SEARCH · PubMed Health

Results for “Signaling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources

PubMed2004

Cytoplasmic c-Fos induced by the YXXQ-derived STAT3 signal requires the co-operative MEK/ERK signal for its nuclear translocation.

A STAT3 (signal transducer and activator of transcription 3)- and a MEK/Erk-mediated signal can be activated by cytokines, including IL-6 (interleukin-6), PDGF, and EGF. Recently, STAT3 and an ERK-signal were shown to co-operatively activate the c-fos gene. Activation of a truncated form of the IL-6 receptor subunit, gp130, that had only one YXXQ motif, induced both c-Fos and JunB in NIH3T3 cells through STAT3 without an apparent increase in the AP-1 (activator protein-1) activity. In contrast, concomitant stimulation of the STAT3 signal and a MEK/Erk-signal markedly increased AP-1 activity with enhanced c-Fos expression. Surprisingly, the c-Fos induced by the YXXQ-signal alone was localized to the cytoplasm, from which it translocated into the nucleus following TPA (12-O-tetradecanoyl-phorbol 13-acetate) treatment in a MEK/Erk-dependent manner. c-Fos that was expressed from a constitutive promoter localized to the nucleus and did not move into the cytoplasm in response to the YXXQ-signal. Rather, the YXXQ-signal was required during c-Fos production for it to be retained in the cytoplasm. Thus, the YXXQ-signal induces c-Fos expression through STAT3 and anchors the new c-Fos in the cytoplasm. In addition, the YXXQ-signal and an Erk signal co-operatively cause c-Fos activation in the nucleus.

Active Transport, Cell Nucleus↗

PubMed1989

Identification of four nuclear transport signal-binding proteins that interact with diverse transport signals.

The transport of proteins into the nucleus requires not only the presence of a nuclear transport signal on the targeted protein but also the signal recognition proteins and the nuclear pore translocation apparatus. Complicating the search for the signal recognition proteins is the fact that the nuclear transport signals identified share little obvious homology. In this study, synthetic peptides homologous to the nuclear transport signals from the simian virus 40 large T antigen, Xenopus oocyte nucleoplasmin, adenovirus E1A, and Saccharomyces cerevisiae MAT alpha 2 proteins were coupled to a UV-photoactivable cross-linker and iodinated for use in an in vitro cross-linking reaction with cellular lysates. Four proteins, p140, p100, p70, and p55, which specifically interacted with the nuclear transport signal peptides were identified. Unique patterns of reactivity were observed with closely related pairs of nuclear transport signal peptides. Competition experiments with labeled and unlabeled peptides demonstrated that heterologous signals were able to bind the same protein and suggested that diverse signals use a common transport pathway. The subcellular distribution of the four nuclear transport signal-binding proteins suggested that nuclear transport involves both cytoplasmic and nuclear receptors. The four proteins were not bound by wheat germ agglutinin and were not associated tightly with the nuclear pore complex.

Adenovirus Early Proteins↗

PubMed2006

Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation.

Both the Wnt/beta-catenin and Ihh signaling pathways play essential roles in crucial aspects of endochondral ossification: osteoblast differentiation, chondrocyte proliferation and hypertrophy. To understand the genetic interaction between these two signaling pathways, we have inactivated the beta-catenin gene and upregulated Ihh signaling simultaneously in the same cells during endochondral skeletal development using beta-catenin and patched 1 floxed alleles. We uncovered previously unexpected roles of Ihh signaling in synovial joint formation and the essential function of Wnt/beta-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and Ihh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and synovial joint formation in the developing endochondral bone. Beta-catenin is required downstream of Ihh signaling and osterix expression for osteoblast differentiation. But in chondrocyte survival, beta-catenin is required upstream of Ihh signaling to inhibit chondrocyte apoptosis. In addition, Ihh signaling can inhibit chondrocyte hypertrophy and synovial joint formation independently of beta-catenin. However, there is a strong synergistic interaction between Wnt/beta-catenin and Ihh signaling in regulating synovial joint formation.

Animals↗

PubMed2004

Activin-like signaling activates Notch signaling during mesodermal induction.

