Ras/Erk pathway positively regulates Jak1/STAT6 activity and IL-4 gene expression in Jurkat T cells

So, Eui‐Young; Oh, Jiyoung; Jang, Jae-Yeon; Kim, Jeong-Ho; Lee, Choong‐Eun

doi:10.1016/j.molimm.2007.02.022

Cited by 53 publications

(42 citation statements)

References 49 publications

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“…This is consistent with earlier studies showing that perturbation of Ras-MAPK signaling blocked Th2 function (29). Additionally, activation of the MAPK pathway has been implicated in IL-4R signaling and is critical for subsequent propagation of a complete Th2 immune response (29,38), although a role for Lck in IL-4R signaling has not yet been established. Further studies will be required to establish how Lck SH3 domain function specifically controls Th2 immunity.…”

Section: Discussionsupporting

confidence: 91%

Th2-Specific Immunity and Function of Peripheral T Cells Is Regulated by the p56Lck Src Homology 3 Domain

McCoy

Finkelman

Straus

2010

The Journal of Immunology

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T cell activation and effector function is essential for robust immunity. Ag TCR signals are known to regulate T lymphocyte differentiation, but the mechanisms involved in this regulation remain unclear. Recent work has demonstrated that the Src family protein tyrosine kinase p56Lck specifically links TCR signaling to activation of the MAPK pathway through the function of its Src homology 3 (SH3) domain. The MAPK pathway is involved in T cell activation and has previously been implicated in Th2 immunity. We have used Lck SH3 mutant knockin mice (LckW97A) to investigate the potential role of this regulatory mechanism in T lymphocyte activation and effector function. Our results demonstrate that Lck SH3 domain function regulates activation of T lymphocytes as indicated by reduced IL-2 production, CD69 induction, and proliferation of LckW97A T cells following TCR stimulation. Biochemical studies confirm that activation of the MAPK pathway is selectively altered following TCR ligation in LckW97A T lymphocytes. Phospho-ERK induction is reduced, but phospho-phospholipase Cγ1 induction and calcium mobilization are largely unaffected. Immunization with DNP–keyhole limpet hemocyanin, heat-killed Brucella abortus, or infection with Nippostrongylus brasiliensis demonstrates selectively impaired Th2 immunity with reduced serum levels of IgG1, IgE, and IL-4. In vitro studies show that LckW97A T cells can differentiate into Th2-type cells, but they form IFN-γ–producing cells under conditions that normally favor Th2 development. These data indicate that the Lck SH3 domain controls T lymphocyte activation by regulating MAPK pathway induction and demonstrate a novel role for Lck in the regulation of Th2-type immunity.

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Section: Discussionsupporting

confidence: 91%

Th2-Specific Immunity and Function of Peripheral T Cells Is Regulated by the p56Lck Src Homology 3 Domain

McCoy

Finkelman

Straus

2010

The Journal of Immunology

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“…Insulin receptor substrate (IRS), associated with IL-4Rα, can activate the PI-3K/Akt pathway and the MAPK cascade [30,31], that have been implicated in invasion and tumorigenesis. In trophoblast cells PIBF treatment resulted in fast, transient phosphorylation of Akt and ERK, whereas, in the tumour cell line PIBF treatment induced sustained activation of these molecules (Fig.…”

Section: Pibf Induced Signalling Pathways In Trophoblast and Tumour Cmentioning

confidence: 99%

Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity

Halász

Polgar

Berta

et al. 2013

Cell. Mol. Life Sci.

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Invasiveness is a common feature of trophoblast and tumours; however, while tumour invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumour cells express high levels of the immunomodulatory Progesterone-Induced Blocking Factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim we used PIBF silenced or PIBF treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumour (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signalling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumour cells PIBF triggered sustained Akt, ERK and late STAT3 activation. The late signalling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3 activating effect of PIBF was reduced in HB-EGF deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumour cells PIBF induces proteins, which activate invasion signalling, while -based on our previous data -PIBF might control trophoblast invasion by suppressing invasive genes.

