Signal transduction by interleukin 2 in human T cells: Activation of tyrosine and ribosomal S6 kinases and cell‐cycle regulatory genes

Sawami, H; Terada, Naohiro; Franklin, Richard A.; Okawa, Hiroji; Uchiyama, Takashi; Lucas, Joseph J.; Gelfand, Erwin W.

doi:10.1002/jcp.1041510218

Cited by 27 publications

(17 citation statements)

References 60 publications

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“…This finding is consistent with reports that IL-2 does not activate or at least does not require phospholipase C␥ and its downstream signalling events, including mobilization of intracellular calcium and activation of diacylglycerol-dependent cPKCs, to promote cell proliferation (19,61,65,73,74,86,91,109,111). Our results should now make it possible to design experiments aimed at identifying the intermediates in this signalling pathway and to determine how they interact as occurred after the demonstration that c-Ras is upstream of the MAPK phosphorylation cascade (9,31,68).…”

Section: S6ksupporting

confidence: 92%

“…11B and C). Previous studies have shown that cPKC down-regulation does not affect the ability of activated T cells to respond to IL-2 (61,73,74,91,111). Likewise, IL-2-dependent activation of pp70…”

Section: S6kmentioning

confidence: 96%

“…However, it has been shown that IL-2R-mediated signalling and proliferation is independent of phospholipase C␥ and cPKCs (61,73,74,91,109,111; reviewed in reference 19). IL-2-dependent T-cell lines such as CTLL-20 cells contain functional cPKCs which can be activated by phorbol esters such as PMA.…”

Section: S6kmentioning

confidence: 99%

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Activation of pp70/85 S6 Kinases in Interleukin-2-Responsive Lymphoid Cells Is Mediated by Phosphatidylinositol 3-Kinase and Inhibited by Cyclic AMP

Monfar

Lemon

Grammer

et al. 1995

Molecular and Cellular Biology

164

135

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Activation of phosphatidylinositol 3-kinase (PI3K) and activation of the 70/85-kDa S6 protein kinases (␣II and ␣I isoforms, referred to collectively as pp70 S6k ) have been independently linked to the regulation of cell proliferation. We demonstrate that these kinases lie on the same signalling pathway and that PI3K mediates the activation of pp70 by the cytokine interleukin-2 (IL-2). We also show that the activation of pp70 S6k can be blocked at different points along the signalling pathway by using specific inhibitors of T-cell proliferation. Inhibition of PI3K activity with structurally unrelated but highly specific PI3K inhibitors (wortmannin or LY294002) results in inhibition of IL-2-dependent but not phorbol ester (conventional protein kinase C T cells are activated, representing G 0 -to-G 1 transition, by antigen presentation to the multimeric T-cell receptor. This results in the transcription, production, and secretion of the 15-kDa glycoprotein lymphokine, interleukin-2 (IL-2). Antigen stimulation also induces expression of the IL-2 receptor (IL-2R) ␣ subunit (p55) and increases the level of IL-2R ␤ subunit (p75). Together with the ␥ subunit, they form the high-affinity IL-2R (reviewed in references 75 and 103). IL-2 then stimulates activated T cells in an autocrine/paracrine fashion, driving G 1 -S transition and cell proliferation. The IL-2R has no intrinsic kinase activity, yet ligand binding increases tyrosine phosphorylation of many proteins, including the IL-2R ␤ chain. IL-2-dependent signalling also results in activation of c-Ras and phosphatidylinositol 3-kinase (PI3K) and increased serine/ threonine protein phosphorylation. Although much is known about Ras-regulated signal transduction (see references 12, 39, and 68 for reviews), the identities of the signalling proteins lying downstream of PI3K remain to be established.PI3K is a novel signal transducer composed of an 85-kDa SH2-and SH3-domain-containing regulatory subunit and a 110-kDa catalytic subunit with specificity toward the D3 hydroxyl in the inositol ring of phosphatidylinositol (37,54,81,98). Numerous studies provide evidence that PI3K, in association with various mitogenically active receptor and nonreceptor protein tyrosine kinases, mediates the transmission of growth-regulatory information within cells (reviewed in references 18, 21, and 82). These studies suggest that the activation of PI3K contributes a positive, but undefined, cell proliferation signal.The activity of the 70/85-kDa S6 protein kinases (␣I and ␣II isoforms, referred to collectively as pp70 S6k ) is also stimulated by IL-2 in IL-2-responsive cells (16,63,106) as well as in other cell types by many growth factors and oncogenes (reviewed in reference 36). However, the cytosolic mediators involved in its signal cascade have been previously unknown. pp70S6k was identified on the basis of its ability to phosphorylate the 40S ribosomal protein S6 in vitro. A number of other kinases, including the growth-regulated 90-kDa ribosomal S6 kinases (RSKs), can also phosphoryl...