Both activin-like signaling and Notch signaling play fundamental roles during early development. Activin-like signaling is involved in mesodermal induction and can induce a broad range of mesodermal genes and tissues from prospective ectodermal cells (animal caps). On the other hand, Notch signaling plays important roles when multipotent precursor cells achieve a specific cell fate. However, the relationship between these two signal pathways is not well understood. Here, we show that activin A induces Delta-1, Delta-2 and Notch expression and then activates Notch signaling in animal caps. Also, in vivo, ectopic activin-like signaling induced the ectopic expression of Delta-1 and Delta-2, whereas inhibition of activin-like signaling abolished the expression of Delta-1 and Delta-2. Furthermore, we show that MyoD, which is myogenic gene induced by activin A, can induce Delta-1 expression. However, MyoD had no effect on Notch expression, and inhibited Delta-2 expression. These results indicated that activin A induces Delta-1, Delta-2 and Notch by different cascades. We conclude that Notch signaling is activated when activin-like signaling induces various tissues from homogenous undifferentiated cells.

Activins↗

PubMed2003

Triggering of Toll-like receptors modulates IFN-gamma signaling: involvement of serine 727 STAT1 phosphorylation and suppressors of cytokine signaling.

Microbial stimuli activate cells of the innate immune system by triggering Toll-like receptors (TLR). Activation of macrophages and dendritic cells is further enhanced by secondary signals like IFN-gamma. Here we analyzed the interplay of IFN-gamma and TLR signaling in cells of the innate immune system. Using a STAT1-dependent reporter construct we show that IFN-gamma signaling can be enhanced as well as inhibited by simultaneous stimulation with either defined TLR agonists or whole-bacterial lysates. Short costimulation resulted in the amplification of IFN-gamma signaling and was attributable to the p38 mitogen-activated protein kinase (MAPK)-dependent phosphorylation of signal transducer and activator of transcription (STAT)1 on serine 727. In contrast, prolonged co-incubation as well as pre-incubation with TLR agonists led to an inhibition of IFN-gamma signaling. TLR triggering induced expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3 and cytokine-inducible SH2 domain-containing protein (CIS). Overexpression of SOCS-1 and, to a lesser extend, of SOCS-3 and CIS inhibited IFN-gamma signaling as measured by activation of STAT1. Moreover, pre-incubation with TLR-dependent stimuli impaired IFN-gamma-induced MHC class II regulation but enhanced CD40 and CD86 expression. Taken together, the results indicate a tight interplay between TLR and IFN-gamma signaling pathways which involve induction of SOCS proteins and serine phosphorylation of STAT1.

Antigens, CD↗

PubMed2007

The negative regulatory roles of suppressor of cytokine signaling proteins in myeloid signaling pathways.

PURPOSE OF REVIEW: Suppressor of cytokine signaling proteins are key regulators of the response of myeloid cells to cytokines and other extracellular stimuli. This review explores recent developments that have shed light on how two of the best-characterized suppressor of cytokine signaling proteins, SOCS1 and SOCS3, attenuate myeloid signaling pathways that lead to inflammation, hematological malignancy, and related disorders. RECENT FINDINGS: In addition to its 'classic' role as an inhibitor of IFNgamma signaling, a number of new regulatory roles in IFNalpha and toll-like receptor signaling have been defined for SOCS1, and substantial progress has been made in identifying the factors that give rise to lethal inflammation in Socs1 neonatal mice. The aberrant transcriptional regulation of suppressor of cytokine signaling genes in myeloid leukemia and related proliferative disorders has also been further defined. Finally, positive signs have emerged in mice that exogenous delivery of SOCS3 may be of therapeutic value. SUMMARY: Suppressor of cytokine signaling proteins have pivotal roles in attenuating cytokine and toll-like receptor signaling in myeloid cells. Understanding how defective suppressor of cytokine signaling activity contributes to inflammatory and malignant disease promises to create significant new therapeutic opportunities.

Animals↗

PubMed2003

Alterations in Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy.