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“…Cytokines commonly trigger signal transduction in target cells via the Janus kinase (Jak)-signal transducer and activator of transcription (Stat) pathway, 17 with downstream nuclear translocation of specific Stat transcription factors. Cross-talk demonstrated between the Jak-Stat pathway and other signaling pathways such as the mitogenactivated protein (MAP) kinase pathway, 18 the NFB signaling pathway, 19 and the TGF␤ signaling pathway 20 underscore the complexity of signaling networks activated by cytokine stimulation.…”

Section: Introductionmentioning

confidence: 99%

IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma

Calvo

Dabir

Kovach

et al. 2008

Blood

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IntroductionFollicular lymphoma (FL) is a non-Hodgkin lymphoma of germinal center B-cell origin. FL is the second most common nonHodgkin lymphoma and represents 20% of all lymphomas in the adult population. 1 Although the course of disease is indolent, it is largely incurable, with a median survival of 7 to 10 years. With time, FL typically transforms into a high-grade lymphoma. FL is characterized by the t(14;18) (q32;q21) translocation, 2-4 which leads to constitutive expression of the antiapoptotic Bcl-2 protein, conferring survival advantage to FL cells. 5 The BCL-2/JH translocation is required but not sufficient for lymphomagenesis, underscored by the fact that the BCL2/JH translocation has been identified in B cells from lymph nodes (LNs) and blood in healthy individuals. 6,7,8 Hence, there are likely other genetic alterations within tumor cells that cooperate with Bcl-2 to drive the malignant phenotype in FL.There is compelling evidence that FL tumor cells are dependent upon the LN microenvironment for continued survival and proliferation. [9][10][11] Two distinct gene expression signatures that predict patient survival independent of clinical prognostic variables have been identified by gene expression profiling. 11 The expression profile designated immune response 1 (IR1) includes T cell-and macrophage-restricted genes and was predictive of a favorable clinical outcome. In contrast, IR2 is associated with genes primarily expressed by monocytes and dendritic cells and was predictive of a poorer outcome. Other studies have also implicated the importance of the tumor-host microenvironment in FL. Patients with spontaneous regression of FL reportedly demonstrated increased numbers of T-helper cells with no apparent differences in cytotoxic T cells or macrophages when compared with patients with FL exhibiting no regression. 9 Increased numbers of CD57 ϩ T cells have been associated with a higher frequency of B symptoms and bone marrow involvement. 12 The presence of high numbers of CD68 ϩ macrophages (Ͼ 15 per high-power field) was an independent negative predictor of survival in one study. 13 Intratumoral T cells and macrophages presumably exert effects on the FL microenvironment via secretion of cytokines and/or by direct interaction with tumor cells. Studies have shown FL cells to proliferate in vitro in the presence of autologous CD4 ϩ T cells, 14 and in the presence of CD4 ϩ T-cell clones that recognize alloantigens expressed by FL cells. 10 Polymorphisms of several cytokines have been implicated in susceptibility to non-Hodgkin lymphoma, including tumor necrosis factor (TNF) and interleukin-10 (IL-10). 15 Single-nucleotide polymorphisms (SNPs) of IL-8, IL-2, IL-12␤, and the IL-1 receptor were shown in one study to be predictive of survival in patients diagnosed with FL. 16 Cytokines play key roles in the regulation of hematopoietic differentiation, proliferation, and apoptosis. Cytokines commonly trigger signal transduction in target cells via the Janus kinase (Jak)-signal transducer and activator of tr...

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Ras/Erk pathway positively regulates Jak1/STAT6 activity and IL-4 gene expression in Jurkat T cells

Cited by 53 publications

References 49 publications

Th2-Specific Immunity and Function of Peripheral T Cells Is Regulated by the p56Lck Src Homology 3 Domain

Th2-Specific Immunity and Function of Peripheral T Cells Is Regulated by the p56Lck Src Homology 3 Domain

Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity

IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma

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