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At least 19 recordsLinked to original sources
PubMed1998

G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways.

Signalling via the large family of G protein-coupled receptors (GPCRs) can lead to many cellular responses, ranging from regulation of intracellular levels of cAMP to stimulation of gene transcription. Members of this receptor family have been grouped into different categories dependent on the particular G protein subtypes that they predominantly interact with. Thus, receptors that couple to GS proteins will stimulate adenylate cyclase in many cells, while Gq/11-coupled receptors can mobilize intracellular Ca2+ via activation of phospholipase C. There is accumulating evidence, however, that activation of one particular signalling pathway by a GPCR can amplify intracellular signalling within a parallel but separate pathway. In this article Lisa Selbie and Stephen Hill review some of the evidence for these synergistic interactions and suggest that they may have an important role in finetuning signals from multiple receptor signalling pathways.

Animals↗
PubMed1999

XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway.

Signals elicited by transforming growth factor-beta (TGF-beta) superfamily ligands are generated following the formation of heteromeric receptor complexes consisting of type I and type II receptors. TAK1, a member of the MAP kinase kinase kinase family, and its activator, TAB1, participate in the bone morphogenetic protein (BMP) signaling pathway involved in mesoderm induction and patterning in early Xenopus embryos. However, the events leading from receptor activation to TAK1 activation remain to be identified. A yeast interaction screen was used to search for proteins that function in the pathway linking the receptors and TAB1-TAK1. The human X-chromosome-linked inhibitor of apoptosis protein (XIAP) was isolated as a TAB1-binding protein. XIAP associated not only with TAB1 but also with the BMP receptors in mammalian cells. Injection of XIAP mRNA into dorsal blastomeres enhanced the ventralization of Xenopus embryos in a TAB1-TAK1-dependent manner. Furthermore, a truncated form of XIAP lacking the TAB1-binding domain partially blocked the expression of ventral mesodermal marker genes induced by a constitutively active BMP type I receptor. These results suggest that XIAP participates in the BMP signaling pathway as a positive regulator linking the BMP receptors and TAB1-TAK1.

Adaptor Proteins, Signal Transducing↗
PubMed1993

Interleukin-4 signals regulating CD23 gene expression in human B cells: protein kinase C-independent signaling pathways.

Signal transduction by IL-4 leading to the activation of CD23(Fc epsilon RII) gene expression using human tonsillar B cells was studied. IL-4 stimulated CD23 mRNA transcription within hours (1-4 hr) which preceded the later induction of cell surface CD23. The induction of CD23 gene transcription by IL-4 was not adversely affected by cycloheximide, suggesting that post-translational modifications are accounted for the gene activation. PKC activators (PMA, diacylglycerol, indolactam) were effective inducers of CD23 gene expression, whereas calcium ionophores were not. PMA and IL-4 also displayed similar induction kinetics for CD23 mRNA. However, the signaling pathways utilized by the two agents appear distinct as shown by (1) cotreatment of IL-4 and PMA caused CD23 gene expression over the maximum level inducible by each agent alone and (2) unlike the PMA-induced CD23 expression, the IL-4-induced expression was not affected by PKC inhibitors. These results strongly suggest that IL-4 signals leading to CD23 gene activation are mediated via a PKC-independent pathway. A possible role of tyrosine kinases in the regulation of CD23 expression is discussed.

B-Lymphocytes↗
PubMed1999

Guanylate cyclase and the .NO/cGMP signaling pathway.

Signal transduction with the diatomic radical nitric oxide (NO) is involved in a number of important physiological processes, including smooth muscle relaxation and neurotransmission. Soluble guanylate cyclase (sGC), a heterodimeric enzyme that converts guanosine triphosphate to cyclic guanosine monophosphate, is a critical component of this signaling pathway. sGC is a hemoprotein; it is through the specific interaction of NO with the sGC heme that sGC is activated. Over the last decade, much has been learned about the unique heme environment of sGC and its interaction with ligands like NO and carbon monoxide. This review will focus on the role of sGC in signaling, its relationship to the other nucleotide cyclases, and on what is known about sGC genetics, heme environment and catalysis. The latest understanding in regard to sGC will be incorporated to build a model of sGC structure, activation, catalytic mechanism and deactivation.

Animals↗
PubMed2002

T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse.

