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

Hartley, David A.; Cooper, Geoffrey M.

doi:10.1074/jbc.m000709200

Cited by 33 publications

(44 citation statements)

References 29 publications

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“…A YXPQ motif of Tip (Y72; equivalent to Y114 of C488) conforms to a putative consensus binding site for STAT factors (62). Tyrosine 72 phosphorylation was required for STAT binding and transcription activation (33). This has also been demonstrated for the equivalent Y114 of strain C488 (43).…”

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confidence: 77%

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Heck

Lengenfelder

Schmidt

et al. 2005

J Virol

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Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that were originally discovered as key mediators of cytokine signaling. They are involved in signaling by the interleukin-6 (IL-6) family cytokines, the IL-2 family cytokines, and numerous growth factors, including epidermal growth factor, platelet-derived growth factor, and colony-stimulating factor 1. Latent inactive STATs reside in the cytoplasm; in response to receptor activation, they are recruited to a receptor where they are tyrosine phosphorylated by receptor tyrosine kinases (RTK) or receptor-associated tyrosine kinases, such as JAK or Trk kinases (reviewed in references 36, 42, 46, and 48). Active STAT dimers are then formed via the reciprocal interaction between the SH2 domain of one monomer and the phosphorylated tyrosine of the other. Activated dimers translocate to the nucleus, where they bind to specific DNA response elements in the promoters of target genes and activate transcription. Furthermore, various oncoproteins can activate specific STAT molecules (especially STAT3 and STAT5) (8,15), and inappropriate STAT activation directly contributes to oncogenesis by stimulating cell proliferation and preventing apoptosis. Constitutive activation of several STATs was frequently detected in a wide range of human cell lines and primary tumors, including lymphoid malignancies (lymphomas, leukemias, and multiple myelomas) (30,63,67). Constitutively activated mutant STAT3 and STAT5 proteins have been shown to possess transforming properties and to be strongly associated with tumor development and progression (7, 9).

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mentioning

confidence: 77%

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Heck

Lengenfelder

Schmidt

et al. 2005

J Virol

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“…Interestingly, Tip-114 that contains an in ViVo phosphorylation site and was reported to be important for STAT-3 binding (17) does not interact with the LckSH2 domain at all ( Figure 6). This complete absence of interaction is observed for Tip-114 and Tip-114L that originate from HVS strains C488 and C484-77, respectively, and differ by a R f L exchange at the Y + 1 position (Figure 1).…”

Section: Investigation Of the Tip-lcksh3mentioning

confidence: 99%

“…Tip also contains three conserved tyrosines; phosphorylation of Tyr114 was demonstrated to be required for the activation of STAT factors (17), while the ability of Tip to interact with Lck via phosphorylated tyrosines remains to be investigated. Interestingly, tyrosine phosphorylation was shown to create an LckSH2 domain interaction site in the Tip homologue Tio from HerpesVirus ateles (18), suggesting that the existence of an LckSH2 interaction motif might represent a common feature of herpesviral regulatory proteins.…”

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confidence: 99%

Characterization of Lck-Binding Elements in the Herpesviral Regulatory Tip Protein

et al. 2004

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HerpesVirus saimiri encodes a tyrosine kinase interacting protein (Tip) that binds to T-cellspecific tyrosine kinase Lck via multiple sequence motifs and controls its activity. The regulation of Lck by Tip represents a key mechanism in the transformation of human T-lymphocytes during herpesviral infection. In this study, the interaction of Tip with the regulatory SH3 and SH2 domains of Lck was investigated by biophysical and computational techniques. NMR spectroscopy of isotopically labeled revealed that the interaction with the LckSH3 domain is not restricted to the classical prolinerich motif, but also involves the C-terminally adjacent residues which pack into a hydrophobic pocket on the surface of the SH3 domain, thus playing a likely role in mediating binding specificity. Fluorescence binding studies of Tip further demonstrate that Tyr127 in its phosphorylated form represents a strong ligand of the LckSH2 domain, indicating the presence of an additional Lck interaction motif. In contrast, Tyr114, known to be essential for STAT-3 binding, does not interact with the LckSH2 domain, showing that the tyrosines in Tip exhibit distinct binding specificity. The existence of numerous interaction sites between Tip and the regulatory domains of Lck implies a complex regulatory mechanism and may have evolved to allow a gradual regulation of Lck activity in different pathogenic states.Src-family tyrosine kinases act as signaling molecules in a wide array of cellular activation processes (1). These enzymes share a general common organization: a myristylated N-terminal "unique" domain followed by the regulatory SH3 1 and SH2 domains and by the kinase domain containing the active site. The C-terminal region contains a regulatory tyrosine which is bound to the SH2 domain in its phosphorylated form, thereby reducing kinase activity. Activation of Src kinases can be achieved by dephosphorylation of the tyrosine in the C-terminal region and/or the presence of SH3/ SH2 competing ligands. For full catalytic activity, however, dissociation of both SH3 and SH2 from the kinase domain is required (2, 3). To ensure an effective activation, numerous proteins therefore target Src kinases by a two-domain interaction with their SH3 and SH2 domains. Examples include the activation of Src or Fyn by focal adhesion kinase (4-6), p62 (7), p68 (8), AFAP-110 (9), p130Cas (10), and SIN (11).For the herpresviral Tip protein that interacts with the lymphoid-specific Src kinase Lck, a variation in the strategy for kinase activation has emerged (12, 13). In Tip, a sequence of 37 of the 256 amino acids is necessary as well as sufficient for binding Lck in Vitro (12,14). This stretch comprises two binding motifs called CSKH and SH3B (12,15). The SH3B (SH3 binding) motif that matches the consensus of a class II polyproline helix binds to the SH3 domain of Lck (12,16). The second motif (CSKH, C-terminal Src-related kinase homology) shares some sequence similarity with helix RI of the kinase domain (12) and was reported to interact with the C-...

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“…Tip also activates STAT-1, STAT-3, and NF-AT-dependent transcription (22,25). A model has been proposed in which Lck phosphorylates Tip and the phosphorylated Tip then recruits STATs (26).…”

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

Cited by 33 publications

References 29 publications

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

T-Cell Growth Transformation by Herpesvirus Saimiri Is Independent of STAT3 Activation

Characterization of Lck-Binding Elements in the Herpesviral Regulatory Tip Protein

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

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