Inhibitory B7-family molecules in the tumour microenvironment

The B7 family consists of activating and inhibitory co-stimulatory molecules that positively and negatively regulate immune responses. Recent studies have shown that human and rodent cancer cells, and stromal cells and immune cells in the cancer microenvironment upregulate expression of inhibitory B7 molecules and that these contribute to tumour immune evasion. In this Review, we focus on the roles of these B7 molecules in the dynamic interactions between tumours and the host immune system, including their expression, regulation and function in the tumour microenvironment. We also discuss novel therapeutic strategies that target these inhibitory B7 molecules and their signalling pathways to treat human cancer.     

Wnts as morphogens? The view from the wing of Drosophila

Morphogens are diffusible signalling molecules that pattern cellular fields by setting up differential gene expression in a concentration-dependent manner. Members of the Wnt family of signalling molecules are generally considered to be classical morphogens. However, a close analysis of their activity indicates that they do not fulfil all of the critera that are associated with the classical definition.     

Non-conducting functions of voltage-gated ion channels

Various studies, mostly in the past 5 years, have demonstrated that, in addition to their well-described function in regulating electrical excitability, voltage-dependent ion channels participate in intracellular signalling pathways. Channels can directly activate enzymes linked to cellular signalling pathways, serve as cell adhesion molecules or components of the cytoskeleton, and their activity can alter the expression of specific genes. Here, I review these findings and discuss the extent to which the molecular mechanisms of such signalling are understood.     

Long non‐coding RNAs in rheumatoid arthritis

Rheumatoid arthritis, a disabling autoimmune disease, is associated with altered gene expression in circulating immune cells and synovial tissues. Accumulating evidence has suggested that long non‐coding RNAs (lncRNAs), which modulate gene expression through multiple mechanisms, are important molecules involved in immune and inflammatory pathways. Importantly, many studies have reported that lncRNAs can be utilized as biomarkers for disease diagnosis and prognostication. Recently, dysregulation of lncRNAs in rheumatoid arthritis and other autoimmune diseases has been revealed. Experimental studies also confirmed their crosstalk with matrix metalloproteinases, nuclear factor‐κB signalling and T‐cell response pertinent to autoimmunity and inflammation. Circulating lncRNAs, such as HOTAIR, differentiated patients with rheumatoid arthritis from healthy subjects. Taken together, lncRNAs are good candidates as biomarkers and therapeutic targets in rheumatoid arthritis. Further investigation on in vivo delivery of these regulatory molecules and large‐cohort validation of their clinical applicability may be useful.     

New perspectives on integrin-dependent adhesions

Integrins are heterodimeric transmembrane receptors that connect the extracellular matrix environment to the actin cytoskeleton via adaptor molecules through assembly of a range of adhesion structures. Recent advances in biochemical, imaging and biophysical methods have enabled a deeper understanding of integrin signalling and their associated regulatory processes. The identification of the consensus integrin-based ‘adhesomes’ within the last 5 years has defined common core components of adhesion complexes and associated partners. These approaches have also uncovered unexpected adhesion protein behaviour and molecules recruited to adhesion sites that have expanded our understanding of the molecular and physical control of integrin signalling.     

GDNF and its receptors in the regulation of the ureteric branching.

Recent transgenic and organ culture experiments have inevitably shown that glial cell line-derived neurotrophic factor (GDNF) is a mesenchyme-derived signal for ureteric budding and branching. The signalling receptor complex for GDNF includes a dimer of Ret receptor tyrosine kinase and two molecules of GDNF family receptor alpha1. Alpha-receptors are not only needed for the ligand binding and Ret activation, but they might mediate signals without Ret. While GDNF is clearly required for ureteric branching, tissue recombination studies have shown that it is not sufficient for the completion of ureteric morphogenesis, and other signalling molecules are needed. Different experimental models have resulted in somewhat contradictory results on their molecular identity, but transforming growth factor-beta1, -beta2, fibroblast growth factor-7 and hepatocyte growth factor form, obviously among others, a redundant set of growth factors in ureteric differentiation. Three other members of the GDNF family, neurturin, artemin and persephin, are also expressed in the developing kidney, and at least neurturin and persephin promote ureteric branching in vitro, but their true in vivo roles are still unclear.     

Oxylipins as developmental and host-fungal communication signals

Pathogenic microbes and their hosts have acquired complex signalling mechanisms to appraise themselves of the environmental milieu in the ongoing battle for survival. Several recent studies have implicated oxylipins as a novel class of host-microbe signalling molecules. Oxylipins represent a vast and diverse family of secondary metabolites that originate from the oxidation or further conversion of polyunsaturated fatty acids. Among the microbial oxylipins, the fungal oxylipins are best characterized and function as hormone-like signals that modulate the timing and balance between asexual and sexual spore development in addition to toxin production. Coupled with other studies that implicate a role for fungal oxylipins in pathogenesis by Aspergillus and Candida spp., these results suggest that host and microbial oxylipins might interfere with the metabolism, perception or signalling processes of each other.     

