The Lck Binding Domain of Herpesvirus Saimiri Tip-484 Constitutively Activates Lck and STAT3 in T Cells

Lund, Troy C.; Prator, Paul C.; Medveczky, Maria M.; Medveczky, Peter G.

doi:10.1128/jvi.73.2.1689-1694.1999

Cited by 53 publications

(17 citation statements)

References 45 publications

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“…Thus, dominant-negative Jaks are unable to inhibit either Stat5 activation or factor-independent cell proliferation induced by Bcr-Abl. 129 In addition, v-Src can directly activate Stat3, 130 whereas the Herpesvirus Tip protein co-associates Lck and Stat3, leading to constitutive Stat3 activation in T cells transformed by this virus, 131 suggesting that in these cases Jaks are also superfluous. In contrast, numerous recent studies have provided strong evidence for a role of Stats in the transformation process.…”

Section: Evidence For Jak-stat Involvementmentioning

confidence: 99%

The Jak-Stat pathway in normal and perturbed hematopoiesis

Ward

Touw

Yoshimura

2000

Blood

224

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The Janus kinase-signal transducer and activator of transcription (Jak-Stat) pathway stands as a paradigm of how diverse extracellular signals can elicit rapid changes in gene expression in specific target cells. This pathway is widely used by members of the cytokine receptor superfamily, including those for the clinically important cytokines granulocyte colony-stimulating factor (G-CSF), erythropoietin, thrombopoietin, the interferons, and numerous interleukins, which makes it central to hematopoietic cell biology and hematologic therapy alike. Indeed, study of the Jak-Stat pathway has provided a wealth of information on hematopoiesis and hematopoietic disease, and conversely, studies of hematopoietic disorders have yielded new insights into the functions of Jaks and Stats. This review aims to detail the role of the Jak-Stat pathway in the normal development and function of hematopoietic cells and to describe how several hematopoietic disorders are caused, at least in part, by perturbations of this pathway.

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Section: Evidence For Jak-stat Involvementmentioning

confidence: 99%

The Jak-Stat pathway in normal and perturbed hematopoiesis

Ward

Touw

Yoshimura

2000

Blood

224

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“…Similarly, Tip-C484 markedly increases the in vitro phosphotransferase activity when Lck immuncomplexes from transiently transfected Jurkat T cells [84] or Lck-reconstituted JCaM1 cells [98] were used. The activating function could be mapped to the Lck binding site of Tip spanning the CSKH and the SH3B motifs [99]. A more detailed analysis revealed that both motifs are required to achieve Lck activation as mutation of either one resulted in a Tip protein that has no impact on the phosphotransferase activity of CD4-Lck immune complexes [97].…”

Section: R E G U L a T I O N O F L C K A C T I V I T Y B Y T I Pmentioning

confidence: 99%

Lck protein tyrosine kinase is a key regulator of T‐cell activation and a target for signal intervention by Herpesvirus saimiri and other viral gene products

