Like other STAT (signal transducer and activator of transcription) family members, Stat3 is generally believed to be poised in the cytoplasm, waiting for cell surface receptors to activate and trigger its translocation into the nucleus where Stat3 can initiate gene transcription. However, a new study in JCB shows that Stat3 activity in the cytoplasm is also important for fibroblast migration.

Stat3-null mice die during early embryogenesis, but conditional knock-out approaches have revealed that Stat3 is crucial for a variety of biological processes. Stat3-mediated transcription stimulates cell proliferation, prevents apoptosis and induces angiogenesis. A further role for Stat3 in cancer cell motility and wound healing has also been reported, but the mechanism through which Stat3 regulates cell migration is unclear. In this study, Cao and colleagues show that the impaired migration of Stat3-deficient mouse embryonic fibroblasts (MEFs) during wound healing in vitro is partly the result of a disorganized microtubule network — a key component of the migration machinery. Microtubules in Stat3-deficient cells are thinner and fragmented compared to controls; by immunofluorescence and biochemical analyses, it appears that there are fewer polymerized microtubules in cells lacking Stat3. Interestingly, overexpression of Stat3 or a transcriptionally inactive mutant of Stat3 restored the microtubule network, suggesting that the effect of Stat3 on microtubules is independent of its nuclear activity.

Stat3 does not interact directly with tubulin, yet it can directly associate with the microtubule-destabilizing protein stathmin. The authors found that Stat3 attenuates the depolymerization of microtubules induced by stathmin overexpression in MEFs. Conversely, downregulation of endogenous stathmin by RNAi restored the normal levels of polymerized microtubules in Stat3-deficient cells. More importantly, whilst stathmin downregulation in Stat3-depleted MEFs increased their ability to migrate into a wound, expression of a constitutively active stathmin mutant prevented the migration of wild-type MEFs. These findings suggest that overactive stathmin is partially responsible for the attenuated motility of Stat3-null cells.

Finally, the authors examined the kinetics of microtubule assembly in vitro, and show that Stat3 can directly antagonize the inhibitory effect of stathmin on microtubule assembly, by decreasing the interaction between stathmin and tubulin. As Stat3 binds to same region of stathmin as tubulin, it is likely that by competing with tubulin for the microtubule-binding site of stathmin, Stat3 can prevent microtubule depolymerization and promote cell migration without ever entering the nucleus.

Author: Monica Hoyos-Flight