The Experts below are selected from a list of 351 Experts worldwide ranked by ideXlab platform
Patrick A Singleton - One of the best experts on this subject based on the ideXlab platform.
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transactivation of the Receptor tyrosine kinase Ephrin Receptor a2 is required for the low molecular weight hyaluronan mediated angiogenesis that is implicated in tumor progression
Journal of Biological Chemistry, 2014Co-Authors: Frances E Lennon, Tamara Mirzapoiazova, Nurbek Mambetsariev, Bolot Mambetsariev, Ravi Salgia, Patrick A SingletonAbstract:Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, understanding the mechanism(s) by which angiogenesis occurs can have important therapeutic implications in numerous malignancies. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA, ∼2500 Da) promotes endothelial cell (EC) barrier disruption and angiogenesis. However, the mechanism(s) by which this occurs is poorly defined. Our data indicate that treatment of human EC with LMW-HA induced CD44v10 association with the Receptor-tyrosine kinase, EphA2, transactivation (tyrosine phosphorylation) of EphA2, and recruitment of the PDZ domain scaffolding protein, PATJ, to the cell periphery. Silencing (siRNA) CD44, EphA2, PATJ, or Dbs (RhoGEF) expression blocked LMW-HA-mediated angiogenesis (EC proliferation, migration, and tubule formation). In addition, silencing EphA2, PATJ, Src, or Dbs expression blocked LMW-HA-mediated RhoA activation. To translate our in vitro findings, we utilized a novel anginex/liposomal targeting of murine angiogenic endothelium with either CD44 or EphA2 siRNA and observed inhibition of LMW-HA-induced angiogenesis in implanted Matrigel plugs. Taken together, these results indicate LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. These results suggest that targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis-associated diseases including tumor progression.
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transactivation of the Receptor tyrosine kinase Ephrin Receptor a2 is required for the low molecular weight hyaluronan mediated angiogenesis that is implicated in tumor progression
Journal of Biological Chemistry, 2014Co-Authors: Frances E Lennon, Tamara Mirzapoiazova, Nurbek Mambetsariev, Bolot Mambetsariev, Ravi Salgia, Patrick A SingletonAbstract:Abstract Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, understanding the mechanism(s) by which angiogenesis occurs can have important therapeutic implications in numerous malignancies. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA, ~2,500 Da) promotes endothelial cell (EC) barrier disruption and angiogenesis. However, the mechanism(s) by which this occurs are poorly defined. Our data indicate that treatment of human EC with LMW-HA induced CD44v10 association with the Receptor tyrosine kinase, EphA2, transactivation (tyrosine phosphorylation) of EphA2, and recruitment of the PDZ domain scaffolding protein, PATJ, to the cell periphery. Silencing (siRNA) CD44, EphA2, PATJ or Dbs (Rho GEF) expression blocked LMW-HA-mediated angiogenesis (EC proliferation, migration and tubule formation). In addition, silencing EphA2, PATJ, Src or Dbs expression blocked LMW-HA-mediated RhoA activation. To translate our in vitro findings, we utilized a novel Anginex/liposomal targeting of murine angiogenic endothelium with either CD44 or EphA2 siRNA and observed inhibition of LMW-HA-induced angiogenesis in implanted matrigel plugs. Taken together, these results indicate LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. These results suggest that targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis-associated diseases including tumor progression.
Richard Longnecker - One of the best experts on this subject based on the ideXlab platform.