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Section: S6ksupporting

confidence: 92%

Section: S6kmentioning

confidence: 96%

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Activation of pp70/85 S6 Kinases in Interleukin-2-Responsive Lymphoid Cells Is Mediated by Phosphatidylinositol 3-Kinase and Inhibited by Cyclic AMP

Monfar

Lemon

Grammer

et al. 1995

Molecular and Cellular Biology

164

135

View full text Add to dashboard Cite

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“…IL-2 is known to play a central role in the amplification of immune responses, and there is evidence that the defect in some CVID patients in proliferation in response to mitogens is accompanied by a reduction in secretion of IL-2 [5,8,24]. We have detected no impairment of non-specific responses to extrinsic IL-2, which are known to be PKC-independent [26], suggesting that there are no defects in the IL-2-induced signaling pathway that involve tyrosine kinase [27], in IL-2 receptor function, or in the apparatus of DNA synthesis. More importantly, we have shown that rIL-2 will not reverse the antigen-specific defect.…”

Section: Discussionmentioning

confidence: 45%

Defects in antigen-driven lymphocyte responses in common variable immunodeficiency (CVID) are due to a reduction in the number of antigen-specific CD4+ T cells

Funauchi

Farrant

Moreno

et al. 1995

Clinical and Experimental Immunology

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SUMMARYT cells from patients with CVID have defects that may relate to the failure in vivo of B cell production of antibodies. Antigen-driven responses of T cells from CVID patients and normal subjects have been assessed by measuring DNA synthesis in vitro. Low density cells enriched for antigen-presenting dendritic cells were pulsed with purified protein derivative (PPD) and cultured with autologous T cells. Overall, T cells from CVID patients showed a significantly low mean response to PPD, although non-specific DNA synthesis induced in CVID T cells by IL-2 was within the normal range. However, mean PPD-specific T cell responses in CVID were not restored by IL-2 irrespective ofthe presence of monocytes. Depletion of CD8+ cells also failed to restore the mean PPD response of CVID CD4+ T cells. Limiting dilution analysis showed that in CVID there was a reduced frequency of antigen-specific cells within the T cell preparations. The mean frequency of the PPD-specific T cells in cultures from patients vaccinated with bacille Calmette-Guerin (BCG) was reduced to 1 in 109000 T cells compared with 1 in 18 600 T cells in BCG-vaccinated normal donors. These data show that the reduced PPD-specific response in CVID is due to a partial peripheral loss of antigen-specific cells.

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“…In the induction of lymphokine-activated killer (LAK) cells, the signalling of IL-2 from the cell membrane to the nucleus is the essential event. Recently, many studies have demonstrated that phosphatidylinositol (PI) metabolism, intracellular calcium concentration ([Ca 2 ] i ), and protein kinase C (PKC) activity were negligibly increased in IL-2-treated lymphocytes [3] and that protein tyrosine phosphorylation was necessary for IL-2 signalling [4][5][6][7][8][9]. However, IL-2 receptors (IL-2R) have no kinase activity [10,11], and therefore the activation of non-receptor type tyrosine kinases must be the necessary event for the signalling of IL-2 from its receptors.…”

Section: Introductionmentioning

confidence: 99%

IL-2 signalling in T and natural killer (NK) cells associated with their class I-non-restricted killing activity

Yoneda

Osaki

Yamamoto

1996

Clinical and Experimental Immunology

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SUMMARYThe signal transduction of IL-2 in NK cells and T cells was compared. On 5 min incubation of these cells with IL-2, we observed tyrosine phosphorylation of 105-kD and 110-kD proteins in NK cells and of 95-kD and 110-kD proteins in T cells. The phosphorylation reached maximal levels in 15 min in both NK and T cells, but the levels were higher in NK cells, which showed superior killing against Daudi cells. With this phosphorylation, p52shc was also tyrosine-phosphorylated and p21 ras was activated by the short term (10 min) treatment of NK and T cells with IL-2. These signals were completely suppressed by anti-IL-2R MoAb, but only slightly suppressed by anti-IL-2R MoAb, correlated with the suppression of the class-I-non-restricted cytotoxic activity of NK and T cells by these MoAbs. When tyrosine phosphorylation was inhibited by herbimycin A and genistein, the cytotoxic activities of NK and T cells were nearly completely suppressed. In addition, the tyrosine phosphorylation of JAK3 by IL-2 was more prominent in NK cells than in T cells, but JAK1, JAK2, STAT1, STAT2 and STAT3 were not phosphorylated. These results indicate that the IL-2 signal flows downstream via both rasdependent and ras-independent pathways and that the superior killing activity of NK cells depends on their high susceptibility to protein tyrosine phosphorylation by IL-2.

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Signal transduction by interleukin 2 in human T cells: Activation of tyrosine and ribosomal S6 kinases and cell‐cycle regulatory genes

Cited by 27 publications

References 60 publications

Activation of pp70/85 S6 Kinases in Interleukin-2-Responsive Lymphoid Cells Is Mediated by Phosphatidylinositol 3-Kinase and Inhibited by Cyclic AMP

Activation of pp70/85 S6 Kinases in Interleukin-2-Responsive Lymphoid Cells Is Mediated by Phosphatidylinositol 3-Kinase and Inhibited by Cyclic AMP

Defects in antigen-driven lymphocyte responses in common variable immunodeficiency (CVID) are due to a reduction in the number of antigen-specific CD4+ T cells

IL-2 signalling in T and natural killer (NK) cells associated with their class I-non-restricted killing activity

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