Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8 Envelope Glycoprotein gB Induces the Integrin-Dependent Focal Adhesion Kinase-Src-Phosphatidylinositol 3-Kinase-Rho GTPase Signal Pathways and Cytoskeletal Rearrangements

Sharma-Walia, Neelam; Naranatt, Pramod P.; Krishnan, Harinivas H.; Zeng, Ling; Chandran, Bala

doi:10.1128/jvi.78.8.4207-4223.2004

Cited by 144 publications

(224 citation statements)

References 64 publications

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“…The gB⌬TM encoding amino acids 1 to 702 is a recombinant wild-type gB without the transmembrane and cytoplasmic domains. The gB⌬TM-RGA is a recombinant mutant gB with a single amino acid mutation (RGD to RGA) (14,17,40). Similarly to the FAK activation described previously (14,40), we found that an ϳ15 min treatment with 10 nM of gB⌬TM maximally activated VEGFR-3.…”

Section: The Gb-induced Activation Of Vegfr-3 Is Inhibited By Blockinmentioning

confidence: 81%

“…In our previous studies, VEGFR-3 and ␤ 1 integrin formed a complex, and this association was found to activate downstream signaling pathways including PI 3-kinase/Akt and ERK1/2 MAPK (35,36). KSHV infection of target cells activates PI 3-kinase and MAPK, and KSHV gB has been shown to activate PI 3-kinase (40,62). We thus asked if the activation of these kinases by gB could be involved in the activation of VEGFR-3.…”

Section: Vegfr-3 Enhances Kshv Infectionmentioning

confidence: 99%

“…KSHV gB can mediate cell adhesion via its RGD sequence as well as activate focal adhesion components such as FAK and paxillin (14). Recently, it has been shown that KSHV gB regulates integrin-dependent FAK, Src, PI 3-kinase, and Rho GTPase signaling pathways and modulates cytoskeletal rearrangements, which are critical for KS pathogenesis (40). These observations suggest that KSHV gB-induced signaling pathways may play important roles in the infection of target cells and in KS pathogenesis.…”

mentioning

confidence: 96%

“…Integrin ␣ 3 -Several signaling pathways related to cell adhesion, migration, and proliferation can be activated by KSHV gB and KSHV (14,17,40). To assess the functional consequences of KSHV gB protein effects on the endothelium, we studied the gB⌬TM containing the RGD sequence versus the gB⌬TM-RGA mutant.…”

Section: Gb-induced Cell Migration and Proliferation Are Inhibited Bymentioning

confidence: 99%

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Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

Zhang¹,

Wang²,

Chandran

et al. 2005

Journal of Biological Chemistry

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Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8) is the etiologic agent of Kaposi's sarcoma, an endothelial neoplasm. This ␥-herpesvirus encodes for several unique proteins that alter target cell function, including the virion envelope-associated glycoprotein B (gB). Glycoprotein B has an RGD (Arg-Gly-Asp) motif at the extracellular amino terminus region and binds to the ␣ 3 ␤ 1 surface integrin, which enhances virus entry. We now report that gB can activate the vascular endothelial growth factor receptor 3 (VEGFR-3) on the surface of microvascular endothelial cells and trigger receptor signaling, which can modulate endothelial migration and proliferation. Furthermore, we observed that VEGFR-3 expression and activation enhance KSHV infection and participate in KSHV-mediated transformation. These functional changes in the endothelium may contribute to the pathogenesis of Kaposi's sarcoma and suggest that interventions that inhibit gB activation of VEGFR-3 could be useful in the treatment of this neoplasm.

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Section: The Gb-induced Activation Of Vegfr-3 Is Inhibited By Blockinmentioning

confidence: 81%

Section: Vegfr-3 Enhances Kshv Infectionmentioning

confidence: 99%

mentioning

confidence: 96%

Section: Gb-induced Cell Migration and Proliferation Are Inhibited Bymentioning

confidence: 99%

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Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

Zhang¹,

Wang²,

Chandran

et al. 2005

Journal of Biological Chemistry

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“…Integrins bind ECM proteins and adjacent cells to provide cellular attachment functions; however, integrin-binding events are accompanied by a wide range of signal transduction events. Likewise, engagement of integrins and entry of both KSHV and adenovirus have been shown to trigger integrin-specific signaling pathways including the activation of FAK along with inducing distinct cellular morphological changes (32,33). To directly test for integrin activation and downstream integrin-signaling events in response to HCMV, fibroblasts were treated with virus and blotted for specific phosphorylated residues on the cytoplasmic domains of ␤1 and ␤3 integrin or on the soluble cytoplasmic tyrosine kinase that is specifically activated by integrins during integrin binding, FAK.…”

