The transcription factor Stat3 plays a pivotal part in numerous signaling pathways, shuttling from the cytoplasm to the nucleus to switch on target genes in response to receptor activation. Unsurprisingly, malfunctions of this protein are linked to cancer onset and progression.
Studies in mice and zebrafish by various groups have indicated that Stat3 is also essential to gastrulation, a process of dramatic physical rearrangement in embryos that precedes body patterning and organ development. “These [studies] suggest that regulation of cell movement could be one of the fundamental functions of Stat3,” says Xinmin Cao of the A*STAR Institute of Molecular and Cell Biology.
Cao and her co-workers have since explored this possibility by characterizing the effects of Stat3 disruption on migratory behavior of mouse embryonic fibroblasts (MEFs). Typically, when a layer of cultured MEFs is damaged, wild-type cells migrate in an organized fashion to close the wound. In the absence of Stat3, however, they found that healing was impaired and mutant MEFs exhibited signs of disorganization and disorientation (Fig. 1). “The rate of migration is actually increased, but the directionality is lost in a random mode of movement,” says Cao. “This leads to an overall decrease in cell movement in wound-healing assays.”
Control of cell movement by Stat3 involves regulation of Rac1, a protein that helps to coordinate rearrangement of the cytoskeleton during migration and drives the formation of lamella—membrane extensions that help pull cells forward. In the absence of Stat3, Rac1 becomes hyperactivated, resulting in excessive lamella formation and reduced efficiency of migration.
Some studies have suggested that Stat3 and Rac1 interact, but Cao and her co-workers found evidence that Stat3 suppresses Rac1 indirectly by binding to and inhibiting βPIX, an activator of Rac1. Intriguingly, the abnormal migratory behavior of Stat3-deficient MEFs could be rescued by getting these cells to express Y705F Stat3—a mutant protein that is largely trapped in the cytoplasm and unable to modulate gene transcription but maintains the capacity to bind and regulate the activity of βPIX.
The team’s findings suggest a cytoplasmic function for Stat3 distinct from its well-established activities in the nucleus. “Our study shows that this function of Stat3 is independent of its transcriptional activity,” says Cao. “We previously found that cytoplasmic Stat3 could regulate microtubules, and our current findings provide additional evidence for a cytoplasmic function for this protein.” In collaboration with clinicians, they wish to explore the role of Stat3-mediated migration in metastasis—another potential link between Stat3 and cancer risk.
The A*STAR-affiliated authors in this highlight are from the Institute of Molecular and Cell Biology.