Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding of interleukin 2 (IL-2) to the IL-2 receptor (IL-2R) induces a rapid increase in tyrosine phosphorylation of cellular proteins. In a previous study, we have shown that p56lck (lck), a src-family protein tyrosine kinase (src-PTK), physically and functionally associates with the IL-2R beta chain (IL-2R beta). To further investigate a role of src-PTKs in IL-2 signaling, we analyzed a mouse pro-B-cell line, in which lck is not expressed detectably. We observed that in this cell line, IL-2 induces activation of at least two src-PTKs, p59fyn (fyn) and p53/56lyn (lyn). Interestingly, stimulation of this cell line with IL-3 also induces activation of src-PTKs. The activation of fyn or lyn seems to be selective for stimulation with IL-2 or IL-3 since stimulation with IL-6 fails to activate them. Furthermore, we provide evidence for the physical association of fyn with IL-2R beta. Taken together with previous results, our current study suggests that different src-PTKs, each of which is expressed in a cell-type-specific manner, can participate in the IL-2 signal transduction.
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PMID:Functional coupling of the src-family protein tyrosine kinases p59fyn and p53/56lyn with the interleukin 2 receptor: implications for redundancy and pleiotropism in cytokine signal transduction. 848 35

Two T cell-specific src-family tyrosine kinases, p56 lck (lck) and p59 fyn (fyn), are implicated in regulating PI 3-kinase activity in response to interleukin-2 (IL-2), a cytokine that induces T cell proliferation. The src- homology domains 3 (SH3) of src-family kinases can directly interact with the PI 3-kinase regulatory subunit p85 and this may be a mechanism to regulate PI 3-kinase activity. In order to understand the mode of PI 3-kinase activation by the IL-2 receptor, we examined the association of PI 3-kinase to SH2 and SH3 domains of lck and fyn in IL-2-dependent kit 225 cells. The fyn SH3 domain bound more PI 3-kinase and its p85 subunit than the lck SH3 domain, while the lck SH2 domain bound more PI 3-kinase than the fyn SH2 domain. None of these interactions were regulated by IL-2. Low binding of PI 3-kinase to the lck SH3 domain was not observed in IL-2-independent Jurkat T cells. Thus, SH3 and SH2 domains of lck and fyn bound different amounts of PI 3-kinase, a feature that was dependent on a T cell type, but was not influenced by IL-2.
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PMID:Differences in binding of PI 3-kinase to the src-homology domains 2 and 3 of p56 lck and p59 fyn tyrosine kinases. 860 33

The majority of T cells develop in the thymus and exhibit well characterized phenotypic changes associated with their maturation. Previous analysis of intestinal intraepithelial lymphocytes (IEL) from nude mice and a variety of experimentally manipulated models led to the view that at least a portion of these cells represent a distinct T cell population that matures extrathymically. The IEL that are postulated to mature within the intestine include both T cell receptor (TCR) alpha beta- and gamma delta-bearing subpopulations. They can be distinguished from conventional thymically derived T cells in that they express an unusual coreceptor, a CD8alpha homodimer. In addition, they can utilize the Fc receptor gamma-chain in place of the CD3-associated zeta-chain for TCR signaling and their maturation depends on the interleukin 2 receptor beta-chain. Moreover, TCRalpha beta+CD8alpha alpha+ IEL are not subject to conventional thymic selection processes. To determine whether CD3(-)CD8alpha alpha+ IEL represent precursors of T cells developing extrathymically, we examined IEL from knockout mice lacking the recombination activating gene-1 (rag-1), CD3epsilon, or both Lck and Fyn, in which thymic T cell development is arrested. CD3(-)CD8alpha alpha+CD16(+) IEL from all three mutant strains, as well as from nude mice, included cells that express pre-TCRalpha transcripts, a marker of T cell commitment. These IEL from lck-/-fyn-/- animals exhibited TCR beta-gene rearrangement. However, CD3(-)CD8alpha alpha+CD16(+) IEL from epsilon-deficient mice had not undergone Dbeta-Jbeta joining, despite normal rearrangement at the TCRbeta locus in thymocytes from these animals. These results revealed another distinction between thymocytes and IEL, and suggested an unexpectedly early role for CD3epsilon in IEL maturation.
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PMID:Intestinal intraepithelial lymphocytes include precursors committed to the T cell receptor alpha beta lineage. 968 2

