The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Contains an Immunoreceptor Tyrosine-Based Inhibitory Motif That Activates Shp2

Philpott, Nicola J.; Bakken, Thomas; Pennell, Christopher A.; Chen, Liwei; Wu, Jie; Cannon, Mark

doi:10.1128/jvi.01362-10

Cited by 10 publications

(8 citation statements)

References 26 publications

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“…Constitutive activation of the vGPC receptor, the Kaposi's herpes sarcoma virus associated chemokine has been shown to result in the phosphorylation of SHP2 (267). The vGPCR contains a bona fide immunoreceptor tyrosine-based inhibitory motif (ITIM) that binds and constitutively activates Shp2 (268). Moreover, SHP2 is required for vGPCR activation of the MEK-ERK1/2 axis, the transcription factors AP-1 and NFκB and vGPCR-induced endothelial cell migration (267).…”

Section: Breast Cancermentioning

confidence: 99%

The regulatory roles of phosphatases in cancer

et al. 2013

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The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3 - kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies. © 2014 American Heart Association, Inc

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Section: Breast Cancermentioning

confidence: 99%

The regulatory roles of phosphatases in cancer

et al. 2013

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“…HHV-8 vGPCR is unusual in its promiscuous functional association with three classes of G α proteins (i, q, and 13) in addition to its direct association with and activation of the signaling protein SHP2 (Couty et al 2001; Liu et al 2004; Philpott et al 2011; Shepard et al 2001). Initial reports that vGPCR can function as a classical “autocrine” oncogene in in vitro and in vivo experimental systems employing vGPCR-transduced cell lines (Bais et al 1998) implied that vGPCR may be expressed as a latent protein (enabling it to contribute directly to HHV-8 oncogenesis).…”

Section: Novel Virus–host Interactions Via Lytic Activitiesmentioning

confidence: 99%

Molecular Biology of Human Herpesvirus 8: Novel Functions and Virus–Host Interactions Implicated in Viral Pathogenesis and Replication

Cousins

Nicholas

2013

Recent Results in Cancer Research

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Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is the second identified human gammaherpesvirus. Like its relative Epstein-Barr virus, HHV-8 is linked to B-cell tumors, specifically primary effusion lymphoma and multicentric Castleman’s disease, in addition to endothelial-derived KS. HHV-8 is unusual in its possession of a plethora of “accessory” genes and encoded proteins in addition to the core, conserved herpesvirus and gammaherpesvirus genes that are necessary for basic biological functions of these viruses. The HHV-8 accessory proteins specify not only activities deducible from their cellular protein homologies but also novel, unsuspected activities that have revealed new mechanisms of virus–host interaction that serve virus replication or latency and may contribute to the development and progression of virus-associated neoplasia. These proteins include viral interleukin-6 (vIL-6), viral chemokines (vCCLs), viral G protein–coupled receptor (vGPCR), viral interferon regulatory factors (vIRFs), and viral antiapoptotic proteins homologous to FLICE (FADD-like IL-1β converting enzyme)-inhibitory protein (FLIP) and survivin. Other HHV-8 proteins, such as signaling membrane receptors encoded by open reading frames K1 and K15, also interact with host mechanisms in unique ways and have been implicated in viral pathogenesis. Additionally, a set of micro-RNAs encoded by HHV-8 appear to modulate expression of multiple host proteins to provide conditions conducive to virus persistence within the host and could also contribute to HHV-8-induced neoplasia. Here, we review the molecular biology underlying these novel virus–host interactions and their potential roles in both virus biology and virus-associated disease.

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“…Previous studies showed that vGPCR is a membrane-associated protein that maintains chronic activation of NF-κB in PEL cell lines, primary B cells derived from KS patients, and endothelial cells [ 16 , 29 , 32 , 57 – 59 ]. It has also been demonstrated that membrane-associated CADM1 protein interacts with several receptors and regulates their activities [ 60 – 62 ].…”

Section: Resultsmentioning

confidence: 99%

“…However, the expression and functional roles of CADM1 in other viral-induced leukemias and lymphomas are not yet clear. Persistent activation of NF-κB is critical for the survival of most types of leukemias and lymphomas, including PEL cells [ 16 , 57 , 58 , 82 ]. Our current study has provided a link between CADM1 and NF-κB activation in KSHV-infected PEL cells.…”

Section: Discussionmentioning

confidence: 99%

CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation

Hunte

Alonso

Thomas³

et al. 2018

PLoS Pathog

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Approximately 12% of all human cancers worldwide are caused by infections with oncogenic viruses. Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) is one of the oncogenic viruses responsible for human cancers, including Kaposi’s sarcoma (KS), Primary Effusion Lymphoma (PEL), and the lymphoproliferative disorder multicentric Castleman’s disease (MCD). Chronic inflammation mediated by KSHV infection plays a decisive role in the development and survival of these cancers. NF-κB, a family of transcription factors regulating inflammation, cell survival, and proliferation, is persistently activated in KSHV-infected cells. The KSHV latent and lytic expressing oncogenes involved in NF-κB activation are vFLIP/K13 and vGPCR, respectively. However, the mechanisms by which NF-κB is activated by vFLIP and vGPCR are poorly understood. In this study, we have found that a host molecule, Cell Adhesion Molecule 1 (CADM1), is robustly upregulated in KSHV-infected PBMCs and KSHV-associated PEL cells. Further investigation determined that both vFLIP and vGPCR interacted with CADM1. The PDZ binding motif localized at the carboxyl terminus of CADM1 is essential for both vGPCR and vFLIP to maintain chronic NF-κB activation. Membrane lipid raft associated CADM1 interaction with vFLIP is critical for the initiation of IKK kinase complex and NF-κB activation in the PEL cells. In addition, CADM1 played essential roles in the survival of KSHV-associated PEL cells. These data indicate that CADM1 plays key roles in the activation of NF-κB pathways during latent and lytic phases of the KSHV life cycle and the survival of KSHV-infected cells.

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The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Contains an Immunoreceptor Tyrosine-Based Inhibitory Motif That Activates Shp2

Cited by 10 publications

References 26 publications

The regulatory roles of phosphatases in cancer

The regulatory roles of phosphatases in cancer

Molecular Biology of Human Herpesvirus 8: Novel Functions and Virus–Host Interactions Implicated in Viral Pathogenesis and Replication

CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation

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