BACKGROUND: Experimental studies indicate that interleukin-6 (IL-6)-related cytokines, signaling via the shared receptor gp130, Janus kinases (JAKs), and signal transducers and activators of transcription (STATs), provide a critical cardiomyocyte survival pathway in vivo. Little is known about the activation of this signaling pathway in the myocardia of patients with end-stage dilated cardiomyopathy (DCM). METHODS AND RESULTS: We performed a comprehensive expression and activation analysis of IL-6-related cytokines, receptors, signal transducers, and signal transduction inhibitors in left ventricular (LV) myocardia from patients with DCM (n=10) and non-failing (NF) donor hearts (n=5). Differential expression (DCM versus NF) was observed by immunoblotting at each level of the signaling cascade, including receptor ligands (IL-6: -59%, P<0.01; leukemia inhibitory factor [LIF]: +54%, P<0.05), receptor subunits (LIF receptor: -16%, P<0.05), signaling molecules (the Janus kinase TYK2: -48%, P<0.01; STAT3: -47%, P<0.01), and suppressors of cytokine signaling (SOCS1: +97%, P<0.05; SOCS3: -49%, P<0.01). Tyrosine-phosphorylation status of gp130 was increased (+60%, P<0.05), whereas tyrosine-phosphorylation status of JAK2 was reduced in DCM (-72%, P<0.01). Moreover, as shown by immunohistochemistry, the number of STAT3-positive cardiomyocytes was reduced in DCM (-42%, P<0.01). CONCLUSION: Signaling via gp130 and JAK-STAT is profoundly altered in DCM. Importantly, tyrosine-phosphorylation of JAK2 is reduced in the face of increased gp130 phosphorylation, indicating impaired downstream activation of this critical pathway in DCM.

Adult↗

PubMed2003

Integrative nuclear FGFR1 signaling (INFS) as a part of a universal "feed-forward-and-gate" signaling module that controls cell growth and differentiation.

A novel signaling mechanism is described through which extracellular signals and intracellular signaling pathways regulate proliferation, growth, differentiation, and other functions of cells in the nervous system. Upon cell stimulation, fibroblast growth factor receptor-1 (FGFR1), a typically plasma membrane-associated protein, is released from ER membranes into the cytosol and translocates to the cell nucleus by an importin-beta-mediated transport pathway along with its ligand, FGF-2. The nuclear accumulation of FGFR1 is activated by changes in cell contacts and by stimulation of cells with growth factors, neurotransmitters and hormones as well as by a variety of different second messengers and thus was named integrative nuclear FGFR1 signaling (INFS). In the nucleus, FGFR1 localizes specifically within nuclear matrix-attached speckle-domains, which are known to be sites for RNA Pol II-mediated transcription and co-transcriptional pre-mRNA processing. In these domains, nuclear FGFR1 colocalizes with RNA transcription sites, splicing factors, modified histones, phosphorylated RNA Pol II, and signaling kinases. Within the nucleus, FGFR1 serves as a general transcriptional regulator, as indicated by its association with the majority of active nuclear centers of RNA synthesis and processing, by the ability of nuclear FGFR1 to activate structurally distinct genes located on different chromosomes and by its stimulation of multi-gene programs for cell growth and differentiation. We propose that FGFR1 is part of a universal "feed-forward-and-gate" signaling module in which classical signaling cascades initiated by specific membrane receptors transmit signals to sequence specific transcription factors (ssTFs), while INFS elicited by the same stimuli feeds the signal forward to the common coactivator, CREB-binding protein (CBP). Activation of CBP by INFS, along with the activation of ssTFs by classical signaling cascades brings about coordinated responses from structurally different genes located at different genomic loci.

Animals↗

PubMed2005

Effects of minimum sampling rate and signal reconstruction on surface electromyographic signals.

Signal oversampling is frequently used to prevent distortion in time-series representations. When sampling at rates just above the Nyquist critical frequency (f(c)), Shannon's reconstruction theorem provides an alternative means of circumventing this problem. The purpose of this study was to determine whether surface electromyographic (EMG) data is compromised when sampled just above f(c) and whether Shannon's reconstruction theorem can correct these deficiencies, if present. Brief isometric elbow flexion contractions were performed at 100%, 80%, 50%, 25%, 10%, 5% and 2.5% maximum voluntary contraction (MVC) followed by one trial of random cyclic isometric contractions and relaxations. The 2kHz signal was resampled at 1kHz and the 2 and 1kHz signals were reconstructed (2RS and 1RS, respectively) to a sampling rate of 20kHz. Data were full-wave rectified (FWR) and low-pass filtered (LE). Peak amplitudes of the FWR and LE signals, average EMG (AEMG) amplitudes of the FWR and LE signals, mean power frequency of the raw data, number of gaps, and mean gap time of the LE signals were calculated. Significant differences were present in peak EMG and AEMG measurements between the 1 and 2kHz, 2RS and 20kHz signals and occasionally between the 1RS and the 2kHz, 2RS and 20kHz signals. These differences, although statistically significant were quite small amounting to less than 0.5% MVC. No significant differences were found for the gaps parameters. The small differences seen, coupled with the processing time required for signal reconstruction, make oversampling as well as signal reconstruction in surface EMG measurements unnecessary.

