Volume 11 Issue 12, December 2009

MicroRNAs (miRNAs) regulate gene expression in many different organisms and cell types. In mouse embryonic stem cells, a regulatory circuit that involves let-7 and its target mLin41, which encodes an E3 ubiquitin ligase, facilitates polyubiquitylation of the miRNA effector Argonaute 2 (Ago2) and targets it for degradation.

During cell migration, actin retrograde flow is counteracted by integrin-mediated adhesion to the underlying matrix, providing traction for forward movement. But in the absence of this 'clutch' mechanism, some types of cells adapt their actin polymerization to maintain similar migration speeds.

Long-range communication between animal cells can be accomplished through thin tunnelling nanotubes. The generation of these delicate structures involves dynamic remodelling of actin and the plasma membrane. Now, some of the proteins that help to build these intercellular conduits have been identified.

The RME1 ATPases are implicated in endocytic recycling. C. elegans RME1 interacts with Amphiphysin to regulate endocytic recycling in vivo and the two proteins cooperate in the generation of cargo carriers in vitro. The interaction is conserved in other eukaryotes.

Let-7 microRNA (miRNA) and its target gene lin-28 regulate pluripotency. A second Let-7 target, lin-41, controls miRNA function in stem cells by regulating the turnover of the miRNA effector Argonaute2 through its ubiquitin ligase activity.

Drs2, a phospholipid translocase involved in transport from the trans-Golgi network, is shown to be a new effector of PtdIns(4)P (phosphatidylinositol 4-phosphate). Binding to PtdIns(4)P and to the GTPase exchange factor ARF–GEF, a regulator of Golgi transport, stimulates Drs2 activity.

How tunnelling nanotubes form between cells is unclear. A mammalian protein, M-Sec, that has homology to the Sec6 subunit of the exocyst complex, is sufficient and necessary for nanotube formation. The Ral GTPase and its effector, the exocyst complex, are required for M-Sec-dependent regulation of nanotubes.

Autophagy is a bulk degradation process that takes place in specialized membrane structures, the origin of which is still unclear. An electron tomography study shows that the ER is connected to the isolation membranes that initiate autophagosome formation in mammalian cells, suggesting that the ER is the membrane source.

Migrating dendritic cells can adapt their adhesive properties to switch between integrin-dependent and -independent modes of migration. By modulating their actin polymerization dynamics, cells can maintain a steady migration speed through a changing environment.

The Hippo pathway regulates proliferation and survival in Drosophila and mammals, although shared transcriptional targets of their effectors have not been identified. Mammalian YAP controls expression of the EGFR ligand amphiregulin to regulate epithelial-to-mesenchymal transition in mammary epithelial cells, and the EGFR pathway genetically interacts with Yorkie in Drosophila.

TAp63, a splice variant of the p53 homologue p63, suppresses tumorigenesis in p53-null mice by mediating Ras oncogene-induced senescence. TAp63-mediated senescence is independent of p53, but requires p21Waf/Cip1 and Rb. TAp63 overrides Ras-driven transformation, while its loss accelerates Ras oncogenesis.

In differentiating cells, ERK activation shifts from transient to sustained. Quantitative proteomics reveals that, during differentiation, dynamic changes in ERK-interacting proteins regulate the pathway at several levels and by different mechanisms, suggesting a distributed control mechanism for the ERK pathway.

During mitosis, store-operated Ca²⁺ entry (SOCE) is suppressed. Translocation of the ER Ca²⁺ sensor STIM1 to the plasma membrane is critical to SOCE activation, but in mitotic cells STIM1 is phosphorylated and fails to rearrange into near-plasma membrane puncta. Mutation of mitosis-specific phosphorylation sites rescues mitotic SOCE.

Under prolonged ER stress, expression of the unfolded protein response effector CHOP becomes cytotoxic. Toll-like receptor engagement activates TRIF signalling to inhibit the translational activation of the UPR effector ATF4 and thus suppresses CHOP-associated cell death and organ dysfunction in mice.

Yeast mating-type switching requires ubiquitylation of the transcriptional repressor α2. This results in removal of α2 from its DNA targets by the ubiquitin-selective AAA-ATPase Cdc48, thus revealing a nuclear function of Cdc48 and an ubiquitin-dependent extraction pathway for dismantling transcription factor—DNA complexes.

The epithelial-to-mesenchymal transition transcription factor ZEB1 is involved in metastasis. It is now shown to regulate the tumour-initiating capacity of pancreatic and colorectal cancer cells, through the repression of the stemness-inhibiting miR200s, which are found to inhibit the polycomb repressor Bmi-1.