Part 1 of this review will highlight the basic components and signaling pathways by which the T-cell antigen receptor (TCR) activates mature extrathymic T cells. TCR signaling commences with an early wave of protein tyrosine kinase activation, which is mediated by the Src kinases Lck and Fyn, the 70-kd zeta-associated protein kinase, and members of the Tec kinase family. This early wave of protein tyrosine phosphorylation leads to the activation of downstream signaling pathways, including an increase in intracellular free calcium, protein kinase C, nuclear factor kappaB and Ras-mitogen-activated protein kinase activation. These pathways activate transcription factors, such as activator protein 1, nuclear factor of activated T cells, and Rel proteins, which ultimately lead to the expression of genes that control cellular proliferation, differentiation, anergy, or apoptosis. This review also describes how costimulatory receptors assist in signal transduction and assembly of macromolecular complexes at the TCR contact site with the antigen-presenting cell, also known as the immune synapse. These basic concepts of TCR signal transduction will be used in part 2 to explain how T-cell function can be altered by therapeutic targeting of TCR signaling components, as well as to explain modification of TCR signaling during T(H)1/T(H)2 differentiation, tolerance, and immune senescence.

Antigen-Presenting Cells↗
PubMed2000

Retention of PDGFR-beta function in mice in the absence of phosphatidylinositol 3'-kinase and phospholipase Cgamma signaling pathways.

Signal transduction by the platelet-derived growth-factor receptor beta (PDGFR-beta) tyrosine kinase is required for proper formation of vascular smooth muscle cells (VSMC). However, the importance of individual PDGFR-beta signal transduction pathways in vivo is not known. To investigate the role of two of the pathways believed to be critical for PDGF signal transduction, we have generated mice that bear a PDGFR-beta that can no longer activate PI3kinase or PLCgamma. Although these mutant mice have normal vasculature, we provide multiple lines of evidence in vivo and from cells derived from the mutant mice that suggest that the mutant PDGFR-beta operates at suboptimal levels. Our observations indicate that although loss of these pathways can lead to attenuated PDGF-dependent cellular function, certain PDGFR-beta-induced signal cascades are not essential for survival in mice.

Animals↗
PubMed1998

Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway.

Signal transduction via MAP kinase pathways plays a key role in a variety of cellular responses, including growth factor-induced proliferation, differentiation and cell death. In mammalian cells, p38 MAP kinase can be activated by multiple stimuli, such as pro-inflammatory cytokines and environmental stress. Although p38 MAP kinase is implicated in the control of inflammatory responses, the molecular mechanisms remain unclear. Upon activation, CD4+ T cells differentiate into Th2 cells, which potentiate the humoral immune response or pro-inflammatory Th1 cells. Here, we show that pyridinyl imidazole compounds (specific inhibitors of p38 MAP kinase) block the production of interferon-gamma (IFNgamma) by Th1 cells without affecting IL-4 production by Th2 cells. These drugs also inhibit transcription driven by the IFNgamma promoter. In transgenic mice, inhibition of the p38 MAP kinase pathway by the expression of dominant-negative p38 MAP kinase results in selective impairment of Th1 responses. In contrast, activation of the p38 MAP kinase pathway by the expression of constitutivelyactivated MAP kinase kinase 6 in transgenic mice caused increased production of IFNgamma during the differentiation and activation of Th1 cells. Together, these data demonstrate that the p38 MAP kinase is relevant for Th1 cells, not Th2 cells, and that inhibition of p38 MAP kinase represents a possible site of therapeutic intervention in diseases where a predominant Th1 immune response leads to a pathological outcome. Moreover, our study provides an additional mechanism by which the p38 MAP kinase pathway controls inflammatory responses.

Animals↗
PubMed2003

The hepatitis C virus non-structural NS5A protein inhibits activating protein-1 function by perturbing ras-ERK pathway signaling.

The hepatitis C virus nonstructural 5A (NS5A) protein is a pleiotropic phosphoprotein that has been shown to associate with a wide variety of cellular signaling proteins. Of particular interest is the observation that a highly conserved C-terminal Class II polyproline motif within NS5A mediated association with the Src homology 3 domains of members of the Src family of tyrosine kinases and the mitogenic adaptor protein Grb2 (A. Macdonald, K. Crowder, A. Street, C. McCormick, and M. Harris, submitted for publication). In this study, we analyzed the consequences of NS5A expression on mitogenic signaling pathways within a variety of cell lines. Utilizing a transient luciferase reporter system, we observed that NS5A inhibited the activity of the mitogenic and stress-activated transcription factor activating protein-1 (AP1). This inhibition was dependent upon a Class II polyproline motif within NS5A. Using a combination of dominant active and negative mutants of components of the MAPK signaling pathways, selective inhibitors, together with immunoblotting with phospho-specific and phosphorylation-independent antibodies, we determined the signaling pathways targeted by NS5A to inhibit AP1. These studies demonstrated that in both stable NS5A-expressing cells and Huh-7-derived cells harboring subgenomic hepatitis C virus (HCV) replicons, this inhibition was mediated through the ERK signaling pathway. Importantly, a comparable inhibition of AP1 reporter activity was observed in hepatocyte-derived cell lines transduced with a baculovirus vector driving expression of full-length HCV polyprotein. In conclusion, these data strongly suggest a role for the NS5A protein in the perturbation of mitogenic signaling pathways in HCV-infected hepatocytes.

