Induced Cancer Cell Motility

Larsen, Alice Bjerregaard; Pedersen, Mikkel Wandahl; Stockhausen, Marie-Thérése; Grandal, Michael V.; Deurs, Bo van; Poulsen, Hans Skovgaard

doi:10.1158/1541-7786.mcr-06-0321

Cited by 124 publications

(128 citation statements)

References 45 publications

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“…c-Cbl has been reported to participate in EphA receptor degradation induced by ligand stimulation (Walker-Daniels et al, 2002;Wang et al, 2002;Sharfe et al, 2003). Larsen et al, 2007 showed that other than transcriptional target of EGFR, EphA2 colocalized with activated EGFR. Thus, recruitment of c-Cbl by activated EphA receptor upon ligand binding potentially facilitates its access to EGFR, and promotes subsequent ubiquitylation of the receptor, which could interpret the potential role of Eph forward signaling.…”

Section: Discussionmentioning

confidence: 99%

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

et al. 2009

Oncogene

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Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands play important roles in nervous system development. Recently, they have been implicated in tumorigenesis of different cancers. In this study, we showed that the expression of ephrinA5 was dramatically downregulated in primary gliomas compared with normal tissues. Forced expression of ephrinA5 reduced tumorigenicity of human glioma U373 cells. Epidermal growth factor receptor (EGFR), which frequently acts as an oncoprotein in glioma, was greatly decreased in ephrinA5-transfected glioma cells, and the two molecules exhibited a mutually exclusive expression pattern in primary glioma samples. We found that ephrinA5 enhanced c-Cbl binding to EGFR, thus promoted ubiquitylation and degradation of the receptor. Either ephrinA5-Fc or EphA2-Fc treatment simulating bidirectional signaling of Eph/ephrin system resulted in EGFR decrease. This study discovered that ephrinA5 acted as a tumor suppressor in glioma, and its negative regulation of EGFR contributed to the suppressive effects. In addition to identifying a novel mechanism underlying tumor suppressor activity of ephrinA5, we also showed cross-talk between different receptor tyrosine kinase families in glioma. These findings may improve therapeutic strategies for glioma.

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Section: Discussionmentioning

confidence: 99%

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

et al. 2009

Oncogene

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“…EphA2 knockout mice were shown to be very susceptible to DMBA/ TPA-induced skin carcinogenesis (25). Further, activation of EPHA2 by its ligand EFNA1 or small molecule induced activation of EPHA2 reduces cell proliferation and cell motility and suppresses integrin function, suggesting its tumor-suppressive function (26)(27)(28). Our high-throughput approach identified EphA2 as a prime tumor suppressor candidate, and we hypothesized that, if deleted in a tumor cell-specific manner, EphA2 would function as a KRas G12D -cooperative tumor suppressor in lung adenocarcinoma.…”

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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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“…[23][24][25][26][27][28][29][30][31][32][33][34][35] Yet, there is also some evidence that EphA2 may function as a tumor suppressor, as activation of EphA2 receptors following ligand binding has been shown to lead a reduction in cell growth that is associated with inhibition of the RAS/MAPK pathways, and EphA2 2/2 gene trap mice demonstrate increased susceptibility to skin carcinogenesis. [36][37][38][39] Further, EphA2 has been reported to be a transcriptional target of the p53 tumor suppressor, 40 and expression of EphA2 was shown to negatively affect the proliferation and promote apoptosis in lung and breast cancer cells.…”

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“…41,42 This is further supported by adenoviral vector delivery of EphrinA1 and EphA2 activating antibodies that inhibit malignant cell behavior. 24,34,36 Independent of ligand binding, phosphorylation of EphA2, both autophosphorylation and phosphorylation by other receptor tyrosine kinases (RTKs) may play a critical role in EphA2's oncogenicity. In some breast cancer cells, overexpression of wildtype EphA2 leads to constitutive phosphorylation of the receptor while EphA2 mutants that lack either the cytoplasmic domain or a kinase-dead point mutant (D738N) act in a dominant negative fashion to inhibit both receptor phosphorylation and endogenous receptor signaling, such as through the RAS/MAPK pathways.…”

