Cell Migration

Staying on Track

Science Signaling  17 Nov 2009:
Vol. 2, Issue 97, pp. ec367
DOI: 10.1126/scisignal.297ec367

Members of the signal transducer and activator of transcription (STAT) family of proteins are best known for regulating gene expression. However, evidence is mounting for a role for STAT3 in regulation of cell migration that is independent from its transcriptional activity. Teng et al. showed that compared with wild-type cells, Stat3-deficient mouse embryo fibroblasts (ΔSt3 MEFs) had reduced stress fibers, failed to form lamellipodia, and exhibited increased motility with decreased directional migration. The active form of the guanosine triphosphatase (GTPase) Rac1 (GTP-Rac1) was increased in the ΔSt3 MEFs, in resting cells, and in cells moving in response to monolayer scratching and during cell attachment and spreading. Expression of a dominant-negative form of Rac1 or an autoinhibitory domain peptide of p21-activated kinase (PAK), a target of Rac1, increased stress fiber formation in the ΔSt3 MEFs, thus connecting Rac1 activity to the stress fiber defect. Reconstitution of ΔSt3 MEF cells with a mutant form of Stat3 (Y705F Stat3) that lacked transcriptional activity (and was not tyrosine phosphorylated) rescued the movement defects and restored formation of lamellipodia, showing that the role of Stat3 in cell migration was not mediated by transcriptional regulation. The authors could not detect an interaction between Rac1 and Stat3, but endogenous Stat3 coimmunoprecipitated with the Rac1 guanine-nucleotide exchange factor βPIX, and the Y705F mutant and a tagged form of βPIX also coimmunoprecipitated when coexpressed in a fibroblast cell line. Overexpression of βPIX in a fibroblast cell line stimulated Rac1 activity during cell spreading and adhesion, and this was inhibited by coexpression of Stat3 or the Y705F mutant. Knockdown of βPIX in the ΔSt3 MEFs decreased Rac1 activity during cell spreading. Thus, Stat3 appears to interact with βPIX to inhibit its activity toward Rac1 and thereby maintain proper directionality during cell migration.

T. S. Teng, B. Lin, E. Manser, D. C. H. Ng, X. Cao, Stat3 promotes directional cell migration by regulating Rac1 activity via its activator βPIX. J. Cell Sci. 122, 4150–4159 (2009). [Abstract] [Full Text]