Posted by: Dan | August 5, 2006

New insights on Rho, Rac and PI3-Kinase

Two brief but interesting notes on recent findings regarding polarized cell migration and cytoskeleton dynamics, in the August issue of Nature Cell Biology.

The first is a bit of a review paper – Front and back by Rho and Rac, introducing a report further on in the NCB issue, “FilGAP, a Rho- and ROCK-regulated GAP for Rac binds filaminA to control actin remodelling,” which describes a newly discovered regulatory mechanism whereby Rho (through ROCK) antagonizes Rac to suppress leading edge protrusion and promote cell retraction to achieve cellular polarity. As Burridge and Doughman describe in their brief review of how this study fits into the overall understanding of the important GTPases Rho and Rac:

During directed cell migration, it is important that protrusion is restricted to the front of a cell and does not occur at the rear or sides. On page 803 of this issue, Ohta et al. provide evidence for a novel mechanism by which Rac-mediated protrusive activity may be suppressed by Rho activity and thus be confined to regions of the cell where Rho activity is low. They have identified a Rac GAP that is regulated by Rho and its downstream effector ROCK. Interestingly, this protein, FilGAP, binds to and is localized by the actin crosslinking protein filaminA (FLNa) – a major component of the actin cytoskeleton. This study provides evidence that Rho and Rac crosstalk can be spatially controlled.

This is conceptually similar to the spatially controlled antagonistic regulation of the lipid kinase/phosphatase pair, PI3-Kinase and PTEN.

The second brief report comes from May EMBO workshop on Cell Migration in Heidelberg: Moving matters: signals and mechanisms in directed cell migration. In it, Insall and Jones note that “key insights included altered ideas for the roles of Rac and inositol lipids, for the ways that groups of cells coordinate their migration and for the importance of considering movement from both a cell biological and mechanical perspective.”

Among the interesting and suprising data presented were:

  • In macrophages, Racs were found to not be fundamentally required for cell movement, as was previously though, presenting a bit of a connundrum for understanding the role of Rac proteins.
  • Comparing N-WASP in mammalian cells with its homolog in yeast and using FRET to localize active and inactive forms of the protein in cells, found that N-WASP activity relating to actin polymerization was primarily in a possibly new set of actin-rich puncta, not at the leading edge, as previously thought.
  • And a number of presentations questioned how PI3-Kinase affects migration, whose production of PIP3 may not act as simply as previously thought. Largely in data involving Dictyostelium cells, researchers are finding that PI3-Kinase’s roles in determining polarity and enabling motility are highly nuanced, likely involving other regulators of lipid metabolism and signal transduction that require further study.

Overall, Insall and Jones summarize the meeting as such:

We clearly still have a great deal to learn about cell movement. Old certainties are under attack (roles for Rac and PI(3)K); observations made long ago (surface blebs driving movement, see Tickle & Trinkaus, Nature, vol. 261, pg 413, 1976) are coming back in new guises; and mathematics is being used intelligently to help us understand and manipulate both the mechanics and underlying models of cell migration.

… and I’m stuck trying to figure out how my own findings on interactions between FAK and PI3K on gradients of fibronectin fit in with this changing field!


Responses

  1. Re: Rac and Rho. Not that surprising. These two molecules are the yin/yang of morphology, Rac activating spreading, Rho activating contraction. Also it had been noted for a long time that Rac and Rho activities are antagonistic. Turn on Rho (via nocodazole or by adding LPA) and Rac activity goes down. Activate Rac via readhesion to ECM, and Rho activity drops.


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