Syk Tyrosine Kinase Mediates Epstein-Barr Virus Latent Membrane Protein 2A-induced Cell Migration in Epithelial Cells

Lu, Jean; Lin, Wan Hsin; Chen, Shao Yin; Longnecker, Richard; Tsai, Shu Chun; Chen, Chi Long; Tsai, Ching Hwa

doi:10.1074/jbc.m507305200

Cited by 81 publications

(79 citation statements)

References 48 publications

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“…Binding of Syk to the ITAMs of FcRg and DAP12 was shown to regulate the development of osteoclasts (Fodor et al, 2006) and SLP76 and Syk participate in the developmental separation of blood and lymphatic vascular epithelial cells, perhaps dependent on an as yet unidentified ITAM-containing receptor (Koretzky et al, 2006). The observation that Syk acts as a tumor suppressor gene in breast carcinoma (Coopman et al, 2000) has raised the question whether LMP2A might contribute to the tumorigenic development in nasopharyngeal carcinoma through its effects on Syk (Lu et al, 2006). ITAM motifs are present in a number of viral proteins (Grande et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…LMP2A and bovine leukemia virus gp 30 were first shown to issue ITAM-dependent signals in T cells (Beaufils et al, 1993). Some functions of the ITAM-containing viral proteins may relate to tumorigenicity, such as survival signalling by activation of the PI3K-Akt pathway by LMP2A and KSHV K1 (Scholle et al, 2000;Swart et al, 2000;Tomlinson and Damania, 2004) and stimulation of cellular migration and invasiveness by LMP2A and MMTV env (Katz et al, 2005;Lu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

et al. 2007

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The Epstein-Barr virus latency-associated membrane protein LMP2A has been shown to activate the survival kinase Akt in epithelial and B cells in a phosphoinositide 3-kinase-dependent fashion. In this study, we demonstrate that the signalling scaffold Shb associates through SH2 and PTB domain interactions with phosphorylated tyrosine motifs in the LMP2A N-terminal tail. Additionally, we show that mutation of tyrosines in these motifs as well as shRNA-mediated downregulation of Shb leads to a loss of constitutive Akt-activation in LMP2A-expressing cells. Furthermore, utilization by Shb of the LMP2A ITAM motif regulates stability of the Syk tyrosine kinase in LMP2A-expressing cells. Our data set the precedent for viral utilization of the Shb signalling scaffold and implicate Shb as a regulator of LMP2A-dependent Akt activation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

et al. 2007

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“…In the human Burkitt's lymphoma cell line and gastric carcinoma cell line, the PI3-K inhibitor blocks the anti-apoptotic effect of LMP2A, suggesting that LMP2A utilizes the PI3-K signaling pathway in mediating anti-apoptotic effects [132]. In addition, one study suggested that the LMP2A-induced Syk activity in 293 and HaCat human epithelial cell lines is involved in cell migration, and this activation requires the tyrosine residues in the LMP2A ITAM motif [133]. LMP2A regulates cell survival and apoptotic inhibition through various routes.…”

Section: The Pi3-k/akt Pathwaymentioning

confidence: 99%

The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

Pang

Lin

Peh

2009

Cellular and Molecular Biology Letters

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Epstein-Barr virus (EBV) is a ubiquitous virus with infections commonly resulting in a latency carrier state. Although the exact role of EBV in cancer pathogenesis remains not entirely clear, it is highly probable that it causes several lymphoid and epithelial malignancies, such as Hodgkin's lymphoma, NK-T cell lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma. EBV-associated malignancies are associated with a latent form of infection, and several of these EBV-encoded latent proteins are known to mediate cellular transformation. These include six nuclear antigens and three latent membrane proteins. Studies have shown that EBV displays distinct patterns of viral latent gene expression in these lymphoid and epithelial tumors. The constant expression of latent membrane protein 2A (LMP2A) at the RNA level in both primary and metastatic tumors suggests that this protein might be a driving factor in the tumorigenesis of EBV-associated malignancies. LMP2A may cooperate with the aberrant host genome, and thereby contribute to malignant transformation by intervening in signaling pathways at multiple points, especially in the cell cycle and apoptotic pathway. This review summarizes the role of EBV-encoded LMP2A in EBV-associated viral latency and cancers. We will focus our discussions on the molecular interactions of each of the conserved motifs in LMP2A, and their involvement in various signaling pathways, namely the B-cell receptor blockade mechanism, the ubiquitin-mediated (Notch and Wnt) pathways, and the MAPK, PI3-K/Akt, NK-κB and STAT pathways, which can provide us with important insights into the roles of LMP2A in the EBVassociated latency state and various malignancies.

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“…In breast cancers, reduced Syk expression was associated with invasion and its overexpression in cell lines was shown to inhibit cell migration (5). In contrast, Syk mediates cell migration in nasopharyngeal carcinoma (15). The role of Syk in squamous cell carcinomas of the head and neck (SCCHN) has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Syk Tyrosine Kinase Is Linked to Cell Motility and Progression in Squamous Cell Carcinomas of the Head and Neck

et al. 2007

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Syk, a non-receptor tyrosine kinase, is an important component of immunoreceptor signaling in hematopoietic cells. It has been implicated in key regulatory pathways including phosphoinositide 3-kinase and phospholipase C; (PLC;) activation in B cells and integrin signaling in platelets and bronchial epithelial cells. Recently, potential roles in cancer have been reported. In breast cancers, reduced Syk expression was associated with invasion, and its overexpression in cell lines was shown to inhibit cell motility. In contrast, Syk has been shown to mediate chemomigration in nasopharyngeal carcinoma cells. Its role in squamous cell carcinomas of the head and neck (SCCHN) has not yet been investigated. Syk mRNA and protein expression was detected in 6 of 10 SCCHN cell lines. When Syk was transfected into Syknegative cells (SIHN-011A), chemomigration was enhanced in vitro and this was associated with activation of PLC;1. Conversely, abrogation of Syk activity by pharmacologic inhibition or small interfering RNA in HN6 cells with high levels of endogenous expression inhibited migration, haptotaxis, and engagement with matrix proteins; this was accompanied by decreased levels of phosphorylated AKT. Similar effects were seen in Syk-positive CAL 27 cells but not in Syk-negative SIHN-011A cells. Immunoprecipitation suggested co-association of Syk with epidermal growth factor receptor and GRB-2. Syk expression in SCCHN patient tissues was examined by semiquantitative real-time PCR (n = 45) and immunohistochemistry (n = 38) in two independent cohorts. Higher levels of Syk expression were observed in tumors and lymph node metastases relative to normal tissues. High Syk expression significantly correlated with worse survival and may be of prognostic value in SCCHN due to its potential role in cell migration and invasion. [Cancer Res 2007;67(16):7907-16]

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Syk Tyrosine Kinase Mediates Epstein-Barr Virus Latent Membrane Protein 2A-induced Cell Migration in Epithelial Cells

Cited by 81 publications

References 48 publications

The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

Syk Tyrosine Kinase Is Linked to Cell Motility and Progression in Squamous Cell Carcinomas of the Head and Neck

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