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Loss of EphA2 receptor tyrosine kinase reduces Apc^min/+ tumorigenesis

Bogan

Chen

O’Sullivan

et al. 2008

Intl Journal of Cancer

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The Eph receptor A2 (EphA2) is overexpressed in a range of human epithelial cancers, a phenotype that is associated with cancer cell proliferation, progression and angiogenesis. Mouse models of mammary neoplasia have confirmed the role of EphA2 as mice carrying a knockout allele of EphA2 were resistant to breast cancer, a phenotype that was associated with interactions between EphA2 and ErbB2. We investigated in vivo the role of EphA2 in GI cancer. To determine whether EphA2 influences intestinal tumorigenesis, we used qRT-PCR to examine the mRNA expression levels of EphA2 in tumors from the small intestine and colon of Apc Min/1 mice. We found that EphA2 was significantly up-regulated in tumors from both regions when compared with normal control tissues. We then evaluated the spatial expression patterns of EphA2 protein using immunohistochemistry in both the small intestine and colon and found that in normal tissues EphA2 was robustly expressed in highly differentiated cells, such as cells of the villi, but that EphA2 expression was largely absent from the stem cell niche and proliferative zones of intestinal crypts. In contrast, in tumors EphA2 was broadly expressed. Finally, we created a strain of Apc Min/1 mice carrying a genetic knockout of the EphA2 gene. These mice developed significantly fewer and smaller tumors in both the small and large intestine. Overall, our results indicate that EphA2 plays an oncogenic role in the mammalian intestine suggesting that strategies to target EphA2 activity may offer new therapeutic modalities for colorectal cancer. ' 2008 Wiley-Liss, Inc.Key words: colon cancer; receptor tyrosine kinase; EphA2; Apc; Min The Eph receptor tyrosine kinase (RTK) family consists of 16 receptors and 9 ligands that play diverse roles in development, cellular growth, angiogenesis, cell adhesion, cell migration, cell signaling, differentiation and neoplasia, and together constitute the largest family of RTKs in vertebrates. [1][2][3][4][5][6][7][8] Eph RTKs are subdivided into class A and class B molecules based on homology and their ability to bind distinct set of membrane anchored ligands (ephrins). Class A Eph receptors bind to glycosol-phosphatidylinositol-linked class A ephrins, whereas class B Ephs bind to class B ephrins that contain a transmembrane spanning domain. Notably, dysregulation of both class A and B Ephs are implicated in cancer processes in a wide range of mammalian tissues. Eph receptor A2 (EphA2), which maps to human chromosome 1p36.1, is associated with tumor progression, angiogenesis and poor prognosis in breast, pancreatic, ovarian, cervical, mesothelioma, bladder, colon, gastric, lung, melanoma, esophageal, prostate and kidney cancers. 9-15 In mammary cancers, EphA2 promotes adenocarcinoma development and metastatic progression, [16][17][18][19] in some cases by amplifying ErbB2 signaling. 17 Further, in metastatic breast cancer, EphA2 has been reported to be negatively regulated by estrogen and c-Myc, and EphA2 over-expression decreases estrogen dependence; phenotyp...

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Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor–Induced Cancer Cell Motility

Cited by 124 publications

References 45 publications

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

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

Loss of EphA2 receptor tyrosine kinase reduces Apc^min/+ tumorigenesis

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Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor–Induced Cancer Cell Motility

Cited by 124 publications

References 45 publications

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

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

Loss of EphA2 receptor tyrosine kinase reduces Apcmin/+ tumorigenesis

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Loss of EphA2 receptor tyrosine kinase reduces Apc^min/+ tumorigenesis