Dr Eric Griffis
| Position: | Wellcome Trust Research Career Development Fellow |
|---|---|
| Address: | College of Life Sciences University of Dundee Dundee |
| Telephone: | +44 (0)1382 385118, internal ext. 85118 |
| Email: | e.griffis@dundee.ac.uk |
| Links: | Griffis Lab Website |
Research Overview
Myosin II redistributes rapidly as cells progress from metaphase to anaphase
During cytokinesis, the final step of cell division, a ring of proteins (mainly consisting of actin and myosin, which also power muscle contraction) contracts to create two daughter cells and physically segregate the two copies of the genome that were divided during mitosis. Cytokinesis is evolutionarily ancient, very highly conserved among eukaryotes, and utilizes a common set of proteins. Accurate execution of cytokinesis is important for each cell to receive a complete copy of the genome, and errors in cytokinesis can lead to genome instability and cancer. At the heart of all cytokinetic programs are microtubules, actin, and the actin-sliding motor non-muscle myosin II. Myosin II forms large bipolar filaments when it is activated, and we are interested in understanding how microtubules and signaling molecules control the localization, assembly, and activity of the myosin motor. We are specifically focusing on how this myosin functions during cytokinesis, which is the most dramatic instance of myosin reorganization that takes place within the cell. We have shown that a microtubule-associated kinesin is required for directing the accumulation and clearance of myosin at the cellular equator and poles respectively(2), and that myosin assembly appears to be suppressed during mitosis(1). We also demonstrated that myosin can be properly targeted to the site of contractile ring formation even if it can’t interact with actin filaments. We are using super-resolution(3) and TIRF imaging combined with in vitro reconstitution and proteomics to further probe myosin regulation and function.
Specifically, we are probing how myosin is regulated during mitosis to prevent its assembly, dissecting thesignalling pathways that direct the formation of the cytokinetic ring, and working to identify the proteins that anchor the cytokinetic ring to the plasma membrane to drive the ingression of the cleavage furrow. Beyond cytokinesis, myosin II is essential for many other critical cellular activities including migration, adhesion, metastasis, and invasion. The cell strictly regulates the assembly state and localization of myosin II in order to modulate when and where its contractile activity is utilized. However, the exact mechanisms for controlling assembly and localization are not well understood. We will be probing how the cell regulates myosin activity in multiple other circumstances. Specifically, we want to define basic kinetic parameters of myosin assembly and disassembly and to identify the molecules that control these parameters spatially and temporally. A better understanding of how the cell controls myosins activity
may show how normal cellular behaviour is maintained and how abnormal cells may corrupt this normal program for their benefit.
In addition to understanding how the final act of cell division is executed, we are also interested in how the cell regulates the assembly of the mitotic spindle and controls the timing of mitotic exit. We identified a protein that we named Spindly that localizes to kinetochores (the structures on the chromosome that allow for their accurate segregation). Spindly controls the recruitment of the minus-end directed microtubule motor protein dynein to kinetochores. Kinetochore bound dynein facilitates chromosome alignment and
the inactivation of proteins that monitor chromosome alignment and prevent errors in DNA segregation (4). We are now working to identify how this protein functions to coordinate chromosome attachment to the mitotic spindle and the inactivation of the mitotic checkpoint. We are also investigating how a conserved protein that is mutated in
a neurological disorder called Allgrove Syndrome plays a role in spindle assembly in somatic cells and ooctyes. We’ve found that Drosophila and human cells lacking this protein build short spindles and have difficulty aligning their chromosomes. We’re working now to understand the molecular mechanisms behind these phenotypes.