Differential Regulation of EphA2 in Normal and Malignant Cells

Walker‐Daniels, Jennifer; Hess, Angela R.; Hendrix, Mary J.C.; Kinch, Michael S.

doi:10.1016/s0002-9440(10)63899-0

Cited by 118 publications

(110 citation statements)

References 64 publications

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“…However, despite the low phosphorylation level, EphA2 kinase activity was not affected (Zantek et al, 1999). Ligand-induced EphA2 phosphorylation induces receptor endocytosis and degradation, reducing malignant behavior of the cells and tumor growth in vivo (Walker-Daniels et al, 2002). Such evidence supports the idea that EphA2 receptor phosphorylation is not necessary to confer kinase activity and tumorigenicity, but leaves question unanswered as to whether kinase activity is required for tumor malignancy.…”

Section: Introductionsupporting

confidence: 55%

“…Eph RTKs and their ligands, the ephrins, are frequently overexpressed in different types of cancer (reviewed in Nakamoto and Bergmann, 2002;Brantley-Sieders et al, 2004b;Ireton and Chen, 2005). One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma (Ogawa et al, 2000;Walker-Daniels et al, 2003). In cell lines, EphA2 overexpression is associated with increased cell growth in soft agar (Zelinski et al, 2001), increased invasion into matrigel (Zelinski et al, 2001;Duxbury et al, 2004a), increased resistance to anoikis (Duxbury et al, 2004a), and increased tumor growth when these cells were implanted into nude mice (Zelinski et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

et al. 2005

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Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear. In certain tumor cell lines, EphA2 receptor is underphosphorylated, raising the question of whether ligandinduced receptor phosphorylation and its kinase activity play a role in oncogenesis. To test directly the role of EphA2 receptor phosphorylation/kinase activity in tumor progression, we generated EphA2 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its kinase activity. Expression of these EphA2 mutants in breast cancer cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, the numbers of lung metastases were significantly reduced in both experimental and spontaneous metastasis models. Reduced tumor volume and metastasis are not due to defects in tumor angiogenesis, as there is no significant difference in tumor vessel density between wild-type tumors and tumors expressing EphA2-signaling-defective mutants. In contrast, tumor cells expressing the EphA2 mutants are defective in RhoA GTPase activation and cell migration. Taken together, these results suggest that receptor phosphorylation and kinase activity of the EphA2 receptor, at least in part, contribute to tumor malignancy.

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Section: Introductionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

et al. 2005

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“…[27][28][29] It has been suggested that EphA2 may facilitate cell-ECM interactions. 30,31 Therefore, we next determined the effect of EphA2 on cell adhesion to a defined Matrix (collagen I/FBS/ and fibronectin). A2780-EphA2 cells (clone #1 and clone #2) showed significantly greater ability to adhere to collagen, FBS and fibronectin in comparison to A2780-neo cells (Fig.…”

Section: Epha2 Overexpression Promotes Cell-ecm Attachmentmentioning

confidence: 99%

EphA2 overexpression promotes ovarian cancer growth

Lü

Shahzad

Wang

et al. 2008

Cancer Biology & Therapy

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Background: Silencing EphA2 has been shown to result in anti-tumor efficacy. However, it is not known whether increasing EphA2 expression specifically results in increased tumor growth and progression. We examined the effects of stable EphA2 transfection into poorly invasive ovarian cancer cells with regard to in vitro invasive and in vivo metastatic potential.Results: In low cell density, EphA2-overexpressing A2780 cells (A2780-EphA2) displayed less cell-cell contact, increased cell-extracellular matrix (ECM) attachment and anchorage-independent cell growth compared to empty vector controls. There was no significant effect on anchorage-dependent cell proliferation, migration or invasion. Increased expression of EphA2 promoted tumor growth and enhanced the metastatic potential in A2780-EphA2 human ovarian cancer xenografts. The overexpression of EphA2 resulted in enhanced microvessel density (MVD), but had no effect on tumor cell proliferation.Methods: EphA2 gene was introduced into A2780 cells by retroviral infection. The effects of increased EphA2 expression were examined on cellular morphology, and anchorage-dependent and independent cell growth. Furthermore, the effect of EphA2 overexpression on metastatic ability was determined using an orthotopic nude mouse model of ovarian carcinoma.Conclusions: EphA2 promotes tumor growth by enhancing cell-ECM adhesion, increasing anchorage-independent growth and promoting angiogenesis.

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“…Unlike these reports, our data link the events of EphA 2 -mediated negative feedback inhibition of Ras with Raf-induced loss of AKT activity and cellular arrest. Interestingly, the EphA 2 -mediated Ras inhibition is lost in both breast cancer and aggressive melanomas, due to loss of the EphA 2 ligand ephrin-1A (reviewed in Kinch and Carles-Kinch, 2003;Walker-Daniels et al, 2003). In fact, adding back recombinant ephrin-1A ligand is a therapeutic treatment that can inhibit tumor growth and angiogenesis Cheng et al, 2002).…”

Section: Raf-mek1 Regulates Ras-pi3k-akt Through Epha 2 Cw Menges Andmentioning

confidence: 99%

Constitutive activation of the Raf–MAPK pathway causes negative feedback inhibition of Ras–PI3K–AKT and cellular arrest through the EphA2 receptor

Menges

McCance

2007

Oncogene

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The Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-AKT pathways are two downstream effectors of the small GTPase Ras. Although both pathways are positively regulated by Ras, the Raf-MAPK and PI3K-AKT pathways have been shown to control opposing functions within the cell, suggesting a need for cross-talk regulation. The PI3K-AKT pathway can inhibit the Raf-MAPK pathway directly during processes such as muscle differentiation. Here we describe the ability of the Raf-MAPK pathway to negatively regulate the PI3K-AKT pathway during cellular arrest. Constitutive activation of Raf or methyl ethyl ketone 1 (MEK1) leads to inhibition of AKT and cellular arrest. Furthermore, we show that activation of Raf-MEK1 signaling causes negative feedback inhibition of Ras through the ephrin receptor EphA 2 . EphA 2 -mediated negative feedback inhibition is required for Raf-induced AKT inhibition and cell cycle arrest, therefore establishing the inhibition of the Ras-PI3K-AKT pathway as a necessary event for the Raf-MEK1-regulated cellular arrest.

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Differential Regulation of EphA2 in Normal and Malignant Cells

Cited by 118 publications

References 64 publications

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

EphA2 overexpression promotes ovarian cancer growth

Constitutive activation of the Raf–MAPK pathway causes negative feedback inhibition of Ras–PI3K–AKT and cellular arrest through the EphA2 receptor

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