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Ephrin Receptor a4 is a new kaposi s sarcoma associated herpesvirus virus entry Receptor
Mbio, 2019Co-Authors: Jia Chen, Xianming Zhang, Samantha Schaller, Theodore S Jardetzky, Richard LongneckerAbstract:Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with the development of Kaposi's sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells is a complex multistep process and is initiated by the binding and interaction of viral envelope glycoproteins with the cellular Receptors. In the current studies, we have found that EphA4 promotes KSHV glycoprotein H/glycoprotein L (gH/gL)-mediated fusion and infection better than does Ephrin A2 (EphA2) in HEK293T cells, indicating that EphA4 is a new KSHV entry Receptor. To confirm that epithelial cells express EphA2 and EphA4, we analyzed the expression of EphA2 and EphA4 in epithelial cells, endothelial cells, B cells, monocytes, fibroblasts using RNA sequencing (RNA-seq) data analysis of existing data sets. We found that these cell types broadly express both EphA2 and EphA4, with the exception of monocytes and B cells. To confirm EphA4 is important for KSHV fusion and infection, we generated EphA2 and EphA4 single- and double-knockout cells. We found that both EphA2 and EphA4 play a role in KSHV fusion and infection, since EphA2-EphA4 double-knockout cells had the greatest decrease in fusion activity and infection compared to single-knockout cells. Fusion and infection of KSHV were rescued in the EphA2-EphA4 double-knockout cells upon overexpression of EphA2 and/or EphA4. EphA2 binds to both Epstein-Barr virus (EBV) and KSHV gH/gL; however, EphA4 binds only to KSHV gH/gL. Taken together, our results identify EphA4 as a new entry Receptor for KSHV.IMPORTANCE The overall entry mechanism for herpesviruses is not completely known, including those for the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). To fully understand the herpesvirus entry process, functional Receptors need to be identified. In the current study, we found that EphA4 can also function for a KSHV entry Receptor along with EphA2. Interestingly, we found that EphA4 does not function as an entry Receptor for EBV, whereas EphA2 does. The discovery of EphA4 as a KSHV entry Receptor has important implications for KSHV pathogenesis in humans, may prove useful in understanding the unique pathogenesis of KSHV infection in humans, and may uncover new potential targets that can be used for the development of novel interventional strategies.
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Ephrin Receptor a4 epha4 is a new kaposi s sarcoma associated herpesvirus virus entry Receptor
bioRxiv, 2019Co-Authors: Jia Chen, Samantha Schaller, Theodore S Jardetzky, Zianming Zhang, Richard LongneckerAbstract:Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus associated with the development of Kaposi’s sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells is a complex multistep process and is initiated by the binding and interaction of viral envelope glycoproteins with the cellular Receptors. In our current studies, we have found that EphA4 promotes KSHV gH/gL-mediated fusion and infection better than EphA2 in HEK293T cells indicating that EphA4 is a new KSHV entry Receptor. To confirm that epithelial cells express EphA2 and EphA4, we analyzed the expression of EphA2 and EphA4 in epithelial cells, endothelial cells, B cells, monocytes, fibroblasts using RNA-seq data analysis of existing data sets. We found these cell types broadly express both EphA2 and EphA4 with the exception of monocytes and B cells. To confirm EphA4 is important for KSHV fusion and infection, we generated EphA2 and EphA4 single and double knockout cells. We found that both EphA2 and EphA4 play a role in KSHV fusion and infection, since EphA2/EphA4 double knockout cells had the greatest decrease in fusion activity and infection compared to single knockout cells. Fusion and infection of KSHV was rescued in the EphA2/EphA4 double knock cells upon overexpression of EphA2 and/or EphA4. EphA2 binds to both EBV and KSHV gH/gL; however, EphA4 binds only to KSHV gH/gL. Taken together, our results identify EphA4 as a new entry Receptor for KSHV. Importance The overall entry mechanism for herpesviruses is not completely known including that for the human γ-herpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). To fully understand the herpesvirus entry process, functional Receptors need to be identified. In our current study, we found that EphA4 can also function for a KSHV entry Receptor along with EphA2. Interestingly, we found that EphA4 does not function as an entry Receptor for EBV whereas EphA2 does. The discovery of EphA4 as KSHV entry Receptor has important implications for KSHV pathogenesis in humans and may prove useful in understanding the unique pathogenesis of KSHV infection in humans and may uncover new potential targets that can be used for the development of novel interventional strategies.
