Research articles

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.

Cell polarity is important for the function of many animal cells, and several aspects of its establishment are conserved across species, from worm to human. Ahringer and colleagues have performed large-scale genetic interaction screens in Caenorhabditis elegans to identify a network of polarity regulators that includes genes not previously associated with polarity, such as the nuclear pore protein NPP-2.

The amount of the BubR1 checkpoint protein declines with age in mouse models, suggesting that it has a role in ageing. Van Deursen and colleagues reveal that expressing a BubR1 transgene in mice reduces tumorigenesis and aneuploidy, and delays ageing-related phenotypes.

Clark and colleagues have characterized the stages during which global epigenetic reprogramming occurs in human primordial germ cells, and delineate the appearance of these changes at 16 days of differentiation.

The Cdc2 (also called Cdk1) kinase is first activated at the centrosome to initiate mitosis in human cells. Hagan and colleagues demonstrate that in fission yeast, Cdc2 and Polo kinase activation at the spindle pole body remotely controls not only mitotic commitment but also ‘new end take off’, the initiation of bipolar growth in G2.

To segregate chromosomes, spindle microtubules must attach to chromosomes through kinetochores, in a process involving several types of microtubule behaviour. Tolic-Norrelykke and colleagues find that fission yeast microtubules rapidly rotate around the spindle poles, and mathematical modelling confirms that this random microtubule movement facilitates kinetochore capture.

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.

Patterning of Drosophila embryos involves the localization of RNAs to specific places in the oocytes before fertilization. Although both gurken (grk) and bicoid (bcd) mRNA localize to the dorsoanterior of the oocyte, only grk mRNA is translated at this stage. Davis and colleagues find that grk mRNA co-localizes with proteins involved in translation at the periphery of P bodies whereas bcd is enriched into their central region—which the authors show is devoid of ribosomes—where it is translationally repressed.

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.

The mitochondrial calcium uniporter (MCU) mediates calcium uptake by mitochondria and thus regulates cellular bioenergetics, but how MCU activity is modulated is not fully understood. Madesh, Foskett and colleagues report that the integral mitochondrial membrane protein MCUR1 (mitochondrial calcium uniporter regulator 1) binds to the MCU and promotes MCU-dependent calcium uptake to control ATP production and autophagy.

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.

Brown adipose tissue generates heat on exposure to cold temperatures. Stoffel and colleagues identify a cold-regulated pathway that increases levels of the transcriptional regulator Prdm16 to promote brown adipogenesis.

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.