Amino Acid Motifs↗
PubMed1994

Activation of the progesterone receptor by the gonadotropin-releasing hormone self-priming signaling pathway.

Signal amplification is fundamental to the normal operation of the preovulatory LH surge and is achieved through processes such as GnRH self-priming and augmentation of stimulated LH secretion by progesterone. We have proposed a model for GnRH self-priming that requires cross-communication between a GnRH receptor-activated protein kinase A pathway and the progesterone receptor (PR) to achieve amplification of the GnRH signal. We found that a pulse of GnRH administered to gonadotrope-enriched pituitary cells cultured in medium containing charcoal-treated serum plus estradiol (E2) potentiated the LH secretory response to subsequent GnRH pulses, and this potentiation could be blocked by a PR antagonist, RU486, in the absence of progesterone. Similarly, exposure of gonadotrope-enriched cultures to forskolin augmented the response to a pulse of GnRH, and the augmentation due to cAMP elevation could be reduced by RU486 in the absence of progesterone. To directly test whether stimulation with either GnRH or a cAMP analog results in transactivation of the endogenous PR, we used rat anterior pituitary cells cultured in the presence of E2 and transfected with reporter plasmids containing progesterone-responsive elements (PRE) and either a E1b or a thymidine kinase (tk) promoter linked to the chloramphenicol acetyltransferase (CAT) gene. For pituitary cells transfected with the PRE-E1b-CAT plasmid, exposure to either progesterone, GnRH, or 8-bromo-cAMP (8BrcAMP) for 6 h resulted in an induction of CAT activity which could be suppressed by coincubation with RU486. RU486 by itself had no effect on CAT activity. Similar results were obtained when a plasmid containing a different promoter (PRE-tk-CAT) was used. For cells transfected with a construct lacking a PRE (pSV2CAT), 8BrcAMP was without effect on CAT expression. When cells were made PR-deficient by omission of E2 from the incubation medium and transfected with PRE-E1b-CAT, neither progesterone, GnRH, nor 8BrcAMP was able to induce CAT activity. In summary we found that either GnRH or 8BrcAMP is able to stimulate transcription of reporter genes linked to two different PRE-containing promoters in anterior pituitary cells that contain endogenous PR; this occurred in the absence of progesterone and was suppressed by a PR antagonist. A simple interpretation of these data is that a GnRH-triggered signaling cascade can result in progesterone-independent transactivation of the PR. We propose that, in the normal operation of the preovulatory LH surge, the pathways for GnRH self-priming and progesterone augmentation converge at the PR and that the pathways serve as physiological redundancies to ensure the LH surge.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Evidence for regulation of resistance in Arabidopsis to Egyptian cotton worm by salicylic and jasmonic acid signaling pathways.

Signaling cross-talk between wound- and pathogen-response pathways influences resistance of plants to insects and disease. To elucidate potential interactions between salicylic acid (SA) and jasmonic acid (JA) defense pathways, we exploited the availability of characterized mutants of Arabidopsis thaliana (L.) Heynh. and monitored resistance to Egyptian cotton worm (Spodoptera littoralis Boisd.; Lepidoptera: Noctuidae). This generalist herbivore is sensitive to induced plant defense pathways and is thus a useful model for a mechanistic analysis of insect resistance. As expected, treatment of wild-type Arabidopsis with JA enhanced resistance to Egyptian cotton worm. Conversely, the coil mutant, with a deficiency in the JA response pathway, was more susceptible to Egyptian cotton worm than wild-type Arabidopsis. By contrast, the nprl mutant, with defects in systemic disease resistance, exhibited enhanced resistance to Egyptian cotton worm. Pretreatment with SA significantly reduced this enhanced resistance of nprl plants but had no influence on the resistance of wild-type plants. However, exogenous SA reduced the amount of JA that Egyptian cotton worm induced in both npr1 mutant and wild-type plants. Thus, this generalist herbivore engages two different induced defense pathways that interact to mediate resistance in Arabidopsis.

Animals↗
PubMed2002

Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways.

