Latent Membrane Protein 2A-Mediated Effects on the Phosphatidylinositol 3-Kinase/Akt Pathway

Swart, Rachel; Ruf, Ingrid K.; Sample, Jeffery T.; Longnecker, Richard

doi:10.1128/jvi.74.22.10838-10845.2000

Cited by 137 publications

(143 citation statements)

References 68 publications

(62 reference statements)

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“…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%

“…Tyrosine residues involved in Shb binding to LMP2A control constitutive Akt activation The LMP2A ITAM tyrosines Y74 and Y85 were previously shown to bind the Syk tyrosine kinase (Longnecker et al, 1991) and mutations of these tyrosines were shown to influence Syk binding to LMP2A as well as LMP2A-mediated Akt activation and survival signalling (Scholle et al, 2000;Swart et al, 2000). Here, we confirm the negative effect of the Y74F and Y85F mutations on the ability of LMP2A to activate Akt (Figure 6, lanes 11 and 12) and extend this observation by showing that the Y64F mutation suppresses Akt activation by LMP2A, either alone (lanes 5 and 6) or in combination with the Y74F mutation (lanes 9 and 10).…”

Section: Downregulation Of Shb Impairs Lmp2a-mediated Akt Activationmentioning

confidence: 99%

“…In B cells, it can deliver signals that permit survival of B-cell receptor (BCR)-negative cells in the peripheral circulation (Caldwell et al, 1998;Merchant et al, 2000). These signals were shown to depend on a constitutive activation of the PI3K (phosphoinositide 3-kinase)-Akt signalling pathway (Scholle et al, 2000, Swart et al, 2000 mediated by the LMP2A ITAM motif. Depending on its expression level, LMP2A can direct B-cell differentiation either to the B1 or the follicular (B2) and marginal zone B cells (Casola et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Although Syk can mediate PI3K activation in B cells, it is not clear whether the association between Syk and LMP2A leads to both PI3K activation and Syk ubiquitination or whether LMP2A inactivates Syk and another interacting protein mediates PI3K activation. If so, then such a protein must utilize the LMP2A ITAM motif, which was shown to be required for LMP2A-mediated Akt-activation (Scholle et al, 2000;Swart et al, 2000;Morrison and Raab-Traub, 2005). One such regulatory protein is the signalling scaffold Shb, which is recruited to the ITAM SH2-binding motifs of the CD3z upon T-cell receptor (TCR)-stimulation (Welsh et al, 1998).…”

Section: Introductionmentioning

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: Downregulation Of Shb Impairs Lmp2a-mediated Akt Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…These proteins include EpsteinBarr virus (EBV) LMP2A, murine mammary tumor virus (MMTV) Env, and Kaposi's sarcoma-associated herpesvirus (KSHV) K1 (Caldwell et al, 1998;Lee et al, 1998a;Katz et al, 2005). Studies of signaling by LMP2A (Longnecker et al, 1991;Caldwell et al, 1998;Swart et al, 2000) and K1 (Lee et al, 1998a;Lagunoff et al, 1999) in B cells suggests that these ITAMs are capable of signaling in a manner similar to traditional cellular ITAMs. Additionally, nonhematopoietic cells expressing K1 and LMP2A are susceptible to transformation and in vivo tumor development (Lee et al, 1998b;Scholle et al, 2000;Prakash et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

et al. 2005

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Immunoreceptor tyrosine-based activation motifs (ITAMs) are involved in the transduction of signals necessary for activation, differentiation, and survival in hematopoietic cells. Several viruses have been shown to encode ITAM-containing transmembrane proteins. Although expression of these viral proteins has in some cases been shown to transform nonhematopoietic cells, a causal role for a functional ITAM in this process has not been elucidated. To examine the potential transforming properties of ITAM-containing proteins, a recombinant protein consisting of ITAM-containing cytoplasmic regions of the B-cell antigen receptor was expressed in immortalized murine mammary epithelial and fibroblast cells. Mammary epithelial cells expressing this construct exhibited depolarized morphology in three-dimensional cultures. This transformed phenotype was characterized by a loss of anchorage dependence and hallmarks of epithelial to mesenchymal transition. Fibroblasts expressing this ITAM construct also lost contact inhibition and anchorage dependence. The transformed phenotype seen in both cell types was abrogated upon tyrosine to phenylalanine substitutions of the ITAMs. Inhibition of Syk tyrosine kinase, which associates with the ITAM, also prevented cell transformation. Our results indicate that expression of a nonviral ITAM-containing protein is sufficient for cell transformation. Despite lacking intrinsic enzymatic activity, ITAM-containing proteins can function as potent oncoproteins by scaffolding downstream mediators.

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Viruses in colorectal cancer

Marongiu

Allgayer

2021

Molecular Oncology

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Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.

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Latent Membrane Protein 2A-Mediated Effects on the Phosphatidylinositol 3-Kinase/Akt Pathway

Abstract: Epstein-Barr virus (EBV

Cited by 137 publications

References 68 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

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

Viruses in colorectal cancer

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