Bovine Leukemia Virus Transmembrane Protein gp30 Physically Associates with the Down-Regulatory Phosphatase SHP-1

Cantor, Glenn H.; Pritchard, Suzanne M.; Orlik, O.; Splitter, Gary A.; Davis, William C.; Reeves, Raymond

doi:10.1006/cimm.1999.1475

Cited by 14 publications

(14 citation statements)

References 44 publications

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“…[32][33][34] The hematopoietic-specific SHP-1 is expressed exclusively from the P2 promoter located 5Ј to the exon 2, 35 present constitutively in cells and able to down-regulate signaling immediately upon activation of receptor/kinase complexes. 36,37 For example, IL-2 induces association of SHP-1 with the IL-2R complex. Once SHP-1 is recruited to the activated complex, it is able to decrease tyrosine phosphorylation of IL-2R␤ and the associated tyrosine kinases Jak1 and Jak3, 36 acting as the earliest negative regulator of IL-2-mediated Jak/STAT signaling.…”

Section: Introductionmentioning

confidence: 99%

Negative regulation of the SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein

Cheng

Kydd

Nakase

et al. 2007

Blood

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Expression of SH 2 -homology-containing protein-tyrosine phosphatase-1 (SHP-1), a candidate tumor suppressor, is repressed in human T-cell leukemia virus type-1 (HTLV-1)-transformed lymphocyte cell lines, adult T-cell leukemia (ATL) cells, and in other hematologic malignancies. However, the mechanisms underlying regulation and repression of SHP-1 remain unclear. Herein, we cloned the putative full-length, hematopoietic cellspecific SHP-1 P2 promoter and identified the "core" promoter regions. HTLV-1 Tax profoundly represses P2 promoter activity and histone deacetylase-1 (HDAC1) potentiates such inhibition. NF-B was implicated as both a rate-limiting factor for basal P2 promoter activity and important for Tax IntroductionAdult T-cell leukemia (ATL) is an aggressive malignancy of CD4 ϩ , CD25 ϩ T cells, and the human T-cell leukemia virus type-1 (HTLV-1) has been identified as the causative agent. 1,2 While the understanding of ATL pathogenesis currently remains incomplete, the HTLV-1 virusencoded Tax protein has been implicated as a major contributor in the development of ATL. [3][4][5][6] The oncogenic potential of HTLV-1 Tax has been associated with its ability to modulate expression and function of cellular targets involved in cell proliferation and differentiation. 7,8 For example, Tax has been shown to induce the activation of NF-B, CREB, AP-1, and SRF 6 as well as to up-regulate IL-2/IL-2 receptor-␣, 9 IL-15, 10 IL-4, 11 12 and OX40/OX40L 6 pathways, resulting in the stimulation of cell growth. Tax can also be a negative regulator of gene expression/function and can down-regulate expression of genes involved in host DNA repair, 13 maintaining genetic stability 14 and cell cycle progression. 15 Of particular importance to this study, Tax has been shown to exert negative effects on at least 3 cellular tumor suppressorsRb, [16][17][18][19] hDLG, a human homolog of the Drosophila discs large tumor suppressor protein, 6,20-22 and p53. 6,23,24 Tax alone is able to immortalize primary human T lymphocytes and transform rodent fibroblast in vitro. 25,26 Transgenic mice expressing Tax can also develop tumor in vivo with a wide range of phenotypes . 25,27,28 Among the cellular dysfunctions caused by HTLV-1 infection, the loss of IL-2 dependence is remarkable in many HTLV-1-transformed cells. 29 In HTLV-1-infected cord blood lymphocytes, the transition from IL-2-dependent to IL-2-independent growth has been shown to correlate with the acquisition of a constitutively activated Jak/STAT pathway, suggesting the involvement of this pathway in HTLV-1-mediated T-cell transformation. 30 In addition, proliferation of uncultured leukemic cells from ATL patients has been reported to be associated with constitutive activation of Jak/STAT proteins. 31 A number of cellular factors have been demonstrated to negatively regulate Jak/STAT activities, including SHP-1 (SH2-homology-containing protein-tyrosine phosphatase-1), PIAS-3 (protein inhibitors of activated STATs), SOCS-1 (suppressors of cytokine signaling), and CIS (cytokine-in...

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Section: Introductionmentioning

confidence: 99%

Negative regulation of the SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein

Cheng

Kydd

Nakase

et al. 2007

Blood

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“…The phosphorylated tyrosine can then become part of a ligand for SH2 domains of signaling molecules (12,56,63). SHP-1 phosphatase, which contains two SH2 motifs, associates with the BLV CTM in cultured peripheral blood mononuclear cells from BLV-infected cows if tyrosine phosphatases are inhibited prior to cell lysis (11). Since only phosphoserine was present in CD8-CTM chimeric protein in transfected COS cells, our results suggest that an SHP-CTM interaction is unlikely to take place in those cells.…”

Section: Discussionmentioning

confidence: 99%

“…Since only phosphoserine was present in CD8-CTM chimeric protein in transfected COS cells, our results suggest that an SHP-CTM interaction is unlikely to take place in those cells. The cytoplasmic tail of BLV TM may become phosphorylated at tyrosine and interact with SHP-1 only in virus-infected primary cells and only at certain stages of infection, because in some infected animals, no association of SHP-1 with TM could be detected (11). Disappointingly, systematic attempts to demonstrate phosphorylation of BLV TM in infected cells from infected animals have been unsuccessful (23).…”

