Review Articles in 2010

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.

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.

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.

Homologous recombination maintains genome stability in mammalian mitotic cells through precise repair of DNA double-strand breaks and other lesions that occur during normal cellular metabolism and through exogenous insults. Deficiencies in genes that encode proteins involved in homologous recombination are associated with developmental abnormalities and tumorigenesis.

Genomic architecture can be markedly affected during meiosis by non-allelic homologous recombination (NAHR), which generates chromosomal rearrangements that can lead to genome instability. Studies in yeast have provided insights into the mechanisms of NAHR and the strategies used to restrain it.

An unstable genome is a hallmark of many cancer cells. Telomeres prevent the ends of linear chromosomes from being recognized as damaged DNA, thus protecting them from DNA repair mechanisms and inhibiting the breakage–fusion–bridge cycles that cause genome instability.

The swinging lever arm model of myosin movement was challenged by myosin VI, which takes larger steps along actin filaments than its structure seems to allow. Myosin VI achieves this by using a 180° lever arm swing and special structural features in its tail.

The protein kinase C (PKC) family has been increasingly implicated in the organization of signal propagation, particularly in the spatial distribution of signals. Examples of where and how various PKC isoforms direct this tier of signal organization are becoming more evident.

Protein synthesis is regulated at the initiation stage. Determining the structures and activities of initiation factors, and mapping their interactions in ribosomal initiation complexes, has advanced our understanding of translation initiation and provided a foundation for studying its regulation.

During mitosis, cells distribute their genetic material to two daughter cells. The attachment of chromosomes to the spindle, and their ensuing congression to the spindle equator, are emerging as the most important aspects for maintaining genomic fidelity during mitosis.

Primordial germ cells (PGCs) arise far from the somatic cells of the developing gonad and have to migrate across the embryo to reach their site of function. Studies of different model organisms reveal that, despite important differences, several features of PGC migration are conserved.

Urokinase-type plasminogen activator receptor (uPAR) regulates extracellular matrix (ECM) proteolysis by binding the extracellular protease uPA and also activates many intracellular signalling pathways. Coordination of ECM proteolysis and intracellular cell signalling by uPAR is important for cell migration, proliferation and survival.

The AGC kinase subfamily of protein kinases contains 60 members, including PKA, PKG and PKC. Research has shed light onto the architecture and regulatory mechanisms of these kinases, which mediate important cellular functions and are dysregulated in many human diseases.