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Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor
American Society for Microbiology, 2019Co-Authors: Jia Chen, Xianming Zhang, Samantha Schaller, Theodore S Jardetzky, Richard LongneckerAbstract:The overall entry mechanism for herpesviruses is not completely known, including those for the human gammaherpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). To fully understand the herpesvirus entry process, functional Receptors need to be identified. In the current study, we found that EphA4 can also function for a KSHV entry Receptor along with EphA2. Interestingly, we found that EphA4 does not function as an entry Receptor for EBV, whereas EphA2 does. The discovery of EphA4 as a KSHV entry Receptor has important implications for KSHV pathogenesis in humans, may prove useful in understanding the unique pathogenesis of KSHV infection in humans, and may uncover new potential targets that can be used for the development of novel interventional strategies.Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with the development of Kaposi’s sarcoma (KS). KSHV target cells include endothelial cells, B cells, monocytes, epithelial cells, dendritic cells, macrophages, and fibroblasts. KSHV entry into target cells is a complex multistep process and is initiated by the binding and interaction of viral envelope glycoproteins with the cellular Receptors. In the current studies, we have found that EphA4 promotes KSHV glycoprotein H/glycoprotein L (gH/gL)-mediated fusion and infection better than does Ephrin A2 (EphA2) in HEK293T cells, indicating that EphA4 is a new KSHV entry Receptor. To confirm that epithelial cells express EphA2 and EphA4, we analyzed the expression of EphA2 and EphA4 in epithelial cells, endothelial cells, B cells, monocytes, fibroblasts using RNA sequencing (RNA-seq) data analysis of existing data sets. We found that these cell types broadly express both EphA2 and EphA4, with the exception of monocytes and B cells. To confirm EphA4 is important for KSHV fusion and infection, we generated EphA2 and EphA4 single- and double-knockout cells. We found that both EphA2 and EphA4 play a role in KSHV fusion and infection, since EphA2-EphA4 double-knockout cells had the greatest decrease in fusion activity and infection compared to single-knockout cells. Fusion and infection of KSHV were rescued in the EphA2-EphA4 double-knockout cells upon overexpression of EphA2 and/or EphA4. EphA2 binds to both Epstein-Barr virus (EBV) and KSHV gH/gL; however, EphA4 binds only to KSHV gH/gL. Taken together, our results identify EphA4 as a new entry Receptor for KSHV
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Ephrin Receptor a2 is a functional entry Receptor for epstein barr virus
Nature microbiology, 2018Co-Authors: Jia Chen, Karthik Sathiyamoorthy, Xianming Zhang, Samantha Schaller, Bethany Perez E White, Theodore S Jardetzky, Richard LongneckerAbstract:Epstein-Barr virus (EBV) is an oncogenic virus that infects more than 90% of the world's population 1 . EBV predominantly infects human B cells and epithelial cells, which is initiated by fusion of the viral envelope with a host cellular membrane 2 . The mechanism of EBV entry into B cells has been well characterized 3 . However, the mechanism for epithelial cell entry remains elusive. Here, we show that the integrins αvβ5, αvβ6 and αvβ8 do not function as entry and fusion Receptors for epithelial cells, whereas Ephrin Receptor tyrosine kinase A2 (EphA2) functions well for both. EphA2 overexpression significantly increased EBV infection of HEK293 cells. Using a virus-free cell-cell fusion assay, we found that EphA2 dramatically promoted EBV but not herpes simplex virus (HSV) fusion with HEK293 cells. EphA2 silencing using small hairpin RNA (shRNA) or knockout by CRISPR-Cas9 blocked fusion with epithelial cells. This inhibitory effect was rescued by the expression of EphA2. Antibody against EphA2 blocked epithelial cell infection. Using label-free surface plasmon resonance binding studies, we confirmed that EphA2 but not EphA4 specifically bound to EBV gHgL and this interaction is through the EphA2 extracellular domain (ECD). The discovery of EphA2 as an EBV epithelial cell Receptor has important implications for EBV pathogenesis and may uncover new potential targets that can be used for the development of novel intervention strategies.
