Articles in 2012

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.

The endoplasmic reticulum (ER) forms an intricate network of interconnected tubules. Sey1 is known to govern tubule formation, but the proteins that counteract tubule fusion remained unclear. Chen, Novick and Ferro-Novick propose that Lnp1 antagonizes the activity of Sey1 to modulate ER network formation.

Li and colleagues report that c-Abl regulates the responses downstream of bone morphogenetic protein (BMP) that direct proliferation or senescence in osteoblasts. They show that phosphorylation of the BMP receptor BMPR1A by c-Abl promotes downstream Smad-mediated responses and osteoblast expansion, whereas in the absence of c-Abl, BMP activates Erk signalling, leading to p16^INK4a-induced senescence.

Ten Dijke and colleagues identify USP4 as a deubiquitylating enzyme (DUB) for the TGF-β receptor I in a screen for ubiquitin-specific proteases affecting TGF-β signalling. USP4, present in a complex with other DUBs, is regulated by AKT-mediated phosphorylation and is required for TGF-β-induced breast cancer cell migration and metastasis.

Reik and colleagues show that deletion of the large intergenic non-coding RNA H19 leads to unlimited placenta growth. They find that the H19 RNA contains a microRNA that targets the insulin-like growth factor receptor IGF-1R, and demonstrate that the RNA-binding protein HuR prevents miR-675 excision from H19 until miR-675 activity is required to halt placenta growth.

Ciliogenesis requires the removal of CP110 from the mother centriole, and is influenced by actin dynamics. Zhu and colleagues now show that the microRNA miR-129-3p controls primary cilia formation in vertebrates by downregulating CP110 and targeting multiple actin regulators to suppress actin dynamics.

Exosomes are increasingly recognized as key intermediaries of intercellular communication, yet the mechanisms governing their biogenesis remain unclear. Zimmermann, David and colleagues report that interactions between the transmembrane protein syndecan, its associated protein syntenin and the ESCRT adaptor ALIX are necessary for exosome formation, supporting a role for the ESCRT machinery in this process.

RAB-11-positive recycling endosomes participate in the establishment and maintenance of epithelial polarity. Zerial and colleagues carry out an in vivo image-based RNAi screen for factors that regulate recycling endosome positioning in Caenorhabditis elegans. They identify, among other candidates, PAR-5 as a key determinant of recycling endosome positioning and, thus, apicobasal polarity.

Wu and colleagues delineate an mTORC2-dependent cell migration pathway. They show that stimulation of the Gα₁₂ protein subunit induces the ARAF/ERK-mediated expression of the RFFL E3 ubiquitin ligase. RFFL, in turn, targets the inhibitory PRR5L subunit of the mTORC2 complex for ubiquitylation and degradation, enabling mTORC2 to phosphorylate PKC-δ and promote cell migration.

Radisky and colleagues show that, in contrast to its pro-tumorigenic properties, the MYC oncogene is also able to inhibit metastasis by suppressing cell migration and invasiveness. Mechanistically, they show that MYC transcriptionally represses the integrin αv and β3 subunits, which are needed for efficient cell motility and invasion.

The replication origin licensing factor Cdt1 is now demonstrated to function at the kinetochore in mitosis. Cook, Salmon and colleagues show that Cdt1 binds to the loop domain of Hec1 in the Ndc80 kinetochore complex and stabilizes kinetochore–microtubule attachment.

Multi-protein kinetochore complexes bind to the centromeric region of chromosomes to ensure accurate spindle attachment and chromosome segregation, although centromere organization differs widely between species. Westermann and colleagues now identify the budding yeast protein Cnn1 as the orthologue of mammalian CENP-T. They show that it binds to the Ndc80 kinetochore complex and functions in chromosome segregation, illustrating a conserved role for this protein.

The kinetochore is a multiprotein complex that tethers chromosomes to the mitotic spindle for accurate chromosome segregation. De Wulf and colleagues now show in budding yeast that the protein Cnn1 functions at the kinetochore and is recruited to the inner kinetochore, in a manner dependent on its phosphorylation mediated by the Cdc28, Mps1 and Ipl1 kinases.

Mak and colleagues report that TRADD, an adaptor protein important in tumour necrosis factor receptor (TNFR) signalling, contributes to tumour suppression independently of TNFR. They show that nuclear TRADD binds to the tumour suppressor p19^Arf and inhibits its interaction with the E3 ubiquitin ligase ULF, leading to p19^Arf stability and promoting cell senescence.

Integrin internalization through the endosomal pathway can lead either to recycling back to the surface or to lysosomal degradation. Faessler and colleagues now show that, following internalization, β1 integrins are bound by sorting nexin 17 in early endosomes to prevent integrin degradation in lysosomes and to promote surface recycling.

MCL-1 is an anti-apoptotic BCL-2 family member and is frequently upregulated in cancer, but the mechanism by which it promotes cell survival has been elusive. Opferman and colleagues provide insight into this process by showing that MCL-1 exists in different forms with discrete localizations and functions. MCL-1 variants targeted to the outer mitochondrial membrane antagonize BAX and BAK activation, whereas an N-terminally truncated isoform localizes to the mitochondrial matrix and regulates mitochondrial metabolism.

Iavarone, Lasorella and colleagues develop genetic mouse models to study the roles of inhibitor of DNA-binding (Id) proteins in neural stem-cell maintenance. They show that Id proteins promote neural stem-cell adhesion to their niche by driving the transcriptional repression of Rap1GAP, thereby maintaining the activity of the Rap1 GTPase, a known regulator of integrin adhesion.

Transcription-factor-directed reprogramming of somatic cells is inefficient but can be enhanced by the addition of enzymes that modulate chromatin modifications. Zhang and colleagues report that the Kdm2b H3K36me2 demethylase promotes reprogramming through its enzymatic activity and independently of its role in senescence, by enhancing the transcription of genes known to be activated early during the process, including cadherin.

Schweisguth and colleagues have uncovered a Notch-independent role for the E3 ubiquitin ligase Neuralized that entails disrupting existing epithelial polarity and cell junctions to allow cell movements that are critical during Drosophila development. They show that Neuralized’s effect on polarity is normally antagonized by Bearded, which is a known target of the Snail repressor, a transcription factor involved in polarity regulation at gastrulation. Targets for Snail that are relevant in this process have, until now, been elusive.

Repair of double-strand breaks (DSBs) by homologous recombination is thought to involve the movement of damaged chromosomes to facilitate pairing of homologues. Rothstein and colleagues have now followed the movement of damaged loci in diploid yeast by time-lapse microscopy, revealing the dynamics of damage-induced movement and the requirement for repair proteins in this process.