The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma–associated herpesvirus

Hahn, Alexander; Kaufmann, Johanna K.; Wies, Effi; Naschberger, Elisabeth; Panteleev-Ivlev, Julia; Schmidt, Katharina; Holzer, Angela; Schmidt, Martin; Chen, Jin; König, Simone; Ensser, Armin; Myoung, Jinjong; Brockmeyer, Norbert H.; Stürzl, Michael; Fleckenstein, Bernhard; Neipel, Frank

doi:10.1038/nm.2805

Cited by 174 publications

(247 citation statements)

References 65 publications

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“…The higher the number of receptors on the surface, the greater the concentration of inhibitor that will be needed to block entry. In fact, the rank order of EC 50 s in the three different cell lines used in our recent Journal of Virology article (14, 47, and 276 M) (2) corresponds exactly to the EPHA2 mRNA levels in these same cells measured previously (5). Thus, receptor density along with a diverse array of other factors can explain the wide variation in EC 50 s on different cell types in our publication.…”

supporting

confidence: 76%

Reply to “On the Use of 2,5-Dimethyl-Pyrrol-1-yl-Benzoic Acid Derivatives as EPH-Ephrin Antagonists”

Desrosiers¹,

Hahn²

2014

J Virol

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L odola, Incerti, and Tognolini (1) have raised questions regarding the effective concentrations of inhibitors that we used and the specificity of inhibition described in our recently published article (2).We thank Lodola et al. for pointing out that some spontaneous transformations of compounds 1 and 2 may be required for their inhibitory activity. In addition to the possible explanations already listed in our publication for the considerable differences in 50% inhibitory concentrations (IC 50 s) measured in different laboratories, we agree that it would be appropriate to also include the effective concentration of the inhibitory substance.We feel that it is important to reiterate the substantial body of evidence for the specificity of inhibition that is presented in our publication (2). The compound did not inhibit entry of a vesicular stomatitis virus (VSV) G-transcomplemented retrovirus at concentrations that potently inhibited entry of Kaposi's sarcoma-associated herpesvirus (KSHV). Binding of monoclonal antibody 6F8 to EPHA2 was not inhibited by the compound at concentrations that potently inhibited binding of gH-gL to EPHA2. The ability of the compound to inhibit the different interactions (EPHA2-ephrinA4, EPHA2-ephrin A5, and EPHA2-gH/gL) was shown to be directly related to the measured affinities; the inhibitory potencies toward binding and infection were correlated. Neither compound 1 nor compound 2 exhibited toxic effects in cell culture. Others have similarly shown the specificity for targeting of EPHA2 and EPHA4 by these compounds or their active products (3, 4). For example, Noberini et al. (3) found no inhibition of ephrin A5 binding to EPHA7, EPHB1, EPHB2, EPHB3, and EPHB4 by these compounds despite their potent inhibition of binding to EPHA2 and EPHA4.It is erroneous to think that the IC 50 for a protein-protein interaction should be exactly reflected in the 50% effective concentration (EC 50 ) for inhibition of entry of virus into a cell, as suggested by Lodola et al. (1). A large number of additional factors will influence the ability of an inhibitor to block entry of a virus into a cell. For example, receptor density will be one crucial factor.The virus needs to engage only one receptor complex on the surface of a cell to gain entry. The higher the number of receptors on the surface, the greater the concentration of inhibitor that will be needed to block entry. In fact, the rank order of EC 50 s in the three different cell lines used in our recent Journal of Virology article (14, 47, and 276 M) (2) corresponds exactly to the EPHA2 mRNA levels in these same cells measured previously (5). Thus, receptor density along with a diverse array of other factors can explain the wide variation in EC 50 s on different cell types in our publication.