Section: Discussionmentioning

confidence: 99%

“…Upon phosphorylation of the tyrosine residues, ITIM-containing proteins are bound by SH2 domains, for example, in phosphatases and signaling is inhibited (reviewed in reference 23). SHP-1 phosphatase, an important negative regulator of B-cell signaling (38), associates with the BLV CTM in cultured peripheral blood mononuclear cells from BLV-infected cows when tyrosine phosphatases are inhibited prior to cell lysis (11). SHP-1, which contains two SH2 motifs, may bind to YXXLs in the BLV CTM when the tyrosines are phosphorylated.…”

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confidence: 99%

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Dileucine and YXXL Motifs in the Cytoplasmic Tail of the Bovine Leukemia Virus Transmembrane Envelope Protein Affect Protein Expression on the Cell Surface

Novakovic

Sawai

Radke

2004

J Virol

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Several retroviruses downmodulate the cell surface expression of envelope (Env) proteins through peptide sequences located in the cytoplasmic tail of the transmembrane (TM) subunit. We investigated whether cell surface expression of a chimeric protein containing the cytoplasmic domain of the TM protein (CTM) of bovine leukemia virus (BLV) was regulated by two membrane-proximal dileucine motifs or by tyrosine Y487 or Y498 in YXXL motifs. A chimeric protein composed of the extracellular and membrane-spanning portions of human CD8-␣ plus a wild-type (wt) BLV CTM was detectable on the surface of only 40% of the cells in which it was transiently expressed. Replacement of either dileucine pair with alanines increased the level of surface display of chimeric proteins. Nearly all cells became surface positive when both dileucine motifs were altered simultaneously and when either an N-terminal segment containing both dileucine motifs or a C-terminal segment containing all YXXL motifs was deleted. In contrast, replacement of Y487 or Y498 with alanine or phenylalanine enabled only small increases in surface display compared with wt levels. Chimeric proteins had similar stabilities but were downmodulated from the cell surface at three different rates. Point mutants segregated into each of the three groups of proteins categorized according to these different rates. Interestingly, Y487 mutants were downmodulated less efficiently than Y498 mutants, which behaved like wt. CD8-CTM chimeric proteins were phosphorylated on serine residues, but the native BLV Env protein was not phosphorylated either in transfected cells or in a lymphoid cell line constitutively producing BLV. Thus, both dileucine and YXXL motifs within the BLV CTM contribute to downmodulation of a protein containing this domain. Interactions with other proteins may influence surface exposure of Env protein complexes in virus-infected cells, assisting in viral evasion of adaptive immunity.The cytoplasmic domains of several retroviral envelope (Env) proteins control the level of Env present on the surface of infected cells. A low level of surface expression is mediated by intracellular retention of Env proteins as well as their rapid endocytosis from the plasma membrane (22,51,54). The existence of mechanisms to ensure low-level cell surface display of Env proteins points to a feature of the retroviral life cycle that most probably evolved to reduce clearance of virus-producing cells by the immune system (21, 22, 35). The main target for antibody recognition of retroviral Env protein complexes is the surface (SU) protein subunit, which is anchored onto the membranes of infected cells and virions by the membrane-spanning domain of the transmembrane (TM) subunit of an Env monomer (26). A labile disulfide bond links the SU and TM subunits of bovine leukemia virus (BLV) (30), a deltaretrovirus. Upon binding of oligomers of retroviral SU to cellular receptors, the TM subunits mediate virus-cell fusion (26). In parallel with other retroviral TM proteins, the extracellular...

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“…Recently, it was found that the B-cell protein tyrosine phosphatase (PTPase) SHP-1 associates with the viral transmembrane protein, gp30, indicating that gp30 acts as a decoy to sequester SHP-1. 41 The removal of this downregulatory PTPase could promote signaling through the BCR, representing yet another mechanism for viral activation of B lymphocytes.…”

Section: Interference With Normal B-cell Receptor Signalingmentioning

confidence: 99%

Subversion of B lymphocyte signaling by infectious agents

Harmatz

Zouali

2003

Genes Immun

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Infectious agents and their hosts interact in a complex manner, involving not only superficially apparent mechanisms, but also the signaling machinery that governs host cells responses. Thus, signaling events, surface molecule expression, and transcriptional control may be affected in various cell types, with profound consequences for the function of individual cells and organ systems. Studies of the biochemistry of cell signaling and cell invasion by infectious agents have begun to detail the interplay between elements of infectious organisms and the host at the molecular level. Consequently, the resulting interferences with lymphocyte signaling may disturb the function of the immune system. In B cells, alterations of immune receptor signaling has implications for human diseases. By affecting the mechanisms of the host's immune defense, this may not only lead to inadequate elimination of an infectious agent, but also to autoimmunity or neoplasia.

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Bovine Leukemia Virus Transmembrane Protein gp30 Physically Associates with the Down-Regulatory Phosphatase SHP-1

Cited by 14 publications

References 44 publications

Negative regulation of the SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein

Negative regulation of the SH2-homology–containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein

Dileucine and YXXL Motifs in the Cytoplasmic Tail of the Bovine Leukemia Virus Transmembrane Envelope Protein Affect Protein Expression on the Cell Surface

Subversion of B lymphocyte signaling by infectious agents

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