Signal transducer and activator of transcription (STAT) 5b-retinoic acid receptor (RAR) alpha is the fifth fusion protein identified in acute promyelocytic leukemia (APL). Initially described in a patient with all-trans retinoic acid (ATRA)-unresponsive disease, STAT5b-RARalpha resulted from an interstitial deletion on chromosome 17. To determine the molecular mechanisms of myeloid leukemogenesis and maturation arrest in STAT5b-RARalpha(+) APL and its unresponsiveness to ATRA, we examined the effect of STAT5b-RARalpha on the activity of myeloid transcription factors including RARalpha/retinoid X receptor (RXR) alpha, STAT3, and STAT5 as well as its molecular interactions with the nuclear receptor corepressor, SMRT, and nuclear receptor coactivator, TRAM-1. STAT5b-RARalpha bound to retinoic acid response elements (RAREs) both as a homodimer and as a heterodimer with RXRalpha and inhibited wild-type RARalpha/RXRalpha transactivation. Although STAT5b-RARalpha had no effect on ligand-induced STAT5b activation, it enhanced interleukin 6-induced STAT3-dependent reporter activity, an effect shared by other APL fusion proteins including promyelocytic leukemia-RARalpha and promyelocytic leukemia zinc finger (PLZF)-RARalpha. SMRT was released from STAT5b-RARalpha/SMRT complexes by ATRA at 10(-6) M, whereas TRAM-1 became associated with STAT5b-RARalpha at 10(-7) M. The coiled-coil domain of STAT5b was required for formation of STAT5b-RARalpha homodimers, for the inhibition of RARalpha/RXRalpha transcriptional activity, and for stability of the STAT5b-RARalpha/SMRT complex. Thus, STAT5b-RARalpha contributes to myeloid maturation arrest by binding to RARE as either a homodimer or as a heterodimer with RXRalpha resulting in the recruitment of SMRT and inhibition of RARalpha/RXRalpha transcriptional activity. In addition, STAT5b-RARalpha and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway.

DNA-Binding Proteins↗
PubMed2000

Functional dissection of BCR signaling pathways.

Signal transduction by the BCR is critical for progression through developmental checkpoints as well as for immune responses. Recent results obtained in mice deficient either in an adaptor molecule, BLNK (alternatively named SLP-65 or BASH), or in phosphatidylinositol 3-kinase have revealed similar - though not identical - phenotypes to those of Btk(-/-) mice, suggesting a functional link between BLNK, Btk and phosphatidylinositol 3-kinase.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Src directly tyrosine-phosphorylates STAT5 on its activation site and is involved in erythropoietin-induced signaling pathway.

Signal transducers and activators of transcription (STAT) proteins are transcription factors activated by phosphorylation on tyrosine residues after cytokine stimulation. In erythropoietin receptor (EPOR)-mediated signaling, STAT5 is tyrosine-phosphorylated by EPO stimulation. Although Janus Kinase 2 (JAK2) is reported to play a crucial role in EPO-induced activation of STAT5, it is unclear whether JAK2 alone can tyrosine-phosphorylate STAT5 after EPO stimulation. Several studies indicate that STAT activation is caused by members of other families of protein tyrosine kinases such as the Src family. We previously reported that reduction of Src by induction of antisense src RNA expression suppressed EPO-promoted erythroid differentiation in K562 cells. In the present study, we explored the function of Src downstream of the EPOR-initiated signaling. Reduction of Src diminished tyrosine phosphorylation of STAT5 in K562 cells regardless of EPO treatment. The tyrosine phosphorylation level of STAT5 induced by EPO in F-36P cells was reduced in the presence of PP1 or PP2 selective Src inhibitor. In addition, the expression of dominant negative Src in F-36P cells reduced the tyrosine phosphorylation of STAT5. When Src and STAT5 were co-expressed in COS7 cells, tyrosine phosphorylation of STAT5 was observed, and tyrosine residue 694 (Tyr 694) of STAT5A was identified as the major phosphorylation site by Src. In vitro kinase assay revealed that GST-STAT5 fusion protein with the conserved C-terminal, but not the C-terminal-truncated mutant which lacks Tyr 694, was tyrosine-phosphorylated by Src. Src can thus directly tyrosine-phosphorylate the activation site of STAT5 (Tyr 694 in STAT5A), and Src may contribute to EPO-induced signal transduction via STAT5.

Animals↗
PubMed2005

Interaction between the androgen receptor and RNase L mediates a cross-talk between the interferon and androgen signaling pathways.

