c-Jun is required for TGF-β-mediated cellular migration via nuclear Ca2+ signaling

Tumor progression involves the acquisition of invasiveness through a basement membrane. The c-jun proto-oncogene is overexpressed in human tumors and has been identified at the leading edge of human breast tumors. TGF-β plays a bifunctional role in tumorigenesis and cellular migration. Although c-Jun and the activator protein 1 (AP-1) complex have been implicated in human cancer, the molecular mechanisms governing cellular migration via c-Jun and the role of c-Jun in TGF-β signaling remains poorly understood. Here, we analyze TGF-β mediated cellular migration in mouse embryo fibroblasts using floxed c-jun transgenic mice. We compared the c-jun wild type with the c-jun knockout cells through the use of Cre recombinase. Herein, TGF-β stimulated cellular migration and intracellular calcium release requiring endogenous c-Jun. TGF-β mediated Ca2+ release was independent of extracellular calcium and was suppressed by both U73122 and neomycin, pharmacological inhibitors of the breakdown of PIP2 into IP3. Unlike TGF-β-mediated Ca2+ release, which was c-Jun dependent, ATP mediated Ca2+ release was c-Jun independent. These studies identify a novel pathway by which TGF-β regulates cellular migration and Ca2+ release via endogenous c-Jun.