Volume 14 Issue 8, August 2012

Most invasive solid tumours display predominantly collective invasion, in which groups of cells invade the peritumoral stroma while maintaining cell–cell contacts. As the concepts and experimental models for functional analysis of collective cancer cell invasion are rapidly developing, we propose a framework for addressing potential mechanisms, experimental strategies and technical challenges to study this process.

RhoA signalling controls many diverse cellular processes, and thus discovering the mechanisms that determine its specific outcomes is a tantalizing challenge. A previously uncharacterized regulatory module operates selectively at the zonula adherens of epithelial cell junctions, in which positive and negative RhoA regulators are coordinated to fine-tune RhoA activity.

Nutrient deprivation and other stress stimuli elicit metabolic changes (such as the induction of autophagy and activation of FOXO transcription factors) that help an organism adapt to stressful conditions. A link between these stress response pathways is revealed by the finding that FOXO3 upregulates the expression of glutamine synthetase to promote glutamine accumulation, inhibit mTOR signalling and promote autophagy.

The steroid hormones found in plants, the brassinosteroids, were originally genetically identified about 15 years ago as critical regulators of seedling photomorphogenesis. Two studies now shed light on the molecular mechanisms behind this observation. Brassinosteroids control seedling morphogenesis through direct interaction with master transcriptional regulators downstream of growth-promoting hormones and light signalling.

Proliferating cells of the Xenopus laevis retina facultatively use aerobic glycolysis instead of oxidative phosphorylation. This demonstrates that the metabolic rewiring usually associated with the Warburg effect in tumorigenesis may be a more widespread feature of proliferative metabolism than generally appreciated.

Microvilli are essential for the function of intestinal cells. Bos and colleagues have found that the polarity kinase LKB-1 induces PtdIns(4,5)P₂ enrichment at the apical membrane. This leads to the successive accumulation of phosphatidic acid and the small GTPase Rap2A with its GEF and its effectors. These, in turn, trigger the changes in the actin cytoskeleton responsible for microvilli formation.

Wang and colleagues have uncovered a direct functional relationship between the brassinosteroid-activated transcription factor BZR1 and the light- and heat-sensitive transcription factor PIF4. This interplay integrates hormonal and environmental signals to modulate cell elongation during plant growth.

Wang and colleagues show that, in Arabidopsis thaliana, brassinosteroid and light-dependent transcription factors are required for giberellin effects on hypocotyl elongation, by modulating transcription of giberellin-induced genes involved in cell wall synthesis and photosynthesis. Conversely, giberellin relieves the brassinosteroid component BZR1 from inhibition by DELLA proteins.

Yap and colleagues identify an extramitotic role for the centralspindlin complex, a Rho signalling regulator during cytokinesis. They show that centralspindlin interacts with α-catenin, and promotes epithelial junctional integrity by recruiting the ECT2 RhoGEF to the zonula adherens, as well as by inhibiting the junctional localization of the p190 B RhoGAP.

Coffer and colleagues report that the transcription factor FOXO3 regulates the induction of autophagy. In response to PI(3)K–Akt signalling, FOXO3 directly induces expression of glutamine synthase, which upregulates glutamine levels and triggers autophagy.

By performing a screen for genes that regulate epithelial architecture, Martín–Belmonte and colleagues identify key roles for the synaptotagmin-like proteins Slp2-a and Slp4-a in restricting lumen generation. They find that Slp2-a targets Rab27a/b-positive vesicles to PtdIns(4,5)P₂-enriched apical membranes, whereas Slp4-a controls subsequent vesicle tethering and fusion. Their coordinated activities ensure the creation of a single lumen per cell.

Zhang, McNaughton and colleagues show that inflammatory stimuli promote a direct association between the heterotrimeric G-protein subunit Gα_q and the temperature-sensitive ion channel TRPM8. This interaction inhibits TRPM8 channel activity, providing a mechanism by which inflammation produces aberrant sensations of temperature changes.

It is unclear whether proliferating and differentiating cells produce energy through different metabolic pathways. Harris and colleagues show, in the embryonic Xenopus retina, that dividing progenitors use glycogen for glycolysis, and that a transition to oxidative phosphorylation occurs as cells differentiate.

Avidor-Reiss and colleagues show that the nucleotide status of tubulin regulates recruitment of pericentriolar material. Binding of GTP-bound tubulin to the Sas-4 centrosomal protein prevents the Sas-4-dependent formation of centrosomal protein complexes, whereas the Sas-4-stimulated hydrolysis of tubulin–GTP into tubulin–GDP has the opposite effect.

N-BAR-domain-containing proteins regulate membrane dynamics, as they stabilize curved membrane topologies, but whether they primarily sense or generate curvature has remained unclear. Galic, Meyer and colleagues now report that N-BAR proteins accumulate at highly curved membrane areas.

Shakhova, Sommer and colleagues use mouse models to demonstrate that the Sox10 transcription factor is crucial for the formation and maintenance of giant congenital naevi and melanoma. They show, in human melanoma cells, that Sox10 promotes neural crest stem cell properties, cell proliferation and cell survival.