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Ephrin Receptor a2 is a functional entry Receptor for epstein barr virus
Nature microbiology, 2018Co-Authors: Jia Chen, Karthik Sathiyamoorthy, Xianming Zhang, Samantha Schaller, Bethany Perez E White, Theodore S Jardetzky, Richard LongneckerAbstract:Epstein–Barr virus (EBV) is an oncogenic virus that infects more than 90% of the world’s population 1 . EBV predominantly infects human B cells and epithelial cells, which is initiated by fusion of the viral envelope with a host cellular membrane 2 . The mechanism of EBV entry into B cells has been well characterized 3 . However, the mechanism for epithelial cell entry remains elusive. Here, we show that the integrins αvβ5, αvβ6 and αvβ8 do not function as entry and fusion Receptors for epithelial cells, whereas Ephrin Receptor tyrosine kinase A2 (EphA2) functions well for both. EphA2 overexpression significantly increased EBV infection of HEK293 cells. Using a virus-free cell–cell fusion assay, we found that EphA2 dramatically promoted EBV but not herpes simplex virus (HSV) fusion with HEK293 cells. EphA2 silencing using small hairpin RNA (shRNA) or knockout by CRISPR–Cas9 blocked fusion with epithelial cells. This inhibitory effect was rescued by the expression of EphA2. Antibody against EphA2 blocked epithelial cell infection. Using label-free surface plasmon resonance binding studies, we confirmed that EphA2 but not EphA4 specifically bound to EBV gHgL and this interaction is through the EphA2 extracellular domain (ECD). The discovery of EphA2 as an EBV epithelial cell Receptor has important implications for EBV pathogenesis and may uncover new potential targets that can be used for the development of novel intervention strategies. The Receptor tyrosine kinase EphA2 is identified as an EBV entry and fusion Receptor in epithelial cells. EphA2 depletion or absence, or the use of anti-EphA2 antibodies, precludes infection of epithelial cell lines and oropharyngeal carcinoma cells.
Frances E Lennon - One of the best experts on this subject based on the ideXlab platform.
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transactivation of the Receptor tyrosine kinase Ephrin Receptor a2 is required for the low molecular weight hyaluronan mediated angiogenesis that is implicated in tumor progression
Journal of Biological Chemistry, 2014Co-Authors: Frances E Lennon, Tamara Mirzapoiazova, Nurbek Mambetsariev, Bolot Mambetsariev, Ravi Salgia, Patrick A SingletonAbstract:Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, understanding the mechanism(s) by which angiogenesis occurs can have important therapeutic implications in numerous malignancies. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA, ∼2500 Da) promotes endothelial cell (EC) barrier disruption and angiogenesis. However, the mechanism(s) by which this occurs is poorly defined. Our data indicate that treatment of human EC with LMW-HA induced CD44v10 association with the Receptor-tyrosine kinase, EphA2, transactivation (tyrosine phosphorylation) of EphA2, and recruitment of the PDZ domain scaffolding protein, PATJ, to the cell periphery. Silencing (siRNA) CD44, EphA2, PATJ, or Dbs (RhoGEF) expression blocked LMW-HA-mediated angiogenesis (EC proliferation, migration, and tubule formation). In addition, silencing EphA2, PATJ, Src, or Dbs expression blocked LMW-HA-mediated RhoA activation. To translate our in vitro findings, we utilized a novel anginex/liposomal targeting of murine angiogenic endothelium with either CD44 or EphA2 siRNA and observed inhibition of LMW-HA-induced angiogenesis in implanted Matrigel plugs. Taken together, these results indicate LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. These results suggest that targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis-associated diseases including tumor progression.
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transactivation of the Receptor tyrosine kinase Ephrin Receptor a2 is required for the low molecular weight hyaluronan mediated angiogenesis that is implicated in tumor progression
Journal of Biological Chemistry, 2014Co-Authors: Frances E Lennon, Tamara Mirzapoiazova, Nurbek Mambetsariev, Bolot Mambetsariev, Ravi Salgia, Patrick A SingletonAbstract:Abstract Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, understanding the mechanism(s) by which angiogenesis occurs can have important therapeutic implications in numerous malignancies. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA, ~2,500 Da) promotes endothelial cell (EC) barrier disruption and angiogenesis. However, the mechanism(s) by which this occurs are poorly defined. Our data indicate that treatment of human EC with LMW-HA induced CD44v10 association with the Receptor tyrosine kinase, EphA2, transactivation (tyrosine phosphorylation) of EphA2, and recruitment of the PDZ domain scaffolding protein, PATJ, to the cell periphery. Silencing (siRNA) CD44, EphA2, PATJ or Dbs (Rho GEF) expression blocked LMW-HA-mediated angiogenesis (EC proliferation, migration and tubule formation). In addition, silencing EphA2, PATJ, Src or Dbs expression blocked LMW-HA-mediated RhoA activation. To translate our in vitro findings, we utilized a novel Anginex/liposomal targeting of murine angiogenic endothelium with either CD44 or EphA2 siRNA and observed inhibition of LMW-HA-induced angiogenesis in implanted matrigel plugs. Taken together, these results indicate LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. These results suggest that targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis-associated diseases including tumor progression.