Adult↗

PubMed2005

Long-range Dpp signaling is regulated to restrict BMP signaling to a crossvein competent zone.

The sensitivity of the crossveins of the Drosophila wing to reductions in BMP signaling provides a valuable system for characterizing members of this signaling pathway. We demonstrate here two reasons for that sensitivity. First, the initial stage of posterior crossvein development depends on BMP signaling but is independent of EGF signaling. This is the opposite of the longitudinal veins, which rely of EGF signaling for their initial specification. Second, BMP signaling in the posterior crossvein depends on Decapentaplegic (Dpp) at a stage when it is being produced in the longitudinal veins. Thus, the posterior crossvein will be especially vulnerable to reductions in the levels or range of Dpp signaling. We investigated the roles of the BMP receptor Thickveins (Tkv) and the BMP inhibitor Short gastrulation (Sog) in allowing this long-range signaling. Expression of both is downregulated in the developing posterior crossvein. The Tkv downregulation depends on BMP signaling and may provide a positive feedback by allowing the spread of Dpp. The Sog downregulation is independent of BMP signaling; Sog misexpression experiments indicate that this prepattern is essential for posterior crossvein development. However, this requirement can be overridden by co-misexpression of the BMP agonist Cv-2, indicating the presence of as yet unknown cues; we discuss possible candidates.

Animals↗

PubMed2001

Cross talk of the interferon-alpha/beta signalling complex with gp130 for effective interleukin-6 signalling.

BACKGROUND: Signalling cross talk provides a molecular basis for modulating a given signalling pathway by another, and it is often critical for regulating cellular responses elicited by cytokines. Previously, we reported on the critical role of the IFN-alpha/beta signalling complex, generated by spontaneously produced IFN-alpha/beta, in efficient IFN-gamma signalling. RESULTS: In the present study, we have demonstrated that the IFN-alpha/beta signalling complex also contributes to efficient IL-6 signalling. In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-alpha/beta signalling complex. The induction of several target genes for these factors is also diminished, both in vitro and in vivo. We provide evidence that the cytoplasmic tyrosine residues of IFNAR-1, which remains phosphorylated by a weak IFN-alpha/beta stimulation, provide docking sites for Stat1 and Stat3 to form homo- or heterodimers following IL-6 stimulation. Furthermore, a chemical cross-linking experiment revealed that IFNAR-1 and gp130, a common signal transducer for the IL-6 family of cytokines, exist in close proximity. CONCLUSIONS: The constitutive weak IFN-alpha/beta signal provides a foundation for strong cellular responses to IL-6, IFN-gamma, and possibly other cytokines. Our results also suggest the assembly of cytokine receptor subunits, which may represent a 'receptosome'-like structure, allowing the unique signalling cross talks to occur.

Animals↗

PubMed1988

Positive charges at the NH2 terminus convert the membrane-anchor signal peptide of cytochrome P-450 to a secretory signal peptide.

The NH2-terminal sequences of cytochromes P-450 resemble signal peptides, but these sequences are not cleaved during the insertion of these integral membrane proteins into the microsomes. To examine whether these putative signal peptides are functionally equivalent to signal peptides of secretory proteins, cDNA coding for a fusion protein was produced, in which the signal peptide for preproparathyroid hormone was replaced with the putative signal peptide of cytochrome P450IIC2. The translational product of RNA synthesized in vitro from the cDNA was neither processed nor translocated by chicken oviduct microsomal membranes in a reticulocyte cell-free system but was resistant to extraction from the membranes by alkaline solutions. In addition, the translation of the hybrid RNA was arrested by signal recognition particle. Unlike most signal peptides, the cytochrome P450IIC2 NH2-terminal sequence does not contain basic amino acids preceding the hydrophobic core. Introduction by oligonucleotide-directed mutagenesis of lysine and arginine at the NH2 terminus resulted in a fusion protein that was partially processed by the microsomal membranes, with translocation across the membrane of both the processed and unprocessed proteins. The positive charges convert the cytochrome P450IIC2 NH2 terminus from a combination membrane insertion-halt transfer signal to a more classical secretory membrane-insertion signal, possibly by altering the orientation of the signal peptide in the membrane.

Amino Acid Sequence↗

PubMed2004

Parathyroid hormone receptor trafficking contributes to the activation of extracellular signal-regulated kinases but is not required for regulation of cAMP signaling.