Section: Hcmv Uses Integrins At a Postattachment Stage During The Entrymentioning

confidence: 99%

Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain

Feire

Koss

Compton

2004

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

287

301

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Human cytomegalovirus (HCMV) is capable of manifesting disease in nearly every organ system in immunocompromised patients. This broad pathogenic tropism correlates with the ability of the virus to infect all tested vertebrate cell types in vitro, a characteristic that has made receptor identification extremely difficult. During virus entry, HCMV induces cellular morphological changes and signaling cascades consistent with engagement of cellular integrins; however, HCMV structural proteins do not possess the widely used RGD integrin-binding motif. We identified an integrinbinding disintegrin-like domain within HCMV envelope glycoprotein B, a protein required for virus entry and fusion throughout the Herpesviridae. Accepted receptor criteria are met through the use of function-blocking integrin Abs, ␤1 integrin knockout mouse fibroblasts, and glycoprotein B disintegrin-like peptides, all of which support a critical role for ␣2␤1, ␣6␤1, and ␣V␤3 integrins as HCMV entry receptors and signaling mediators acting during the penetration stage of the entry pathway. Strikingly, the glycoprotein B disintegrin-like domain is conserved in many human and animal herpesviruses, suggesting that integrins may support entry across this medically important virus family.H uman cytomegalovirus (HCMV) is a member of the medically significant Herpesviridae family of viruses. Herpesviruses establish a life-long relationship with their hosts and can manifest disease in an opportunistic manner. HCMV is the most common viral cause of congenital birth defects and is responsible for significant morbidity and mortality in immunocompromised patients, including AIDS patients and organ transplant recipients (1, 2). A notable feature of HCMV pathogenesis is its exceptionally broad tissue tropism. HCMV is capable of manifesting disease in most organ systems and tissue types, which directly correlates with its ability to infect fibroblasts, endothelial cells, epithelial cells, monocytes͞macrophages, smooth muscle cells, stromal cells, neuronal cells, neutrophils, and hepatocytes (3, 4). In vitro entry into target cells is equally promiscuous since HCMV is able to bind, penetrate, and initiate replication in all tested vertebrate cell types (5). HCMV host cell entry begins with a required tethering step to cell surface heparan sulfate proteoglycans (HSPGs) (6). After HSPG binding, the virus transitions to a more stable docking step by engaging unidentified protein receptors (7), all of which lead to fusion at the cell surface (8). Recently, epidermal growth factor receptor (EGFR) was identified as a potential cellular attachment and signaling coreceptor for HCMV, the expression of which correlated with the ability of the virus to initiate gene expression (9). However, EGFR is not expressed on several HCMV permissive cells, such as hematopoetic cell types. Therefore, postattachment entry mediating coreceptors must exist.Many of the physiological consequences associated with HCMV infection are consistent with activation of cellular integrins. Host cel...

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Proteomes, kinases and signalling pathways in virus‐induced filopodia, as potential antiviral therapeutics targets

Aliyu

Kumurya

Bala

et al. 2020

Reviews in Medical Virology

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Summary Filopodia are thin finger‐like protrusions at the surface of cells that are internally occupied with bundles of tightly parallel actin filaments. They play significant roles in cellular physiological processes, such as adhesion to extracellular matrix, guidance towards chemo‐attractants and in wound healing. Filopodia were recently reported to play important roles in viral infection including initial viral attachment to host cells, cell surfing, viral trafficking, internalization, budding, virus release and spread to other cells in a form that would avoid the host immune system. The detailed virus‐host protein interactions underlying most of these processes remain to be elucidated. This review will describe some reported virus‐host protein interactions on filopodia with the aim of identifying potential new anti‐virus therapeutic targets. Exploring this research area may lead to the development of novel classes of anti‐viral therapeutics that can block signalling pathways used by the virus to trigger filopodia formation. Successful compounds would inhibit initial virus attachment, formation of filopodia, expression of putative virus binding protein, extracellular virus trafficking, and budding.

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Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8 Envelope Glycoprotein gB Induces the Integrin-Dependent Focal Adhesion Kinase-Src-Phosphatidylinositol 3-Kinase-Rho GTPase Signal Pathways and Cytoskeletal Rearrangements

Cited by 144 publications

References 64 publications

Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection

Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain

Proteomes, kinases and signalling pathways in virus‐induced filopodia, as potential antiviral therapeutics targets

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