T cell activation and clonal expansion is the result of the coordinated functions of the receptors for antigen and interleukin (IL)-2. The protein tyrosine kinase p56(lck) is critical for the generation of signals emanating from the T cell antigen receptor (TCR) and has also been demonstrated to play a role in IL-2 receptor signaling. We demonstrate that an IL-2-dependent, antigen-specific CD4(+) T cell clone is not responsive to anti-TCR induced growth when propagated in IL-2, but remains responsive to both antigen and CD3epsilon-specific monoclonal antibody. Survival of this IL-2-dependent clone in the absence of IL-2 was supported by overexpression of exogenous Bcl-xL. Culture of this clonal variant in the absence of IL-2 rendered it susceptible to anti-TCR-induced signaling, and correlated with the presence of kinase-active Lck associated with the plasma membrane. The same phenotype is observed in primary, resting CD4(+) T cells. Furthermore, the presence of kinase active Lck associated with the plasma membrane correlates with the presence of ZAP 70-pp21zeta complexes in both primary T cells and T cell clones in circumstances of responsive anti-TCR signaling. The results presented demonstrate that IL-2 signal transduction results in the functional uncoupling of the TCR complex through altering the subcellular distribution of kinase-active Lck.
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PMID:Interleukin 2-mediated uncoupling of T cell receptor alpha/beta from CD3 signaling. 980 69

Strength of T cell receptor (TCR) signaling, coreceptors, costimulation, antigen-presenting cell type, and cytokines all play crucial roles in determining the efficiency with which type 2 T lymphocytes (Th2, Tc2) develop from uncommitted precursors. To investigate in vivo regulatory mechanisms that control the population of type 2 T cells and disease susceptibility, we have created lines of transgenic mice in which expression of a chimeric cytokine receptor (the mouse interleukin 2 receptor beta chain [IL-2Rbeta] extracellular domain fused to the cytoplasmic tail of IL-4Ralpha) is targeted to the T lymphoid lineage using the proximal lck promoter. This chimera transduced IL-4-specific signals in response to IL-2 binding and dramatically enhanced type 2 responses (IL-4, IL-5, and immunoglobulin E production) upon in vitro TCR stimulation or in vivo antigen challenge. Thus, type 2 effector function was augmented by IL-4 signals transduced through a chimeric receptor expressed in a T cell-specific manner. This influence was sufficient for establishment of antigen-induced allergic airway hyperresponsiveness on a disease-resistant background (C57BL/6).
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PMID:In vivo function of an interleukin 2 receptor beta chain (IL-2Rbeta)/IL-4Ralpha cytokine receptor chimera potentiates allergic airway disease. 981 58

The Janus kinase, JAK3 plays an important role in interleukin-2 (IL-2)-dependent signal transduction and proliferation of T lymphocytes. Our findings show that prostaglandin E2 (PGE2) can inhibit upregulation of JAK3 protein in naive T cells and can downregulate its expression in primed cells. Reduction in JAK3 was selective because expression of other tyrosine kinases (JAK1, p56(lck), and p59(fyn)) and signal transducer and activator of transcription (STAT)5, which are linked to IL-2 receptor (IL-2R) signaling pathway, were not affected. Inhibition of JAK3 may be controlled by intracellular cyclic adenosine monophosphate (cAMP) levels, as forskolin, a direct activator of adenylate cyclase and dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP suppressed JAK3 expression. Moreover, 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase, potentiated PGE2-induced suppression of JAK3. In naive T cells, but not primed T cells, PGE2 and other cAMP elevating agents also caused a modest reduction in surface expression of the common gamma chain (gammac) that associates with JAK3. The absence of JAK3, but not IL-2R in T cells correlated with impaired IL-2-dependent signal transduction and proliferation. The alteration in IL-2 signaling included decreased tyrosine phosphorylation and DNA binding activity of STAT5 and poor induction of the c-Myc and c-Jun pathways. In contrast, IL-2-dependent induction of Bcl-2 was unaffected. These findings suggest that suppression of JAK3 levels may represent one mechanism by which PGE2 and other cAMP elevating agents can inhibit T-cell proliferation.
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PMID:Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E2 and other cyclic adenosine monophosphate-elevating agents: impact on interleukin-2 receptor signaling pathway. 1009 Sep 41