Signaling by androgens and interferons (IFN) plays an important role in prostate cancer initiation and progression. Using microarray analysis, we describe here a functional cross-talk between dihydrotestosterone and interferon signaling. Glutathione S-transferase pull-down and co-immunoprecipitation experiments reveal that the androgen receptor and the interferon-activated RNase L interact with each other in a ligand-dependent manner. Furthermore, overexpression of wild type RNase L confers IFN sensitivity to a dihydrotestosterone-inducible reporter gene, whereas R462Q-mutated RNase L does not. Based on our data we hypothesize that in 22RV1 cells, activated androgen receptor (AR) contributes to the insensitivity to IFN of the cell. Accordingly, we show that AR knockdown restores responsiveness to IFNgamma. Our findings support a model in which both the activation of AR and the down-regulation of IFN signaling can synergize to promote cell survival and suppress apoptosis. This model provides the molecular basis to understand how mutated RNase L can lead to early onset PCa and illustrates how inflammatory cytokines and nuclear hormone signaling contribute to tumor development.

Androgens↗
PubMed2003

Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling.

OBJECTIVE: To determine whether hydralazine might decrease DNA methyltransferase (DNMT) expression and induce autoimmunity by inhibiting extracellular signal-regulated kinase (ERK) pathway signaling. METHODS: The effect of hydralazine on DNMT was tested in vitro using enzyme inhibition studies, and in vivo by measuring messenger RNA (mRNA) levels and enzyme activity. Effects on ERK, c-Jun N-terminal kinase, and p38 pathway signaling were tested using immunoblotting. Murine T cells treated with hydralazine or an ERK pathway inhibitor were injected into mice and anti-DNA antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: In vitro, hydralazine did not inhibit DNMT activity. Instead, hydralazine inhibited ERK pathway signaling, thereby decreasing DNMT1 and DNMT3a mRNA expression and DNMT enzyme activity similar to mitogen-activated protein kinase kinase (MEK) inhibitors. Inhibiting T cell ERK pathway signaling with an MEK inhibitor was sufficient to induce anti-double-stranded DNA antibodies in a murine model of drug-induced lupus, similar to the effect of hydralazine. CONCLUSION: Hydralazine reproduces the lupus ERK pathway signaling abnormality and its effects on DNMT expression, and inhibiting this pathway induces autoimmunity. Hydralazine-induced lupus could be caused in part by inducing the same ERK pathway signaling defect that occurs in idiopathic lupus.

Animals↗
PubMed2006

Expression and downregulation of WNT signaling pathway genes in rhesus monkey oocytes and embryos.

Mammalian WNT genes encode secreted glycoproteins that are conserved homologues of the Drosophila Wingless gene, which plays a crucial role in Drosophila development. Recently, WNT pathway signaling has been implicated in ovarian development, oogenesis, and early development. We sought to evaluate whether these genes may contribute to the formation of healthy human oocytes or embryos, and whether the expression of these genes could provide informative markers of human oocyte and embryo quality. To do this, we employed the primate embryo gene expression resource (PREGER; www.preger.org) to examine expression of mRNAs encoding 38 components of the WNT signaling pathway in rhesus monkey oocytes and embryos as a nonhuman primate model. We observed considerable conservation between rhesus monkey and mouse of expression of WNT, FZD, and effector gene mRNAs, and a generalized downregulation of genes encoding key components of the WNT signaling pathway during preimplantation development. Our results support a role for WNT signaling during oocyte growth or maturation, but not during preimplantation development. Additionally, we observed differences between in vitro cultured and in vivo developing blastocysts, indicating possible effects of culture on WNT signaling during the peri-implantation period.

Animals↗
PubMed2003

A genomewide survey of developmentally relevant genes in Ciona intestinalis. V. Genes for receptor tyrosine kinase pathway and Notch signaling pathway.

In the present survey, we identified most of the genes involved in the receptor tyrosine kinase (RTK), mitogen activated protein kinase (MAPK) and Notch signaling pathways in the draft genome sequence of Ciona intestinalis, a basal chordate. Compared to vertebrates, most of the genes found in the Ciona genome had fewer paralogues, although several genes including ephrin, Eph and fringe appeared to have multiplied or duplicated independently in the ascidian genome. In contrast, some genes including kit/flt, PDGF and Trk receptor tyrosine kinases were not found in the present survey, suggesting that these genes are innovations in the vertebrate lineage or lost in the ascidian lineage. The gene set identified in the present analysis provides an insight into genes for the RTK, MAPK and Notch signaling pathways in the ancient chordate genome and thereby how chordates evolved these signaling pathway.

Animals↗