Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor β chain

Adachi, Masaaki; Ishino, Masaho; Torigoe, Toshihiko; Minami, Yasuhiro; Matozaki, Takashi; Miyazaki, Tatsuya; Taniguchi, Tadatsugu; Hinoda, Yuji; Imai, Kohzoh

doi:10.1038/sj.onc.1200981

Cited by 43 publications

(30 citation statements)

References 22 publications

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“…Further work is required to determine which receptor(s) of IL-24, and phosphatases mediated its effects. In physiological conditions, SHP-1 and SHP-2, are recruited to the IL-2R␤ and dephosphorylate proteins of the JAK/STAT family, thereby terminating the IL-2-induced signal (50,51). We indeed observed that SHP-1 is present in huge amounts in CLL (data not shown).…”

Section: Discussionmentioning

confidence: 54%

IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression

Sainz-Perez

Gary-Gouy

Gaudin

et al. 2008

The Journal of Immunology

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Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived monoclonal B cells mostly arrested at the G0/G1 phase of the cell cycle. CLL cells strongly express intracellular melanoma differentiation-associated gene-7 (MDA7)/IL-24. However, adenovirus-delivered MDA7 was reported to be cytotoxic in several tumor cell lines. We report herein that rIL-24 alone had no effect; however, sequential incubation with rIL-2 and rIL-24 reduced thymidine incorporation by 50% and induced apoptosis of CLL cells in S and G2/M phases of the cell cycle, but not of normal adult blood or tonsil B cells. IL-24 stimulated STAT3 phosphorylation in IL-24R1-transfected cells but not in normal or CLL B cells. In contrast, IL-24 reversed the IL-2-induced phosphorylation of STAT3 in CLL, and this effect was neutralized by anti-IL-24 Ab. Phospho- (P)STAT3 inhibition induced by IL-24 was reversed by pervanadate, an inhibitor of tyrosine phosphatases. The addition of rIL-24 to IL-2-activated CLL B cells resulted in increases of transcription, protein synthesis. and phosphorylation of p53. The biological effects of IL-24 were reversed by the p53 inhibitor pifithrin-α and partly by the caspase inhibitor zvad. Troglitazone (a protein tyrosine phosphatase, PTP1B activator) phosphatase inhibited PSTAT3 and augmented p53 expression. PSTAT3 is a transcriptional repressor of p53, and therefore IL-24 induction of p53 secondary to PSTAT3 dephosphorylation may be sensed as a stress signal and promote apoptosis in cycling cells. This model explains why IL-24 can protect some resting/differentiated cells and be deleterious to proliferating cells.

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Section: Discussionmentioning

confidence: 54%

IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression

Sainz-Perez

Gary-Gouy

Gaudin

et al. 2008

The Journal of Immunology

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“…This cell line has been widely used for studying proliferative responses to a range of cytokines, including IL-2, IL-3, IL-4, erythropoietin, and granulocytemacrophage colony-stimulating factor. [30][31][32][33][34][35][36] Previous studies with BaF-B03 cells have shown that there are at least 3 pathways that may cooperate to produce a proliferative signal. 37 The results of the present study emphasize the pivotal role of the cyclin:CDK-pRB: E2F-1 pathway in mediating the cellular proliferative response in BaF-B03 cells and suggest that multiple pathways converge at E2F-1.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of E2F-1 leads to cytokine-independent proliferation and survival in the hematopoietic cell line BaF-B03

Gala

Marreiros

Stewart

et al. 2001

Blood

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Cytokine receptors activate signals that regulate the transcription factor E2F-1, which then coordinates the expression of genes essential for DNA synthesis and cell cycle progression. Overexpression of E2F-1 most often induces S-phase entry followed by apoptosis, but in some cell types it leads to continuous proliferation and transformation. Here, it is shown that constitutive expression of E2F-1 promotes cytokine-independent proliferation in the murine pro-B cell line BaF-B03. There was no enhancement of apoptosis following cytokine withdrawal in these cells, despite the presence of intact p53-dependent apoptotic pathways. Notwithstanding the continuous presence of E2F-1, the cell cycle-dependent expression of cyclin A, cyclin B1, cyclin D1, cyclin E, and proliferating-cell nuclear antigen was restored with a pattern equivalent to that associated with cytokine stimulation. These findings provide evidence that, in the absence of cytokine, constitutive expression of E2F-1 can promote cell cycle progression and prevent apoptosis. (Blood. 2001;97:227-234)

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“…These experiments showed that SHP-2 is involved in the development and differentiation of all lineages of hematopoietic cells, such as erythroid progenitors, myeloid and lymphoid cells [9][10][11]. SHP-2 has also been implicated in the signaling of cytokine receptors that signal via the common c-chain, the shared b-chain and the receptor subunit gp130 such as IL-2, IL-3 or IL-6 [12][13][14][15][16]. However, experiments showing functional consequences of SHP-2 in IL-2 signaling were performed in transfected fibroblasts or in unequally activated T cells, but not in synchronized primary T cells [15,17].…”

Section: Introductionmentioning

confidence: 99%

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

Hoff

Brunner‐Weinzierl

2007

Eur J Immunol

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Although phosphatases are key players of intracellular processes, not much is known about the phosphatase SHP-2 during T cell differentiation. Here we show that ectopic over-expression of SHP-2 in primary T helper cells directly reduced the frequency of individual lymphocytes expressing pro-inflammatory cytokines after antigen-specific stimulation by a mechanism impairing activation of protein kinase C. In addition we demonstrate that SHP-2 mediates enhanced migration upon CXCR4 signaling in a G-protein-dependent manner. Most strikingly, SHP-2 mediated a dramatic increase in apoptosis by highly enhanced activation of caspases. Co-immunoprecipitations of SHP-2 and c-Cbl from primary T helper cells demonstrated that SHP-2 strongly interacts with the ubiquitin ligase c-Cbl, indicating that c-Cbl could mediate the negative signals of SHP-2. Our results show that SHP-2 signal transduction regulates central checkpoints of T cell differentiation by the activation of distinct signaling cascades.

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Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor β chain

Cited by 43 publications

References 22 publications

IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression

IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression

Overexpression of E2F-1 leads to cytokine-independent proliferation and survival in the hematopoietic cell line BaF-B03

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

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