Agonist-mediated activation of the type 1 parathyroid hormone receptor (PTH1R) results in several signaling events and receptor endocytosis. It is well documented that arrestins contribute to desensitization of both G(s)- and G(q)-mediated signaling and mediate PTH1R internalization. However, whether PTH1R trafficking directly contributes to signaling remains unclear. To address this question, we investigated the role of PTH1R trafficking in cAMP signaling and activation of extracellular signal-regulated kinases ERK1/2 in HEK-293 cells. Dominant negative forms of dynamin (K44A-dynamin) and beta-arrestin1 (beta-arrestin1-(319-418)) abrogated PTH1R internalization but had no effect on cAMP signaling; neither acute cAMP production by PTH nor desensitization and resensitization of cAMP signaling were affected. Therefore, PTH1R trafficking is not necessary for regulation of cAMP signaling. PTH-(1-34) induced rapid and robust activation of ERK1/2. A PTHrP-based analog ([p-benzoylphenylalanine1, Ile5,Arg(11,13),Tyr36]PTHrP-(1-36)NH2), which selectively activates the G(s)/cAMP pathway without inducing PTH1R endocytosis, failed to stimulate ERK1/2 activity. Inhibition of PTH1R endocytosis by K44A-dynamin dampened ERK1/2 activation in response to PTH-(1-34) by 69%. Incubation with the epidermal growth factor receptor inhibitor AG1478 reduced ERK1/2 phosphorylation further. In addition, ERK1/2 phosphorylation occurred following internalization of a PTH1R mutant induced by PTH-(7-34) in the absence of G protein signaling. Collectively, these data indicate that PTH1R trafficking and G(q) (but not G(s)) signaling independently contribute to ERK1/2 activation, predominantly via transactivation of the epidermal growth factor receptor.

Arrestins↗

PubMed2003

The Database of Quantitative Cellular Signaling: management and analysis of chemical kinetic models of signaling networks.

MOTIVATION: Analysis of cellular signaling interactions is expected to pose an enormous informatics challenge, perhaps even larger than analyzing the genome. The complex networks arising from signaling processes are traditionally represented as block diagrams. A key step in the evolution toward a more quantitative understanding of signaling is to explicitly specify the kinetics of all chemical reaction steps in a pathway. Technical advances in proteomics and high-throughput protein interaction assays promise a flood of such quantitative data. While annotations, molecular information and pathway connectivity have been compiled in several databases, and there are several proposals for general cell model description languages, there is currently little experience with databases of chemical kinetics and reaction level models of signaling networks. RESULTS: The Database of Quantitative Cellular Signaling is a repository of models of signaling pathways. It is intended both to serve the growing field of chemical-reaction level simulation of signaling networks, and to anticipate issues in large-scale data management for signaling chemistry. AVAILABILITY: The Database of Quantitative Cellular Signaling is available at http://doqcs.ncbs.res.in. Links to the signaling model simulator, GENESIS/Kinetikit are at http://www.ncbs.res.in/~bhalla/kkit/index.html and are also provided from within the database. The database source code is available under the GNU Public License.

Abstracting and Indexing↗

PubMed1997

The N-domain of the signal recognition particle 54-kDa subunit promotes efficient signal sequence binding.

The signal recognition particle 54-kDa subunit (SRP54) binds to the signal sequences of nascent presecretory and transmembrane proteins. Previous studies have shown that signal sequences bind to the C-terminal methionine-rich domain of the protein (M-domain), but have raised the possibility that either the N-terminal domain (N-domain) or the central guanosine triphosphatase module (GTPase-domain) also contribute to signal-sequence-binding activity. We have generated a series of N-domain and GTPase-domain mutants to investigate this issue further. Mutations in a conserved N-domain motif (ALLEADV) produced significant defects in signal sequence binding that correlate with the severity of the mutation. The magnitude of the defect was independent of the preprotein substrate, which suggested that the mutations do not alter the specificity of signal sequence recognition. The N-domain mutants also showed defects in promoting the translocation of presecretory proteins across the membrane of microsomal vesicles, but these defects appeared to be a direct consequence of the reduction in signal-sequence-binding activity and not separate effects of the mutations. By contrast, mutations in the guanosine triphosphatase consensus sequence had no effect on signal sequence binding, but instead severely impaired protein translocation activity. These results indicate that a principal function of the SRP54 N-domain is to promote efficient signal sequence binding. These data also suggest that the SRP54 GTPase regulates the cycle of signal sequence binding and release, perhaps by modulating the relative orientation of the N- and M-domains.

