Editors' ChoiceSTATS

A Cytoplasmic Role for Stat3

Science's STKE  24 Jan 2006:
Vol. 2006, Issue 319, pp. tw30
DOI: 10.1126/stke.3192006tw30

The signal transducer and activator of transcription (STAT) family of cytoplasmic proteins translocate to the nucleus to stimulate gene expression. Stat3, which has been identified as an oncogene, not only regulates cell proliferation and survival but also has been implicated in cell migration. However, no target genes have been implicated in its effects on cell migration. Ng et al. identified SCLIP, a member of a family of tubulin-binding proteins that includes stathmin (which destabilizes microtubules), in a yeast two-hybrid screen for Stat3-binding proteins. Immunoprecipitation as well as in vitro binding revealed that stathmin associated with endogenous Stat3 in PC12 cells. Nuclear translocation of Stat3 in response to interleukin-6 and transcriptional activation of a target gene reporter were unaffected by overexpression of myc-tagged stathmin or stathmin knockdown with siRNA. However, mouse embryo fibroblasts (MEFs) lacking Stat3 showed a disorganized microtubule network, a decrease in cell content of acetylated tubulin (associated with microtubule stability), a decrease in tubulin polymerization, and impaired migration. Stat3 restored microtubule acetylation and tubulin polymerization, as did a Stat3 mutant that was deficient at stimulating transcription. Mutational analysis indicated that Stat3 bound the region in stathmin that binds to tubulin, and in vitro analysis revealed that Stat3 antagonized the ability of stathmin to inhibit tubulin polymerization. Expression of Stat3 reduced the effects on microtubule depolymerization of stathmin overexpression, whereas stathmin knockdown with siRNA increased tubulin polymerization and partly restored migration in MEFs lacking Stat3. Thus, Stat3 appears to regulate microtubule dynamics and cell migration through interactions with stathmin in the cell cytoplasm independent of its ability to translocate to the nucleus and activate gene transcription.

D. C. H. Ng, B. H. Lin, C. P. Lim, G. Huang, T. Zhang, V. Poli, X. Cao, Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J. Cell Biol. 172, 245-257 (2006). [Abstract] [Full Text]