Pathogen espionage: multiple bacterial adrenergic sensors eavesdrop on host communication systems

The interactions between bacterial pathogens and their eukaryotic hosts are vital in determining the outcome of infections. Bacterial pathogens employ molecular sensors to detect and facilitate adaptation to changes in their niche. The sensing of these extracellular signals enables the pathogen to navigate within mammalian hosts. Intercellular bacterial communication is facilitated by the production and sensing of autoinducer (AI) molecules via quorum sensing. More recently, AI‐3 and the host neuroendocrine (NE) hormones adrenaline and noradrenaline were reported to display cross‐talk for the activation of the same signalling pathways. Remarkably, there is increasing evidence to suggest that enteric bacteria sense and respond to the host NE stress hormones adrenaline and noradrenaline to modulate virulence. These responses can be inhibited by α and β‐adrenergic receptor antagonists implying a bacterial receptor‐based sensing and signalling cascade. In Escherichia coli O157:H7 and Salmonella, QseC has been proposed as the adrenergic receptor. Strikingly, there is an increasing body of evidence that not all the bacterial adrenergic responses require signalling through QseC. Here we provide additional hypotheses to reconcile these observations implicating the existence of alternative adrenergic receptors including BasS, QseE and CpxA and their associated signalling cascades with major roles in interkingdom communication.     

Production of cell–cell signalling molecules by bacteria isolated from human chronic wounds

Aim: To (i) identify chronic wound bacteria and to test their ability to produce acyl‐homoserine‐lactones (AHLs) and autoinducer‐2 (AI‐2) cell–cell signalling molecules and (ii) determine whether chronic wound debridement samples might contain these molecules. Methods and Results: Partial 16S rRNA gene sequencing revealed the identity of 46 chronic wound strains belonging to nine genera. Using bio‐reporter assays, 69·6% of the chronic wound strains were inferred to produce AI‐2, while 19·6% were inferred to produce AHL molecules. At least one strain from every genus, except those belonging to the genera Acinetobacter and Pseudomonas, were indicated to produce AI‐2. Production of AI‐2 in batch cultures was growth‐phase dependent. Cross‐feeding assays demonstrated that AHLs were produced by Acinetobacter spp., Pseudomonas aeruginosa and Serratia marcescens. Independent from studies of the bacterial species isolated from wounds, AHL and/or AI‐2 signalling molecules were detected in 21 of 30 debridement samples of unknown microbial composition. Conclusion: Chronic wound bacteria produce cell–cell signalling molecules. Based on our findings, we hypothesize that resident species generally produce AI‐2 molecules, and aggressive transient species associated with chronic wounds typically produce AHLs. Both these classes of cell–cell signals are indicated to be present in human chronic wounds. Significance and Impact of the Study: Interbacterial cell–cell signalling may be an important factor influencing wound development and if this is the case, the presence of AHLs and AI‐2 could be used as a predictor of wound severity. Manipulation of cell–cell signalling may provide a novel strategy for improving wound healing.     

The role of Toll-like receptor signalling in the pathogenesis of arthritis

Recent evidence highlighted the role of Toll-like receptors (TLRs) as key recognition structures of the innate immune system. The activation of TLRs initiates the production of inflammatory cytokines, chemokines, tissue destructive enzymes, and type I interferons. In addition, TLR signalling plays an important role in the activation and direction of the adaptive immune system by the upregulation of costimulatory molecules of antigen presenting cells. Considering the important role of TLR signalling as a critical link between innate and adaptive immunity it has been proposed that a dysregulation in TLR signalling might be associated with autoimmunity. In this review, recent studies on TLR signal transduction pathways activated by corresponding ligands are summarized and evidence for a possible role of TLR signalling in the pathogenesis of rheumatoid arthritis is discussed.     

Perception of lipo-chitooligosaccharidic Nod factors in legumes

Lipo-chitooligosaccharides produced by rhizobia are a class of signalling molecules that mediate recognition and nodule organogenesis in the legume-rhizobia symbiosis. Their synthesis is specified by the nodulation genes of rhizobia and hence they are commonly known as Nod factors. They are amphiphilic molecules and induce a variety of responses in the roots of the legume hosts. Studies using plant and rhizobial mutants and purified molecules suggest that Nod factors are recognized by more than one receptor. In this article, we review evidence about the affinity, specificity and location of these putative receptors and describe recent studies with regard to their identification.     

Inter-kingdom signalling: communication between bacteria and their hosts

Microorganisms and their hosts communicate with each other through an array of hormonal signals. This cross-kingdom cell-to-cell signalling involves small molecules, such as hormones that are produced by eukaryotes and hormone-like chemicals that are produced by bacteria. Cell-to-cell signalling between bacteria, usually referred to as quorum sensing, was initially described as a means by which bacteria achieve signalling in microbial communities to coordinate gene expression within a population. Recent evidence shows, however, that quorum-sensing signalling is not restricted to bacterial cell-to-cell communication, but also allows communication between microorganisms and their hosts.     

Growth factors: a role in guiding axons?

