The latest issue of the JCB is out today. You can find the table of contents here, but here's a quick rundown of some of the issue's highlights...
Attachments between kinetochores and spindle microtubules are regulated by the aurora B kinase, which eliminates incorrect attachments by phosphorylating kinetochore proteins to reduce their microtubule-binding capacity . (Our cover image shows the mis-attachments that result when aurora B is inhibited.) But the kinase's activity must be reversed by a phosphatase to stabilize correct kinetochore-microtubule connections. Liu et al. report that Protein Phosphatase I (PPI) is responsible for this stabilization, and that it is recruited to kinetochores by binding to the protein KNL1. PPI's association with KNL1 is inhibited by aurora B until - the authors propose - correct microtubule attachments generate tension that pulls KNL1 out of aurora B's reach, allowing PPI to bind and stabilize the attachments. Senior author Michael Lampson explains here how this mechanism could involve a feedback loop that helps sharpen the transition between strong and weak microtubule binding. Meanwhile, Kiyomitsu et al. demonstrate how the kinetochore protein hMis14 works with the heterochromatin protein HP1 to build the inner centromere structure that links sister kinetochores during mitosis.
Our "In Focus" article this issue highlights a fascinating paper from Okreglak and Drubin that reveals that actin filaments can be constructed from short actin oligomers rather than exclusively from actin monomers. David Drubin tells me here that they made this surprising discovery when they continued to see actin polymerization at yeast endocytic sites in the presence of the monomer-sequestering drug latrunculin A. The short oligomers in question seem to be produced by the actin severing protein cofilin as it disassembles older filaments. Moreover, Okreglak and Drubin show that the cofilin accessory protein Aip1p completely breaks down the short oligomers into monomers and that oligomer-driven filament assembly is thus enhanced in cells lacking Aip1p. Drubin says it remains to be seen if actin filaments at other cellular sites are constructed from oligomers as well as monomers.
Elsewhere, Mittal et al. describe how that TNF-related cytokine TWEAK induces the wasting of skeletal muscle when it's disused (after loss of innervation, for example). The researchers found that TWEAK's receptor, Fn14, is upregulated when muscle is denervated, allowing TWEAK to activate the transcription factor NFkappaB. This drives expression of the ubiquitin ligase MuRF-1, which targets components of the muscle thick filaments for degradation. As I explain in this summary, the pathway may be a viable therapeutic target to prevent muscle atrophy in patients whose muscle usage is curtailed.
From skeletal muscle to the pancreas: Zito et al. report that the endoplasmic reticulum oxidoreductase ERO1-beta, which helps secretory proteins fold by promoting disulphide bond formation, has a surprisingly selective substrate in the form of proinsulin. Mice lacking ERO1-beta develop glucose intolerance (despite the presence of another isoform of the enzyme, ERO1-alpha). Carolyn Sevier puts the data into context in her accompanying commentary.
Onto the vasculature next, as Cain et al. reveal how the phosphatidylinositol-3-kinase subunit p110alpha increases endothelial permeability in response to TNFalpha. p110alpha (and not any other isoforms of the enzyme) regulates the tyrosine kinase Pyk2 and the small GTPase Rac at endothelial cell junctions. The image to the left shows that cells lacking p110alpha (right) maintain their junctions after TNFalpha treatment, unlike control cells (left).
Meanwhile, Herkert et al. demonstrate that cell adhesion (both to each other and to the cell matrix) is globally inhibited by the tumor suppressors Arf and Miz1. Separately, both of these proteins can induce cell cycle arrest in response to a variety of stresses. However, in combination, Arf and Miz1 repress numerous cell adhesion genes and induce apoptosis. This might be a mechanism for tissues to eliminate cells with potentially oncogenic mutations, says senior author Martin Eilers. You can read a longer summary here, including a description of how Myc may switch Arf from arresting damaged cells to killing them. This issue also features a review by Ruoslahti et al., that describes how tumors may be therapeutically targeted using drug conjugates and nanoparticles that specifically dock on cell surface proteins that are highly expressed in the tumor's vasculature.
You can find plenty of other interesting papers in this issue's table of contents, but I'll leave you today with our latest biosights video podcast, which this month features Martin et al.'s description of the integration of contractile forces across whole tissues during epithelial morphogenesis. If you missed the paper in the previous issue of the JCB, you can hear lead author Adam Martin describe his experiments and watch the spectacular movies he took of Drosophila embryos tearing apart when tissue tension is disrupted: