We demonstrated previously that growth factor receptor-bound protein 2 (Grb2) associates with the transforming growth factor-beta (TGF-beta) type II receptor [TbetaR-II] upon its phosphorylation on Tyr284 by Src. Although this phosphotransferase reaction is critical in mediating TGF-beta stimulation of epithelial-mesenchymal transition (EMT) and invasion in mammary epithelial cells (MECs), the necessity of Grb2 in promoting these TGF-beta-dependent events remain purely correlative. Herein, we further evaluated the role of Grb2 in mediating the oncogenic activities of TGF-beta and show that the binding of Grb2 to TbetaR-II paralleled the induction of EMT in MECs stimulated by TGF-beta. Introducing siRNAs against Grb2 or expression of a TbetaR-II mutant that cannot bind Grb2 (i.e. Y284F-TbetaR-II) had no effect on the ability of TGF-beta to activate Smad3, but significantly impaired its stimulation of p38 mitogen-activated protein kinase (MAPK) in MECs. Importantly, these same cellular conditions also prevented the ability of MECs to undergo EMT in response to TGF-beta, and to invade synthetic basement membranes when stimulated by beta3 integrin and TGF-beta. Finally, we show that the ability of TGF-beta to stimulate breast cancer growth and pulmonary metastasis in mice required TbetaR-II to be phosphorylated on Tyr284, which activated p38 MAPK in developing and progressing mammary tumors. Collectively, our findings have established the necessity of Grb2 in mediating TGF-beta stimulation of EMT and invasion in MECs, as well as demonstrated the essential function of the alphavbeta3 integrin:Src:phospho-Y284-TbetaR-II:Grb2:p38 MAPK signaling axis to promote breast cancer growth and metastasis in vivo.