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confidence: 76%

Reply to “On the Use of 2,5-Dimethyl-Pyrrol-1-yl-Benzoic Acid Derivatives as EPH-Ephrin Antagonists”

Desrosiers¹,

Hahn²

2014

J Virol

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“…PELs are also extremely sensitive to NF-κB pathway inhibitors such as bortezomib (186,187), and a clinical trial with adjuvant bortezomib is ongoing. Other targets with encouraging preclinical results are NOTCH (188)(189)(190)(191)(192), and the KSHV receptor, ephrin receptor A2 (EphA2) (193)(194)(195).…”

Section: Viral Mirnas Support Viral Infection and Latent Persistencementioning

confidence: 99%

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

Dittmer

Damania

2016

Journal of Clinical Investigation

181

152

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“…KSHV exploits multiple host cell surface receptors, including integrins ␣3␤1, ␣V␤3, ␣V␤5, and ␣9␤1 and nonintegrins CD98/xCT and EphA2, to enter the adherent target cells such as human dermal microvascular endothelial cells (HMVEC-d) and human foreskin fibroblast (HFF) cells (1)(2)(3)(4)(5)(6). The interaction of KSHV with its specific entry receptors leads to the formation of a multimolecular receptor complex consisting of integrins, xCT, and EphA2 (2,4,7).…”

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ESCRT-0 Component Hrs Promotes Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus in Human Dermal Microvascular Endothelial Cells

Veettil

Kumar

Ansari

et al. 2016

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) enters human dermal microvascular endothelial cells (HMVEC-d), its naturalInteraction between Hrs and ROCK1 is essential for the ROCK1-induced phosphorylation of NHE1 (Na ؉ /H ؉ exchanger 1), which is involved in the regulation of intracellular pH. Thus, our studies demonstrate the plasma membrane association of ESCRT protein Hrs during macropinocytosis and suggest that KSHV entry requires both Hrs-and ROCK1-dependent mechanisms and that ROCK1-mediated phosphorylation of NHE1 and pH change is an essential event required for the macropinocytosis of KSHV. IMPORTANCEMacropinocytosis is the major entry pathway of KSHV in human dermal microvascular endothelial cells, the natural target cells of KSHV. Although the role of ESCRT protein Hrs has been extensively studied with respect to endosomal movement and sorting of ubiquitinated proteins into lysosomes, its function in macropinocytosis is not known. In the present study, we demonstrate for the first time that upon KSHV infection, the endogenous Hrs localizes to the plasma membrane and the membraneassociated Hrs facilitates assembly of signaling molecules, macropinocytosis, and virus entry. Hrs recruits ROCK1 to the membrane, which is required for the activation of NHE1 and an increase in submembranous intracellular pH occurring during macropinocytosis. These studies demonstrate that the localization of Hrs from the cytosol to the plasma membrane is important for coupling membrane dynamics to the cytosolic signaling events during macropinocytosis of KSHV. K aposi's sarcoma-associated herpesvirus (KSHV) entry into its in vitro adherent target cells is a multistage process which involves binding of viral glycoproteins to cell surface heparan sulfate receptors followed by interaction with specific entry receptors, induction of cell signaling pathways, and endocytosis. KSHV exploits multiple host cell surface receptors, including integrins ␣3␤1, ␣V␤3, ␣V␤5, and ␣9␤1 and nonintegrins CD98/xCT and EphA2, to enter the adherent target cells such as human dermal microvascular endothelial cells (HMVEC-d) and human foreskin fibroblast (HFF) cells (1-6). The interaction of KSHV with its specific entry receptors leads to the formation of a multimolecular receptor complex consisting of integrins, xCT, and EphA2 (2, 4, 7). Receptor engagement and multimolecular receptor complex formation result in autophosphorylation of focal adhesion kinase (FAK) and activation of Src, phosphatidylinositol 3-kinase (PI3-K), and Rho GTPases, and all of these molecules are targeted to specific entry sites on the plasma membrane (8-10). Our previous studies have demonstrated that the signal transduction pathways induced by KSHV and the consequent activation of their downstream molecules play a central role in coordinating the actin dynamics and the membrane protein assembly required for the successful entry of the virus into the cytoplasm (8-10). The

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The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma–associated herpesvirus

Cited by 174 publications

References 65 publications

Reply to “On the Use of 2,5-Dimethyl-Pyrrol-1-yl-Benzoic Acid Derivatives as EPH-Ephrin Antagonists”

Reply to “On the Use of 2,5-Dimethyl-Pyrrol-1-yl-Benzoic Acid Derivatives as EPH-Ephrin Antagonists”

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

ESCRT-0 Component Hrs Promotes Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus in Human Dermal Microvascular Endothelial Cells

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