Alexander S. Hahn - One of the best experts on this subject based on the ideXlab platform.
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binding of the kaposi s sarcoma associated herpesvirus to the Ephrin binding surface of the epha2 Receptor and its inhibition by a small molecule
Journal of Virology, 2014Co-Authors: Alexander S. Hahn, Ronald C. DesrosiersAbstract:ABSTRACT The Ephrin Receptor tyrosine kinase A2 (EphA2) is an entry Receptor for Kaposi9s sarcoma-associated herpesvirus (KSHV) that is engaged by the virus through its gH/gL glycoprotein complex. We describe here that natural Ephrin ligands inhibit the gH/gL-EphA2 interaction. The effects of point mutations within EphA2 demonstrated that KSHV gH/gL interacts with EphA2 through a restricted set of the same residues that mediate binding of A-type Ephrins. Two previously described inhibitors of the EphA2 interaction with Ephrin A5 also inhibited binding of KSHV gH/gL to EphA2. The more potent of the two compounds inhibited KSHV infection of blood vessel and lymphatic endothelial cells in the micromolar concentration range. Our results demonstrate that interaction of KSHV with EphA2 occurs in a fashion similar to that of the natural Ephrin ligands. Our data further indicate a new avenue for drug development against KSHV. IMPORTANCE Our study reports two important findings. First, we show that KSHV engages its Receptor, the Receptor tyrosine kinase EphA2, at a site that overlaps the binding site of the natural Ephrin ligands. Second, we demonstrate that KSHV infection of target cells can be blocked by a small-molecule inhibitor of the viral glycoprotein-EphA2 interaction. These findings represent a novel avenue for the development of strategies to treat KSHV-associated diseases.
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rhesus monkey rhadinovirus uses eph family Receptors for entry into b cells and endothelial cells but not fibroblasts
PLOS Pathogens, 2013Co-Authors: Alexander S. Hahn, Ronald C. DesrosiersAbstract:Cellular Ephrin Receptor tyrosine kinases (Ephrin Receptors, Ephs) were found to interact efficiently with the gH/gL glycoprotein complex of the rhesus monkey rhadinovirus (RRV). Since EphA2 was recently identified as a Receptor for the Kaposi's sarcoma-associated herpesvirus (KSHV) (Hahn et al., Nature Medicine 2012), we analyzed RRV and KSHV in parallel with respect to Eph-binding and Eph-dependent entry. Ten of the 14 Eph proteins, including both A- and B-type, interacted with RRV gH/gL. Two RRV strains with markedly different gH/gL sequences exhibited similar but slightly different binding patterns to Ephs. gH/gL of KSHV displayed high affinity towards EphA2 but substantially weaker binding to only a few other Ephs of the A-type. Productive entry of RRV 26-95 into B cells and into endothelial cells was essentially completely dependent upon Ephs since expression of a GFP reporter cassette from recombinant virus could be blocked to greater than 95% by soluble Eph decoys using these cells. In contrast, entry of RRV into fibroblasts and epithelial cells was independent of Ephs by these same criteria. Even high concentrations and mixtures of soluble Eph decoys were not able to reduce by any appreciable extent the number of fibroblasts and epithelial cells productively entered by RRV. Thus, RRV is similar to its close relative KSHV in the use of Eph family Receptors for productive entry into B cells and endothelial cells. However, RRV uses a separate, distinct, Eph-independent pathway for productive entry into fibroblasts and epithelial cells. Whether KSHV also uses an Eph-independent pathway in some circumstances or to some extent remains to be determined.