A remarkable finding to emerge in recent years is that the early brain neuroepithelium is highly patterned before axonogenesis begins. Growth factors are among a variety of classes of molecules whose regionalized expression divides the early brain into molecularly distinct domains. Thus, when axons first grow to their synaptic targets, growth factor signalling may help them to navigate. This review discusses recent studies that reveal that growth factors can act as chemoattractants and repellents and that growth factor signalling is important for target entry. These new findings raise the compelling idea that growth factors play an active role in axon navigation.     

Microbial metabolism of quorum-sensing molecules acyl-homoserine lactones, γ-heptalactone and other lactones

The cell-to-cell communication of microorganisms is known to be via exertion of certain chemical compounds (signal molecules) and is referred to as quorum sensing (QS). QS phenomenon is widespread in microbial communities. Several Gram-positive and Gram-negative bacteria and fungi use lactone-containing compounds (e.g. acyl-homoserine lactones (AHLs), γ-heptalactone, butyrolactone-I) as signalling molecules. The ability of microorganisms to metabolise these compounds and the mechanisms they employ for this purpose are not clearly understood. Many studies, however, have focused on identifying AHL and other lactone-degrading enzymes produced by bacteria and fungi. Various strains that are able to utilise these signalling molecules as carbon and energy sources have also been isolated. In addition, several reports have provided evidence on the involvement of lactones and lactone-degrading enzymes in numerous biological functions. These studies, although focused on processes other than metabolism of lactone signalling molecules, still provide insights into further understanding of the mechanisms employed by various microorganisms to metabolise the QS compounds. In this review, we consider conceivable microbial strategies to metabolise AHL and other lactone-containing signalling molecules such as γ-heptalactones.     

Structural and mechanical functions of integrins

Integrins are ubiquitously expressed cell surface receptors that play a critical role in regulating the interaction between a cell and its microenvironment to control cell fate. These molecules are regulated either via their expression on the cell surface or through a unique bidirectional signalling mechanism. However, integrins are just the tip of the adhesome iceberg, initiating the assembly of a large range of adaptor and signalling proteins that mediate the structural and signalling functions of integrin. In this review, we summarise the structure of integrins and mechanisms by which integrin activation is controlled. The different adhesion structures formed by integrins are discussed, as well as the mechanical and structural roles integrins play during cell migration. As the function of integrin signalling can be quite varied based on cell type and context, an in depth understanding of these processes will aid our understanding of aberrant adhesion and migration, which is often associated with human pathologies such as cancer.     

Signalling via plasmodesmata—the neglected pathway

This review considers recent studies on the role of plasmodesmata in the conduction of small solutes and signalling molecules between plant cells. The substructure of plasmodesmata is described in relation to the potential pathways available for symplastic signalling between cells. At least two discrete pathways are available for transport through plasmodesmata, the cytoplasmic sleeve between the desmotubule and the plasmalemma, and the endoplasmic reticulum which connects contiguous cells via the central desmotubule. This latter pathway has been shown recently to function as a dynamic continuum for the movement of lipids and lipid-signalling molecules between plant cells. The role of plasmodesmata in the conduction of hormones and electrical signals is also considered, as is the potential for movement of macromolecular signalling molecules via the symplast. The factors which regulate plasmodesmatal conductance and the significance of symplast 'domains' are discussed in relation to the control of movement of signalling molecules in the symplast.     

Principal signalling complexes in haematopoiesis: structural aspects and mimetic discovery

Blood production is a highly regulated process involving multiple inhibitory and stimulatory cytokines present in the haematopoietic stem cell niche. Small molecules mimics of these signalling molecules have substantial potential as drugs and in the development of bioreactors to generate blood products. We review the structural biology of the extracellular signalling domains of five of the most important cytokines, analyze their structure-property relationships, and summarize the progress in developing small molecule mimics using the molecular information from structural biology and mutation studies.     

Flavonoids: antioxidants or signalling molecules?

Many studies are accumulating that report the neuroprotective, cardioprotective, and chemopreventive actions of dietary flavonoids. While there has been a major focus on the antioxidant properties, there is an emerging view that flavonoids, and their in vivo metabolites, do not act as conventional hydrogen-donating antioxidants but may exert modulatory actions in cells through actions at protein kinase and lipid kinase signalling pathways. Flavonoids, and more recently their metabolites, have been reported to act at phosphoinositide 3-kinase (PI 3-kinase), Akt/protein kinase B (Akt/PKB), tyrosine kinases, protein kinase C (PKC), and mitogen activated protein kinase (MAP kinase) signalling cascades. Inhibitory or stimulatory actions at these pathways are likely to affect cellular function profoundly by altering the phosphorylation state of target molecules and by modulating gene expression. A clear understanding of the mechanisms of action of flavonoids, either as antioxidants or modulators of cell signalling, and the influence of their metabolism on these properties are key to the evaluation of these potent biomolecules as anticancer agents, cardioprotectants, and inhibitors of neurodegeneration     

Synthetic glycolipid-based TLR4 antagonists negatively regulate TRIF-dependent TLR4 signalling in human macrophages

TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases.