The Product of the Herpesvirus saimiri Open Reading Frame 1 (Tip) Interacts with T Cell-specific Kinase p56lck in Transformed Cells

Biesinger, Brigitte; Tsygankov, Alexander Y.; Fickenscher, Helmut; Emmrich, Frank; Fleckenstein, Bernhard; Bolen, Joseph B.; Bröker, Barbara M.

doi:10.1074/jbc.270.9.4729

Cited by 121 publications

(140 citation statements)

References 38 publications

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“…Both corresponding proteins, tyrosine kinase-interacting protein (Tip) and H. saimiri transformation-associated protein of C strains (STP-C), are absolutely required for growth transformation (19) and interact with signaling proteins. Tip binds to Lck and is phosphorylated by Lck (20). In most (21-23) but not all assay systems (24) Tip activated Lck.…”

Section: Fig 4 Mapk Phosphorylation Primary Cd4mentioning

confidence: 99%

Herpesvirus saimiri Replaces ZAP-70 for CD3- and CD2-mediated T Cell Activation

Meinl¹,

Pirzer²,

Blank³

et al. 2001

Journal of Biological Chemistry

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The protein tyrosine kinase ZAP-70 plays a pivotal role involved in signal transduction through the T cell receptor and CD2. Defects in ZAP-70 result in severe combined immunodeficiency. We report that Herpesvirus saimiri, which does not code for a ZAP-70 homologue, can replace this tyrosine kinase. H. saimiri is an oncogenic virus that transforms human T cells to stable growth based on mutual CD2-mediated activation. Although CD2-mediated proliferation of ZAP-70-deficient uninfected T cells was absent, we could establish H. saimiri-transformed T cell lines from two unrelated patients presenting with ZAP-70 deficiencies. In these cell lines, CD2 and CD3 activation were restored in terms of [Ca 2؉ ] i , MAPK activation, cytokine production, and proliferation. Activation-induced tyrosine phosphorylation of remained defective. The transformed cells expressed very high levels of the ZAP-70-related kinase Syk. This increased expression was not observed in the primary T cells from the patients and was not due to the transformation by the virus because transformed cell lines established from control T cells did not present this particularity. In conclusion, wild type H. saimiri can restore CD2-and CD3-mediated activation in signalingdeficient human T cells. It extends our understanding of interactions between the oncogenic H. saimiri and the infected host cells.The tyrosine kinase ZAP-70 is essential for activation of mature T cells via CD3. An autosomal recessive form of severe combined immunodeficiency in humans has been described as resulting from mutations within the gene encoding ZAP-70. This deficiency is characterized by an absence of CD8 ϩ T cells and an increased number of nonfunctional CD4 ϩ T cells with a mature phenotype in the periphery. These CD4 ϩ T cells are unresponsive to either antigenic stimulation in vivo or CD2-and CD3-mediated activation in vitro (1-3).According to current concepts, binding of antigen to the T cell receptor (TCR) 1 initiates a cascade of early signaling events, which includes activation of the protein tyrosine kinases (PTKs) of the Src family. These PTKs phosphorylate the immune-receptor tyrosine-based activation motifs, which are present in all the chains of the CD3-complex. This allows the recruitment of ZAP-70, which is then phosphorylated and activated and subsequently phosphorylates a number of key substrates including LAT, SLP-76, and Vav. These tyrosine kinase reactions are required for CD3-induced mobilization of intracellular free calcium ([Ca 2ϩ ] i ) and activation of the Ras/mitogen-activated protein kinase (MAPK), leading to cytokine production and proliferation, responses that are all defective in the absence of ZAP-70 (4).ZAP-70 not only plays a crucial role in CD3-mediated T cell activation but also in CD2-mediated activation (5, 6). CD2 constitutes the so-called alternative pathway of T cell activation (7); simultaneous triggering of two distinct epitopes on CD2 by two mAbs induces T cells to proliferate and secrete lymphokines in the absence of antigen and a...

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Section: Fig 4 Mapk Phosphorylation Primary Cd4mentioning

confidence: 99%

Herpesvirus saimiri Replaces ZAP-70 for CD3- and CD2-mediated T Cell Activation

Meinl¹,

Pirzer²,

Blank³

et al. 2001

Journal of Biological Chemistry

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“…The other protein was termed Tip, for tyrosine kinase interacting protein. Tip was found to tightly bind p56 lck both in vitro and in vivo, without any measurable interaction with other Src family members (5). Subsequent evidence has shown that Tip dramatically increases the tyrosine kinase activity of p56 lck , and this appears to be by inducing a conformational change (6,7).…”

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confidence: 99%

Direct Binding and Activation of STAT Transcription Factors by the Herpesvirus saimiri Protein Tip

Hartley¹,

Cooper²

2000

Journal of Biological Chemistry

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“…14,16 The transformation-associated genes, tyrosine kinase-interacting protein (tip) and saimiri transformation-associated protein of subgroup C (stpC) are located at the left end of the L-DNA. 17,18 They are translated from a single bicistronic mRNA, and their transcription can be induced by T-cell activation. 19 Although these genes are dispensable for virus replication, their deletion abolishes the transformation capacity of HVS C488.…”

Section: Introductionmentioning

confidence: 99%

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

2010

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The rhadinovirus herpesvirus saimiri (HVS) as a gene delivery vector allows large DNA insertions and long-termed gene expression. In the case of T-cell transduction, such vectors use the viral transformation-associated genes of HVS C488 for T-cell amplification. In this report, we investigated whether the gene for the catalytic telomerase subunit human telomerase reverse transcriptase (hTERT) can substitute for the transformation-associated genes in rhadinoviral T-cell transduction and amplification. By using virus mutants generated by en passant mutagenesis from bacterial artificial chromosomes, we observed a very early and functional transgene expression even by virus mutants without transformation-associated genes. The markers of T-cell transformation by HVS, namely CD2 hyperreactivity, overexpression of interleukin-26, and of the tyrosine kinase Lyn could neither be induced nor enhanced by ectopic hTERT expression. When the viral transformation-associated genes were replaced by the hTERT gene, it was not sufficient for growth transformation, although hTERT was efficiently transduced and functionally expressed by the rhadinovirus vector. Thus, the transformation-associated proteins StpC and Tip are responsible for the T-cell phenotype after transduction by HVS and, additionally, modulate telomerase activity independently of hTERT expression.

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The Product of the Herpesvirus saimiri Open Reading Frame 1 (Tip) Interacts with T Cell-specific Kinase p56lck in Transformed Cells

Cited by 121 publications

References 38 publications

Herpesvirus saimiri Replaces ZAP-70 for CD3- and CD2-mediated T Cell Activation

Herpesvirus saimiri Replaces ZAP-70 for CD3- and CD2-mediated T Cell Activation

Direct Binding and Activation of STAT Transcription Factors by the Herpesvirus saimiri Protein Tip

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

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