title: c-Jun is required for TGF-β-mediated cellular migration via nuclear Ca²⁺ signaling.
abstract: 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 Ca(2+) release was independent of extracellular calcium and was suppressed by both U73122 and neomycin, pharmacological inhibitors of the breakdown of PIP(2) into IP(3). Unlike TGF-β-mediated Ca(2+) release, which was c-Jun dependent, ATP mediated Ca(2+) release was c-Jun independent. These studies identify a novel pathway by which TGF-β regulates cellular migration and Ca(2+) release via endogenous c-Jun.
authors: Department of Pharmacology, Georgetown University, 3900 Reservoir Road, NW, Washington, DC 20057, United States.
authors: Einsley
authors: E
authors: Janowski
authors: Xuanmao
authors: X
authors: Jiao
authors: Sanjay
authors: S
authors: Katiyar
authors: Michael P
authors: MP
authors: Lisanti
authors: Manran
authors: M
authors: Liu
authors: Richard G
authors: RG
authors: Pestell
authors: Martin
authors: M
authors: Morad
mesh_terms: D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D016758:Genes, jun; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016212:Transforming Growth Factor beta; D000255:Adenosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D002118:Calcium