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the Ephrin Receptor tyrosine kinase a2 is a cellular Receptor for kaposi s sarcoma associated herpesvirus
Nature Medicine, 2012Co-Authors: Alexander S. Hahn, Johanna K Kaufmann, Effi Wies, Elisabeth Naschberger, Julia Panteleevivlev, Katharina Schmidt, Angela Holzer, Martin Schmidt, Jin Chen, Simone KonigAbstract:Kaposi's sarcoma–associated herpesvirus (KSHV) can infect endothelial cells, leading to the development of Kaposi's sarcoma in some individuals. The mechanisms underlying cell entry by KSHV are not fully elucidated. ahn et al. now report that Ephrin Receptor tyrosine kinase A2 (EphA2) acts as a cellular Receptor for KSHV and show that blocking EphA2 inhibits infection of endothelial cells.
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the Ephrin Receptor tyrosine kinase a2 is a cellular Receptor for kaposi s sarcoma associated herpesvirus
Nature Medicine, 2012Co-Authors: Alexander S. Hahn, Johanna K Kaufmann, Effi Wies, Elisabeth Naschberger, Julia Panteleevivlev, Katharina Schmidt, Angela Holzer, Martin Schmidt, Jin Chen, Simone KonigAbstract:Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma(1), a highly vascularized tumor originating from lymphatic endothelial cells, and of at least two different B cell malignancies(2,3). A dimeric complex formed by the envelope glycoproteins H and L (gH-gL) is required for entry of herpesviruses into host cells(4). We show that the Ephrin Receptor tyrosine kinase A2 (EphA2) is a cellular Receptor for KSHV gH-gL. EphA2 co-precipitated with both gH-gL and KSHV virions. Infection of human epithelial cells with a GFP-expressing recombinant KSHV strain, as measured by FACS analysis, was increased upon overexpression of EphA2. Antibodies against EphA(2) and siRNAs directed against EphA2 inhibited infection of endothelial cells. Pretreatment of KSHV with soluble EphA2 resulted in inhibition of KSHV infection by up to 90%. This marked reduction of KSHV infection was seen with all the different epithelial and endothelial cells used in this study. Similarly, pretreating epithelial or endothelial cells with the soluble EphA2 ligand EphrinA4 impaired KSHV infection. Deletion of the gene encoding EphA2 essentially abolished KSHV infection of mouse endothelial cells. Binding of gH-gL to EphA2 triggered EphA2 phosphorylation and endocytosis, a major pathway of KSHV entry(5,6). Quantitative RT-PCR and in situ histochemistry revealed a close correlation between KSHV infection and EphA2 expression both in cultured cells derived from human Kaposi's sarcoma lesions or unaffected human lymphatic endothelium, and in situ in Kaposi's sarcoma specimens, respectively. Taken together, our results identify EphA2, a tyrosine kinase with known functions in neovascularization and oncogenesis, as an entry Receptor for KSHV.
Zoran Minic - One of the best experts on this subject based on the ideXlab platform.
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targeting Ephrin Receptor tyrosine kinase a2 with a selective aptamer for glioblastoma stem cells
Molecular therapy. Nucleic acids, 2020Co-Authors: Alessandra Affinito, Cristina Quintavalle, Carla Lucia Esposito, Giuseppina Roscigno, Catello Giordano, Silvia Nuzzo, Lucia Riccivitiani, Iolanda Scognamiglio, Zoran MinicAbstract:Despite the benefits associated with radiotherapy and chemotherapy for glioblastoma (GBM) treatment, most patients experience a relapse following initial therapy. Recurrent or progressive GBM usually does not respond anymore to standard therapy, and this is associated with poor patient outcome. GBM stem cells (GSCs) are a subset of cells resistant to radiotherapy and chemotherapy and play a role in tumor recurrence. The targeting of GSCs and the identification of novel markers are crucial issues in the development of innovative strategies for GBM eradication. By differential cell SELEX (systematic evolution of ligands by exponential enrichment), we have recently described two RNA aptamers, that is, the 40L sequence and its truncated form A40s, able to bind the cell surface of human GSCs. Both aptamers were selective for stem-like growing GBM cells and are rapidly internalized into target cells. In this study, we demonstrate that their binding to cells is mediated by direct recognition of the Ephrin type-A Receptor 2 (EphA2). Functionally, the two aptamers were able to inhibit cell growth, stemness, and migration of GSCs. Furthermore, A40s was able to cross the blood-brain barrier (BBB) and was stable in serum in in vitro experiments. These results suggest that 40L and A40s represent innovative potential therapeutic tools for GBM.