Cell-scale biophysical determinants of cell competition in epithelia.

How cells with different genetic makeups compete in tissues is an outstanding question in developmental biology and cancer research. Studies in recent years have revealed that cell competition can either be driven by short-range biochemical signalling or by long-range mechanical stresses in the tissue. To date, cell competition has generally been characterised at the population scale, leaving the single-cell-level mechanisms of competition elusive.

PP1 and PP2A Use Opposite Phospho-dependencies to Control Distinct Processes at the Kinetochore.

PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location.

Division of labour between PP2A-B56 isoforms at the centromere and kinetochore.

PP2A-B56 is a serine/threonine phosphatase complex that regulates several major mitotic processes, including sister chromatid cohesion, kinetochore-microtubule attachment and the spindle assembly checkpoint. We show here that these key functions are divided between different B56 isoforms that localise to either the centromere or kinetochore. The centromeric isoforms rely on a specific interaction with Sgo2, whereas the kinetochore isoforms bind preferentially to BubR1 and other proteins containing an LxxIxE motif.

A Kinase-Phosphatase Network that Regulates Kinetochore-Microtubule Attachments and the SAC.

The KMN network (for KNL1, MIS12 and NDC80 complexes) is a hub for signalling at the outer kinetochore. It integrates the activities of two kinases (MPS1 and Aurora B) and two phosphatases (PP1 and PP2A-B56) to regulate kinetochore-microtubule attachments and the spindle assembly checkpoint (SAC). We will first discuss each of these enzymes separately, to describe how they are regulated at kinetochores and why this is important for their primary function in controlling either microtubule attachments or the SAC.

Mitotic kinases and phosphatases cooperate to shape the right response.

Kinases and phosphatases, two sides of the same coin; are they opposing forces that switch signals on and off or enzymes that work together to give the right type of response at the right time? It depends on how close you stand when you view the big picture. Up close and detailed, and you'll see individual phosphorylation sites as binary switches - lights being toggled on/off by antagonistic forces. Take a step back and multiple copies of the same light are being toggled, perhaps leading to a range of intensities, or a flickering pattern, lights flashing in unison or at random.

Negative feedback at kinetochores underlies a responsive spindle checkpoint signal.

Kinetochores are specialized multi-protein complexes that play a crucial role in maintaining genome stability. They bridge attachments between chromosomes and microtubules during mitosis and they activate the spindle assembly checkpoint (SAC) to arrest division until all chromosomes are attached. Kinetochores are able to efficiently integrate these two processes because they can rapidly respond to changes in microtubule occupancy by switching localized SAC signalling ON or OFF.