Articles in 2012

ER tubules grow and fuse to give the ER its characteristic shape. English and Voeltz show that the small GTPase Rab10 is crucial for ER tubule growth and fusion. Rab10 localizes to the leading edge of new ER tubules with enzymes that promote phospholipid synthesis, suggesting that ER tubule growth, fusion and phospholipid synthesis might be coupled.

The mTORC1 complex promotes protein translation and cell growth, whereas mTORC2 promotes survival. The Tel2 and Tt1 proteins belong to both complexes. Bassermann and colleagues demonstrate that following growth-factor deprivation, casein kinase 2 mediates phosphorylation of Tel2 and Tt1, specifically in the mTORC1 complex, to target them for degradation by the SCF^Fbxo9 ubiquitin ligase. This mechanism inactivates mTORC1 and activates mTORC2 and Akt signalling to promote survival of multiple myeloma cells.

Muthuswamy and colleagues demonstrated that loss of the Par3 polarity protein cooperates with ErbB2 activity to promote cell invasion and metastasis by destabilizing E-cadherin-dependent cell–cell junctions.

Mammary gland morphogenesis involves the polarization of epithelial cells and the formation of a lumen. Akhtar and Streuli demonstrate that β₁ integrin and the downstream kinase ILK at the basement membrane are required for polarization in this system, through orientation of microtubules and Golgi positioning.

Robinson and colleagues perform a human-genome-wide siRNA screen to identify regulators of clathrin-coated vesicle formation. The knockdown phenotype of one of their hits, V-ATPase, is rescued by exogenous cholesterol, revealing an intriguing link between cholesterol and clathrin-coated vesicle formation.

An intriguing intersection between the AMPK and Hippo signalling pathways provides fresh insight into how nutrient availability regulates cell growth. Tapon and colleagues show that Drosophila salt-inducible kinases (Sik2/3), members of the AMPK family, phosphorylate the Hippo pathway protein Sav to attenuate Hippo signalling and promote Yki transcriptional activity.

Accurate chromosome segregation requires that sister-chromatid cohesion is resolved first at chromosome arms in prophase and then at centromeres in metaphase. In prophase, centromeric cohesion is protected by shugoshin and protein phosphase 2A (SGO1–PP2A). Yu and colleagues show that CDK1-mediated phosphorylation of SGO1 promotes SGO1–PP2A binding to cohesin, and dephosphorylation of the cohesion-promoting component sororin to prevent cohesin removal.

The Wnt/planar cell polarity (Wnt/PCP) pathway orients cell division in various developmental contexts including zebrafish gastrulation. Gonzalez-Gaitan and colleagues reveal that, downstream of Wnt/PCP, the anthrax toxin receptor 2a interacts with actin to form a cortical actin cap in dorsal epiblast cells, and acts through RhoA and the formin zDia2 to orient the mitotic spindle.

Lu and colleagues delineate a pathway through which the PKM2 enzyme promotes aerobic glycolysis, known as the Warburg effect, in cancer cells. They show that EGFR-activated ERK phosphorylates PKM2, leading to its accumulation in the nucleus. Nuclear PKM2 subsequently promotes the c-Myc-dependent upregulation of genes involved in the Warburg effect, resulting in tumour growth.

Blanpain and colleagues use mouse models of activated Hedgehog signalling to analyse the temporal gene expression changes involved in basal cell carcinoma initiation. They show that tumour initiation involves activation of the Wnt pathway and reprogramming of the adult interfollicular epidermis tumour-initiating cells into a cell fate resembling that of embryonic hair follicle progenitor cells.

Both telomerase activity and NF-κB-driven inflammation occur in tumours, and NF-κB is known to upregulate telomerase levels. Tergaonkar and colleagues now find evidence for a reciprocal direct regulation of NF-κB-dependent gene transcription by telomerase, through an interaction between telomerase and the NF-κB p65 subunit.

Rinkevich, Weissman and colleagues show that mesothelin-expressing cells from the mesothelium, an epithelial monolayer covering vertebrate cavities and internal organs, generate the fibroblasts and smooth muscle cells (FSMCs) essential for the development of internal organs. Using a genetic lineage tracing approach, they find that these cells participate in generating FSMCs and vasculature, with minimal contributions from neural crest or circulating cells.

The peripheral actin cortex in cells is essential for secretory vesicle exocytosis, but also acts as a barrier for vesicle release. Wollman and Meyer report that antigen activation triggers cyclical waves of Ca²⁺ and PtdIns(4,5)P₂ that promote N-WASP-mediated oscillations in F-actin polymerization. These permit secretion when F-actin levels are low, but impede exocytosis when F-actin levels are high.

Malliri and colleagues demonstrate that an apicobasal Rac activity gradient at cell–cell junctions is important for tight-junction assembly and establishment of apicobasal polarity. They show that this gradient is generated by the distinct spatial regulation of the Rac activator Tiam1 by β2-syntrophin and Par-3.

Lemischka and colleagues examine the effects of transient Nanog downregulation on the components of the pluripotent transcriptional regulatory network using single-cell gene expression analysis and modelling approaches. They observe that the initial changes induced by loss of Nanog are stochastic and reversible upon Nanog restoration, owing to the presence of feedback loops in the pluripotency network. Prolonged loss of Nanog compromises these feedback loops and reversion to pluripotency cannot be achieved upon Nanog restoration.

Centrosomes, the microtubule nucleation centre of most cells, consist of two centrioles surrounded by pericentriolar material (PCM). The PCM has been considered as amorphous but, using subdiffraction fluorescence microscopy approaches, Agard and colleagues now reveal the organized structure of the PCM of Drosophila centrosomes.

Kang and colleagues show that the transcription factor Elf5 controls the epithelial–mesenchymal transition (EMT) during development and in metastasis, by repressing the expression of Snail2/Slug, a key EMT-inducing factor.

Centrosomes consist of two centrioles surrounded by pericentriolar material (PCM) that nucleates microtubules. The PCM has been considered as amorphous but, using subdiffraction fluorescence imaging, Pelletier and colleagues now reveal the organized structure of human PCM.

In mammals, polyploidy is only seen in liver hepatocytes and in trophoblast giant cells in the placenta. Leone and colleagues now show that ploidy is controlled in an antagonistic fashion by canonical E2F transcriptional activators and atypical E2F7 and E2F8 repressors, through the control of G2/M-associated genes.

Blanpain and colleagues use inducible genetic lineage tracing to identify and follow the progenitors responsible for the development of the prostate glandular epithelium. They find that multipotent progenitors are initially able to differentiate into the three lineages that make up the prostate, with a later switch to distinct pools of unipotent basal and luminal stem cells.