Animals↗

PubMed2002

Endosomal signaling of epidermal growth factor receptor stimulates signal transduction pathways leading to cell survival.

In spite of intensified efforts to understand cell signaling from endosomes, there is no direct evidence demonstrating that endosomal signaling is sufficient to activate signal transduction pathways and no evidence to demonstrate that endosomal signaling is able to produce a biological outcome. The lack of breakthrough is due in part to the lack of means to generate endosomal signals without plasma membrane signaling. In this paper, we report the establishment of a system to specifically activate epidermal growth factor (EGF) receptor (EGFR) when it endocytoses into endosomes. We treated cells with EGF in the presence of AG-1478, a specific EGFR tyrosine kinase inhibitor, and monensin, which blocks the recycling of EGFR. This treatment led to the internalization of nonactivated EGF-EGFR complexes into endosomes. The endosome-associated EGFR was then activated by removing AG-1478 and monensin. During this procedure we did not observe any surface EGFR phosphorylation. We also achieved specific activation of endosome-associated EGFR without using monensin. By using this system, we provided original evidence demonstrating that (i) the endosome can serve as a nucleation site for the formation of signaling complexes, (ii) endosomal EGFR signaling is sufficient to activate the major signaling pathways leading to cell proliferation and survival, and (iii) endosomal EGFR signaling is sufficient to suppress apoptosis induced by serum withdrawal.

Animals↗

PubMed2006

Seismic signal production in a wolf spider: parallel versus serial multi-component signals.

Animal signals can consist of multiple parts within or across sensory modalities (multi-component signals or multimodal signals). While recent work has focused on multimodal signals, the production, processing and evolution of multi-component signals has received considerably less attention. Here, using synchronous high-speed video and laser vibrometer recordings followed by experimental manipulations of putative sound-producing structures, we explored the mechanisms of seismic signal production in the courtship display of Schizocosa stridulans Stratton. Two types of seismic courtship signals were observed: 'rev' and 'idle' signals. Revs consist of a high-frequency component produced by flexions of the male pedipalp (stridulation) simultaneous with a low-frequency component produced by movements of the abdomen (tremulation). This multi-component signal is produced by independent structures and represents a parallel multi-component display. By contrast, idle displays consist of a high-intensity component produced by drumming of the forelegs on the substrate (percussion) followed by a high-frequency component produced by flexions of the male pedipalp (stridulation). While the components of the idle display are also produced by independent structures, the leg drumming and palp flexions occur serially and do not overlap in time. We discuss the selective pressures that may drive the evolution of multiple sound-producing structures as well as the selective pressures that drive the evolution of parallel versus serial multi-component signals.

Animals↗

PubMed2000

Signal transduction pathways of G protein-coupled receptors and their cross-talk with receptor tyrosine kinases: lessons from bradykinin signaling.

G protein-coupled receptors (GPCRs) represent a major class of drug targets. Recent investigation of GPCR signaling has revealed interesting novel features of their signal transduction pathways which may be of great relevance to drug application and the development of novel drugs. Firstly, a single class of GPCRs such as the bradykinin type 2 receptor (B2R) may couple to different classes of G proteins in a cell-specific and time-dependent manner, resulting in simultaneous or consecutive initiation of different signaling chains. Secondly, the different signaling pathways emanating from one or several GPCRs exhibit extensive cross-talk, resulting in positive or negative signal modulation. Thirdly, GPCRs including B2R have the capacity for generation of mitogenic signals. GPCR-induced mitogenic signaling involves activation of the p44/p42 "mitogen activated protein kinases" (MAPK) and frequently "transactivation" of receptor tyrosine kinases (RTKs), an unrelated class of receptors for mitogenic polypeptides, via currently only partly understood pathways. Cytoplasmic tyrosine kinases and protein-tyrosine phosphatases (PTPs) which regulate RTK signaling are likely mediators of RTK transactivation in response to GPCRs. Finally, GPCR signaling is the subject of regulation by RTKs and other tyrosine kinases, including tyrosine phosphorylation of GPCRs itself, of G proteins, and of downstream molecules such as members of the protein kinase C family. In conclusion, known agonists of GPCRs are likely to have unexpected effects on RTK pathways and activators of signal-mediating enzymes previously thought to be exclusively linked to RTK activity such as tyrosine kinases or PTPs may be of much interest for modulating GPCR-mediated biological responses.

Animals↗