Research articles

The signalling pathway by which ER damage triggers apoptosis remains unclear. Oakes and colleagues identify CT10-regulated kinase (CRK) as a pro-apoptotic protein induced by ER stress. Such stress leads to the accumulation of cleaved CRK fragments at mitochondria, sensitizing them to cytochrome c release in a cell-free system.

Wnt signalling regulates development and differentiation through both canonical and non-canonical pathways. Rudnicki and colleagues find that Wnt7a–Fzd7 activates Gα_s to promote Akt/mTOR pathway activation, and show that this non-canonical Wnt signalling pathway elicits myofibre hypertrophy in vivo.

Peterson and colleagues find that the B9 complex localizes to the base of the primary cilia, where it functions as a ciliary diffusion barrier. Mutations in some B9 components are linked to human ciliopathies. The authors show that depleting components of the complex impairs primary cilia formation and inhibits the proper localization and function of signalling receptors in the cilia.

Bastiaens and colleagues find that PDEδ can solubilize Ras family small GTPases, resulting in their release from cellular membranes. This concentrates Ras proteins at specific subcellular locations, which promotes their eventual association with the plasma membrane and potentiates Ras-mediated signal transduction.

Ostrowski and colleagues identify a tumour-suppressive pathway in the tumour stroma. They show that PTEN loss in stromal fibroblasts downregulates miR-320, leading to the upregulation of the ETS2 transcription factor and the induction of a secretome that promotes tumour growth, invasion and angiogenesis.

Jürgens and colleagues show that the ARF GEFs GNOM and GNL2 have essential roles in polarized cell growth of root hairs and pollen, respectively. Their findings support an important function for endosomal recycling, rather than polarized secretion, in the targeted delivery of proteins necessary for polar tip growth.

Unrestrained Src signalling can be toxic for cancer cells. Wilkinson, Frame and colleagues show that active Src is sequestered in autophagosomes in cancer cells. Inhibition of autophagy induces cancer cell death.

p53 activates Puma-dependent apoptosis and p21-mediated cell-cycle arrest in response to DNA damage. Rudolph and colleagues show that stem-cell functionality in telomerase-deficient mice is improved by the deletion of Puma. Unexpectedly, the accumulation of progenitor cells with damaged short-telomere DNA is not seen in telomerase- and Puma-deficient animals, as p21-mediated cell-cycle arrest is activated to limit the expansion of these cells.

Improperly folded proteins are targeted for destruction through the endoplasmic-reticulum-associated degradation pathway (ERAD). Kopito and colleagues present a high-resolution interaction analysis of the ERAD system in combination with functional genomics, and identify new ERAD components.

Three-colour single-molecule fluorescent in situ hybridization is used by van Oudenaarden and colleagues to show overlapping expression of intestinal stem-cell markers during homeostasis, ageing and regeneration. This approach can help identify putative stem cells in tissues and tumours, and can guide functional studies.

The transcriptional role of c-Myc in maintaining tissue homeostasis is still unclear. Using mice conditionally expressing an activated form of c-Myc in the epidermis, and genome-wide approaches, Frye and colleagues show that c-Myc modulates the expression of the epidermal differentiation complex locus in the skin by displacing or recruiting specific transcriptional regulators. c-Myc activity is negatively regulated in vivo in this context by Sin3a.

Bershadsky and colleagues show that fibroblast polarization depends on matrix rigidity and focal adhesion mechanosensing. They target protein tyrosine kinases through RNAi to identify signalling molecules that regulate traction force generation, focal adhesion assembly and mechanosensitivity.

Chromosomal microtubules participate in formation of kinetochore fibres by attaching their plus ends at kinetochores and focusing their minus ends at the spindle poles. Vernos and colleagues show that the centrosome-localized protein MCRS1 accumulates to chromosomal microtubule minus ends in a RanGTP-dependent manner to prevent microtubule depolymerization and to promote kinetochore-fibre stability and spindle assembly.

Wallerian degeneration occurs in axons following cutting or crush injuries; however, the molecular mechanisms that regulate this process remain elusive. Araki and colleagues find that the ubiquitin ligase ZNRF1 promotes Wallerian degeneration by ubiquitylating AKT, which leads to increased GSK3B activity and subsequent inhibition of the tubulin-binding protein CRMP2.

Caspase 8 is known to suppress necroptosis, but its relevant target protein was unknown. Ting and colleagues show that caspase 8 cleaves the deubiquitylase CYLD to inhibit necroptosis and promote cell survival.

Somatic reprogramming efficiency by expression of defined transcription factors can be enhanced by deletion of p53. He and colleagues found that the microRNA miR-34, which is induced by p53 during reprogramming, inhibits reprogramming, partly by direct repression of pluripotency factors. Deletion of Mir34 from mice increases reprogramming efficiency and kinetics without affecting self-renewal and differentiation.

The MYC proto-oncogene modulates transcription through binding to E-boxes. Di Croce and colleagues find that PAK-2-mediated phosphorylation confers a tumour-suppressive function to MYC, in which MYC cooperates with differentiation signals to positively modulate the transcription of genes targeted by retinoic acid, independently of E-boxes.

Aragón and colleagues show that the phosphatase Cdc14 acts on the CDT subunit of RNA polymerase II to silence transcription of repetitive regions of the yeast genome. At telomeres this event promotes condensin loading and mitotic segregation.

The p97 AAA+ ATPase (also known as VCP) functions in various ubiquitin-regulated processes. Ramadan and colleagues now find that p97 is recruited to sites of DNA damage by Lys-48-linked ubiquitin chains, which are formed in a process mediated by RNF8. p97 then removes Lys-48–ubiquitin conjugates and promotes recruitment of DNA-repair factors.

An epithelial cell can be engulfed by its neighbour through entosis, which frequently results in the death of the entosed cell. Overholtzer and colleagues show that the autophagy machinery is recruited to single-membrane entotic vacuoles and promotes their fusion with lysosomes. Single-membrane macrophage phagosomes containing apoptotic cells are also targeted for destruction by the autophagy pathway.