Isakov

Biesinger

2000

European Journal of Biochemistry

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Protein tyrosine kinases (PTKs) are critically involved in signaling pathways that regulate cell growth, differentiation, activation, and transformation. It is not surprising, therefore, that viruses acquire effector molecules targeting these kinases to ensure their own replication and/or persistence. This review summarizes our current knowledge on Lck, a member of the Src family of PTK, and its viral interaction partners. Lck plays a key role in T lymphocyte activation and differentiation. It is associated with a variety of cell surface receptors and is critical for signal transduction from the T-cell antigen receptor (TCR). Consequently, Lck is targeted by regulatory proteins of T-lymphotropic viruses, especially by the Herpesvirus saimiri (HVS) tyrosine kinase interacting protein (Tip). This oncoprotein physically interacts with Lck in HVS transformed T cells and has an impact on its catalytic activity. However, while Tip inhibits Lck activity in stably expressing cell lines, opposite effects were observed in several in vitro systems. At least in part, this complex situation may be related to the bipartite nature of the interaction surface of the two proteins. Studies on the interrelationships between Lck and its viral partners contribute to the understanding of the mechanisms of T-cell growth regulation, in general, and of viral pathogenicity in particular. In addition, understanding the regulation of Lck activity by viral proteins may serve as a basis for the development of new drugs capable of modifying Lck activity in different pathological situations.Keywords: Lck; Herpesvirus saimiri; Tip; signal transduction; T-cell transformation. I N V O L V E M E N T O F L C K I N T-C E L L A C T I V A T I O N A N D D I F F E R E N T I A T I O NEngagement of the T-cell antigen receptor (TCR) triggers signal transduction pathways that regulate the activation and differentiation of T lymphocytes [1,2]. Many of the individual components of the TCR-linked signaling pathways are physically separated in resting cells, and upon engagement of the receptor, they assemble into functional complexes at the site of contact with the antigen presenting cells [3,4]. The assembly process directs enzymes, substrates, and other effector molecules to the receptor site in a strictly regulated manner, which ensures an efficient signaling and culminates in cellular activation.The TCR-linked signaling machinery depends upon the activity of protein tyrosine kinases (PTKs) which induce the phosphorylation of a number of proteins, including TCR subunits, adapter proteins, and other effector molecules that assemble into multimolecular complexes at the receptor site. Non-receptor PTKs that mediate these functions in T cells predominantly include the Src family members, Lck and Fyn, and the Syk family members, ZAP-70 and Syk [1,2].Lck is a lymphoid-specific cytosolic PTK, which is essential for T-cell development and function (reviewed in [5±7]). It is constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors a...

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“…STAT activation also correlates with the progression of diverse hematopoietic malignancies ( Table 2), such as various leukemias 24,28,37-42 and lymphomas. [42][43][44][45][46][47][48] In addition, Stat3 is frequently activated in both multiple myeloma cell lines and tumors derived from patient bone marrows. 49 Recently, the role of STAT signaling as it relates to the pathogenesis of multiple myeloma has been elucidated.…”

Section: Activation Of Stat Signaling In Human Cancermentioning

confidence: 99%

Signal Transducers and Activators of Transcription: Novel Targets for Anticancer Therapeutics

Bowman

Sebti

et al. 1999

Cancer Control

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The disruption of STAT signaling blocks neoplastic transformation, thus making inhibitors of STAT proteins a potential novel molecular approach to treat human cancer. Background: Through specific activation of gene expression, the family of proteins known as signal transducers and activators of transcription (STATs) converts extracellular stimuli into diverse biological responses. Beyond the normal signaling functions of STATs, recent evidence indicates that aberrant activation of STATs contributes to neoplastic transformation.Methods: Current literature pertaining to the role of STAT proteins in oncogenesis is presented. Also, the rationale for developing novel approaches to disrupt STAT signaling is discussed, and the potential of STATs as anticancer targets in treating human cancer is reviewed. Results:The discovery that certain oncoproteins constitutively activate specific STATs, coupled with observations that elevated STAT activity occurs frequently in a spectrum of human tumors, establishes a direct link between STAT activation and neoplastic transformation. Significantly, abrogation of STAT signaling blocks oncogenesis in model in vitro and in vivo systems. These results make STATs attractive targets for rational design of small molecule inhibitors and gene therapy approaches to disrupt STAT signaling. Conclusions:As a result of genetic, biochemical, and crystallographic analyses, the functional domains of STAT proteins have been well characterized. Based on these data, selective inhibitors of STAT function can be designed. Because disrupting STAT signaling has proven effective in blocking neoplastic transformation, it is proposed that STAT proteins represent promising targets for development of novel molecular therapeutics to treat human cancer. . Oil on canvas. Fig 1. -Generic structure of a STAT protein illustrating common functional domain elements shared by STAT family members. The sites of tyrosine (Y) and serine (S) phosphorylation are shown. SH2 = Src-homology 2 domain, N = amino terminus, C = carboxyl terminus.

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The Lck Binding Domain of Herpesvirus Saimiri Tip-484 Constitutively Activates Lck and STAT3 in T Cells

Cited by 53 publications

References 45 publications

The Jak-Stat pathway in normal and perturbed hematopoiesis

The Jak-Stat pathway in normal and perturbed hematopoiesis

Lck protein tyrosine kinase is a key regulator of T‐cell activation and a target for signal intervention by Herpesvirus saimiri and other viral gene products

Signal Transducers and Activators of Transcription: Novel Targets for Anticancer Therapeutics

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