Reviews & Analysis

Our increasingly sophisticated understanding of the molecular mechanisms of cell signalling networks in eukaryotes has revealed a remarkably modular organization. Synthetic biologists are exploring how this can be exploited to engineer cells with novel signalling behaviours that are useful in medicine and biotechnology.

Microscopic approaches that image protein mobility and reactivity have been integral in understanding the spatial organization of signalling molecules. Data from imaging studies, combined with computational and theoretical models, have given us great insight into how cells process information to elicit morphological changes.

Signalling networks regulate the biology of cells and organisms in normal and disease states. Large-scale 'precision proteomics' based on mass spectrometry now enables the system-wide characterization of signalling events, including the quantitative changes of thousands of proteins and their post-translational modifications, in response to any perturbation.

Complex organisms rely on a fairly small number of signalling pathways to regulate all of their responses to developmental and environmental cues. Traditionally, it has been assumed that signalling pathways are linear, but, as exemplified by the Wnt and Hippo pathways, they are now known to achieve considerable levels of diversity and selectivity through extensive integration and crosstalk.

Current descriptions of eukaryotic chemotaxis focus on how extracellular signals (chemoattractants) cause new pseudopods to form. However, reinterpretation of recent data suggests a 'pseudopod-centred' explanation, whereby most pseudopods form without exogenous signals and chemoattractants only bias the position and rate of pseudopod growth.

Leukocytes use different strategies to migrate through the endothelium of venular walls and in interstitial tissues. These strategies are regulated by soluble and cell-bound signals. Studies have identified many of the cellular and subcellular events that govern transendothelial migration and are beginning to elucidate the nature of leukocyte interstitial motility.

The link between cytoskeletal actin dynamics and correlated gene activities was unclear. However, the discovery that globular actin polymerization liberates myocardin family transcriptional cofactors to induce serum response factor, which modulates the expression of genes encoding effectors of actin dynamics, has helped bridge this gap in our knowledge.

Non-random positioning of chromosomal domains in the nucleus is a common feature of eukaryotic genomes and has been linked to transcriptional activity, DNA repair, recombination and stability. Nuclear pores and other integral membrane protein complexes are key players in the dynamic organization of the genome in the nucleus.

GW182 proteins are key components of microRNA silencing complexes in animals, although their precise molecular function has been poorly understood. Recent findings indicate that they promote gene silencing by interfering with cytoplasmic poly(A)-binding protein 1 (PABPC1) function during translation and mRNA stabilization — a mode of action similar to that of PABP-interacting protein 2 (PAIP2).

Phosphoinositide 3-kinases (PI3Ks), of which there are eight isoforms, function early in intracellular signal transduction pathways and affect many biological functions. Understanding how these isoforms are differentially regulated and how they control signalling might provide new insight into their roles in disease.

The ERMs (ezrin, moesin and radixin) are key organizers of membrane domains because they can interact with transmembrane proteins and the cytoskeleton. Recent studies have provided insights into the regulation of ERMs and theirin vivoroles in development, immune responses and disease.

Integrin activation comprises initial and intermediate signalling events and, finally, the interaction of integrins with cytoplasmic regulators such as talins and kindlins, which changes an integrin's affinity for its ligands. Targeting of these final, integrin-specific, activation events enables integrin-focused therapeutic strategies.

Neurodegenerative diseases are associated with the accumulation of intracellular or extracellular protein aggregates that form because of protein misfolding. These aggregates are capable of crossing cellular membranes and can thereby directly contribute to the propagation of neurodegenerative disease pathogenesis, which might spread in a 'prion-like' manner.

The coordinated organization of membrane receptors into diverse micrometre-scale spatial patterns is emerging as an important theme of intercellular signalling, as exemplified by immunological synapses. New experimental strategies have emerged to manipulate the spatial organization of molecules inside living cells.

The actin cytoskeleton has key roles in many dynamic cellular processes, such as cell movement, cell division and membrane dynamics. The discovery of mammalian proteins that regulate actin nucleation and dynamics has expanded our views on how the actin cytoskeleton influences cellular functions.

Signalling pathways are ideal candidates for microRNA-mediated regulation owing to the sharp dose-sensitive nature of their effects. Emerging evidence suggests that microRNAs affect the responsiveness of cells to various growth factors, serving as nodes of signalling networks that ensure homeostasis and regulate disease.

Histone core particles are spools for wrapping DNA, whereas histone variants have evolved diverse additional roles in chromosome metabolism. Some variants mediate universal functions, such as chromosome segregation and DNA repair, and others specialize in organism-specific tasks.

During DNA replication, secondary structures, highly transcribed DNA sequences and damaged DNA stall replication forks, which then require checkpoint factors and specialized enzymes for their stabilization and subsequent advance. The mechanisms promoting replication fork integrity and genome stability in eukaryotic cells are becoming clear.

Several human neurological and neuromuscular diseases are caused by the expansion of repetitive DNA tracts. Understanding the DNA metabolic processes responsible for the expansion (or lengthening) and contraction (or shortening) of DNA repeats might open new therapeutic avenues for the treatment of these diseases.

Genomic instability in hereditary cancers results from mutations in DNA repair genes, as predicted by the mutator hypothesis. However, high-throughput sequencing studies show that mutations in DNA repair genes are infrequent in non-hereditary cancers, leaving open the possibility that genomic instability in these cancers may be related to oncogene-induced DNA damage.