News & Views in 2011

Autophagy can promote both cancer cell survival and death, and the mechanisms by which it mediates these disparate processes are under intense investigation. Autophagosomes are now shown to entrap and promote degradation of the active tyrosine kinase Src, enabling tumour cell survival. The E3 ubiquitin ligase c-Cbl acts as an autophagosome cargo receptor for Src.

The endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway, which orchestrates the degradation of ER proteins by the proteasome, involves a plethora of proteins with diverse functions. Using a combination of proteomic and genetic approaches, a recent study provides fresh insights into the organization of the mammalian ERAD interaction network and the functions of its components.

To establish and maintain their internal organization, living cells must move molecules to their correct locations. Long-range intracellular movements are often driven by motor molecules moving along microtubules, similarly to trucks driving along a highway. Recent work demonstrates that some randomly dispersed cargos can generate actin filaments that form a connected network whose contraction drives collective cargo movement.

The establishment and maintenance of cell polarity requires targeted recruitment of polarity regulators to the plasma membrane. Phosphatidylserine is now shown to have a key role in polarization of yeast cells and the localization of the central polarity regulator Cdc42.

In mitotic spindles, each sister chromatid is directly attached to a spindle pole through microtubule bundles known as kinetochore fibres. Microspherule protein 1 (MCRS1) is now shown to support spindle assembly by localizing to the minus ends of kinetochore fibres and protecting them from depolymerization.

The activity state of integrins is crucial for cell adhesion, migration and differentiation, and is regulated predominantly by protein interactions of the integrin β cytoplasmic domain. SHARPIN is now shown to negatively regulate integrin activation by binding the α-integrin subunit and interfering with the association of the β cytodomain with activating proteins.

Misfolded proteins are potentially toxic and are therefore subjected to highly selective degradation by the ubiquitin–proteasome system. The identification of the Hul5 ubiquitin ligase as a major mediator of such 'quality-control' ubiquitylation following heat shock raises new questions about the design of these pathways.

Successful completion of meiosis in vertebrate oocytes requires the localization and maintenance of the meiotic spindle at the cell cortex. Arp2/3-nucleated actin filaments are now shown to flow away from the cortex overlying the spindle, resulting in cytoplasmic streaming, which maintains the spindle in its asymmetric position.

A potential role for glycosphingolipids and lipid rafts in apical sorting was initially met with enthusiasm, but genetic analysis has since provided little support for it. A report now establishes that glycosphingolipids mediate apical sorting, and specifically help maintain apicobasal polarity in Caenorhabditis elegans.

A precise role for the canonical Wnt pathway in maintaining pluripotency in mouse embryonic stem cells (mESCs) has been debated. Four recent reports add pieces to the puzzle and together these results may help establish a robust model.

The mitochondrial network fragments during mitosis to allow proper segregation of the organelles between daughter cells. Two mitotic kinases, the cyclin B–CDK1 complex and Aurora A, are now shown to cooperate with the small G protein RALA and its effector RALBP1 to promote DRP1 phosphorylation and mitochondrial fission.

How the unique chromatin configuration of embryonic stem cells (ESCs) integrates inputs from exogenous stimuli to maintain pluripotency remains largely unknown. The ESC-specific ATP-dependent chromatin-remodelling (esBAF) complex maintains the accessibility of the target sites of Stat3, a leukaemia inhibitory factor (LIF) signalling effector, by preventing repressive localized polycomb-mediated trimethylation of Lys 27 of histone 3 (H3K27me3).

Regulatory mechanisms to prevent centriole overduplication during the cell cycle are not completely understood. In this issue, FBXW5 is shown to control the degradation of the centriole assembly factor HsSAS-6. Moreover, the study proposes that FBXW5 is a substrate of both PLK4 and APC/C, two established regulators of centriole duplication.

The retromer complex coordinates retrograde transport of cargo proteins between endosomes and the trans-Golgi network. The sorting nexin SNX3 is required for the retrograde trafficking of Wntless, but not of other retrograde cargo proteins, revealing that the cargo specificity of retromer is provided by the sorting nexins.

Both symmetric and asymmetric divisions rely on alignment of the mitotic spindle with cues from the environment. A study now shows that mitotic spindles find their position by reading the map of forces that load-bearing retraction fibres exert on the cell body.

Microtubule-depolymerizing motor proteins regulate microtubule dynamics during chromosome segregation, but whether they can independently grip the ends of shrinking kinetochore microtubules has remained unresolved. MCAK, a member of the kinesin-13 motor protein family, is now shown to grip microtubules on its own and harness the forces of microtubule disassembly.

The primary cilium is proposed to restrain the level of canonical Wnt signalling, but it was unknown how the cilium achieves this. β-catenin, a component of the canonical Wnt signalling pathway, is now shown to be sequestered to the cilium by the Wnt signalling modulator Jouberin (Jbn) to restrain Wnt responses.

Aurora A kinase is a key regulator of cell division, whose functions were attributed to its ability to phosphorylate diverse substrates. Aurora A is now shown to have a kinase-independent role in the regulation of chromatin-mediated microtubule assembly.

Starvation of animals or cells triggers autophagic degradation of cell contents to retrieve nutrients, but, paradoxically, mitochondria enlarge. This is now shown to result from inhibition of mitochondrial fission through PKA-mediated phosphorylation of the GTPase DRP1. Elongation of mitochondria optimizes ATP production and spares them from autophagy-mediated destruction.

Induced pluripotent stem (iPS) cells offer the possibility to generate patient-specific cell types for use in regenerative medicine. However, a long-lasting question remains: are iPS and embryonic stem cells equivalent? iPS cells retain a transcriptional memory of their origin, which is now shown to endure with passages and to correlate with defects in the re-establishment of DNA methylation. Both selective pressure and genomic environment may account for these defects.