Tyrosine phosphorylation of multiple proteins, including the receptor itself, is an initial event in IL-2 signaling and leads to recruitment of SH2 or PTB domain-containing proteins to the receptor. In this study, we have used subdomains of the IL-2 receptor beta chain (IL-2Rbeta) expressed in Escherichia coli as GST fusion proteins to identify the tyrosine residues that could be phosphorylated by p56(lck), one of the critical tyrosine kinases activated by IL-2. We report that recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain but not those within the IL-2Rgamma chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. Interestingly, phosphorylation of Tyr-358 appears to require the presence of either Tyr-355 or Tyr-361. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. We also investigated the association of p56(lck) with the IL-2Rbeta chain which was found to depend on a short stretch of the IL-2Rbeta chain acidic subdomain, and to be independent of the presence of its tyrosine residues.
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PMID:Biochemical analysis of interleukin-2 receptor beta chain phosphorylation by p56(lck). 1021 54

Engagement of interleukin-2 (IL-2) mediates the heterodimeridation of the common beta chain (beta(c)) and common gamma chain (gamma(c)) of the IL-2 receptor (IL-2R). This is sufficient and necessary for receptor activation and signal transduction. It is generally held that the IL-2R is activated by the trans-activity of the protein tyrosine kinases (PTKs) Jak1 and Jak3 associated with beta(c) and gamma(c) respectively. Transduction of proliferative signals requires Jak3 activity. A Jak3 independent signalling pathway involving p56(lck), generating anti-apoptotic signals, can be observed and requires the PROX domain of gamma(c). p56(lck) can be activated by dephosphorylation of an inhibitory carboxyl terminal phosphorylated tyrosine residue (Y505). We propose that this is mediated by a PROX domain associated protein tyrosine phosphatase (PTP). Activation of p56(lck) alone is insufficient for transduction of proliferative signals and thus works in concert with Jak3 mediated receptor activation. This indicates that both gamma(c) domains are vital for signal transduction.
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PMID:Activation of the interleukin 2 receptor: a possible role for tyrosine phosphatases. 1088 65

There is an alteration of the immune response in aging that leads to the increased incidence of infections, cancers and autoimmune disorders. The aim of the present study was to investigate whether there exists changes in signal transduction under the IL-2 receptor stimulation and the role of plasma membrane cholesterol in the activation of T cells with aging. We report age-related changes in the JAK-STAT signalling pathway that results in decreased tyrosine phosphorylation of STAT5. We present evidence for the importance of cholesterol content in regulating signalling pathways in T cells and in modulating their proliferation by using the plasma membrane cholesterol-depleting agent methyl-beta-cyclodexrin (MBCD). MBCD treatment (0.5 mM) induced a significant decrease in the cholesterol content of T cells of elderly subjects whereas it was increased in T cells of young subjects. MBCD induced changes in the phosphorylation of p56(lck), especially in T cells of elderly subjects. The proliferation of MBCD-treated T cells decreased in lymphocytes of young subjects but did not change in T cells of elderly subjects. These results suggest a role for plasma membrane cholesterol in the regulation of the TcR signalling pathways with differential effects related to aging. However, the data suggest that modulation of the plasma membrane cholesterol content alone may not be enough to restore signal transduction changes with aging.
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PMID:Cyclodextrin modulation of T lymphocyte signal transduction with aging. 1147 Jan 30

Interleukin-2 (IL-2) plays a major role in the proliferation of cell populations during an immune reaction. The beta(c) and gamma(c) subunits of the IL-2 receptor (IL-2R) are sufficient and necessary for signal transduction. Despite lacking known catalytic domains, receptor engagement leads to the activation of a diverse array protein tyrosine kinases (PTKs). In resting or anergised T cells, Jak3 is not activated. Signals arising from the PROX domain of the gamma(c) subunit activate p56(lck) (lck) leading to the induction of anti-apoptotic mechanisms. When Jak3 is activated, in primed T cells, other PTKs predominantly mediate the induction of anti-apoptotic mechanisms and drive cellular proliferation. This review intends to suggest a role for these differences within the context of the immune system.
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PMID:Alternate signalling pathways from the interleukin-2 receptor. 1175 Aug 78


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