Abstract
Genetic and epigenetic events often negate the cytostatic function of transforming growth factor-beta (TGF-beta) in mammary epithelial cells (MEC), which ultimately enables malignant MECs to proliferate, invade, and metastasize when stimulated by TGF-beta. The molecular mechanisms underlying this phenotypic conversion of TGF-beta function during mammary tumorigenesis remain poorly defined. We previously established alpha(v)beta(3) integrin and Src as essential mediators of mitogen-activated protein kinase (MAPK) activation, invasion, and epithelial-to-mesenchymal transition stimulated by TGF-beta in normal and malignant MECs. Mechanistically, beta(3) integrin interacted physically with the TGF-beta type II receptor (TbetaR-II), leading to its tyrosine phosphorylation by Src and the initiation of oncogenic signaling by TGF-beta. We now show herein that Src phosphorylated TbetaR-II on Y284 both in vitro and in vivo. Interestingly, although the expression of Y284F-TbetaR-II mutants in breast cancer cells had no effect on TGF-beta stimulation of Smad2/3, this TbetaR-II mutant completely abrogated p38 MAPK activation by TGF-beta. Accordingly, Src-mediated phosphorylation of Y284 coordinated the docking of the SH2 domains of growth factor receptor binding protein 2 (Grb2) and Src homology domain 2 containing (Shc) TbetaR-II, thereby associating these adapter proteins to MAPK activation by TGF-beta. Importantly, Y284F-TbetaR-II mutants also abrogated breast cancer cell invasion induced by alpha(v)beta(3) integrin and TGF-beta as well as partially restored their cytostatic response to TGF-beta. Our findings have identified a novel alpha(v)beta(3) integrin/Src/Y284/TbetaR-II signaling axis that promotes oncogenic signaling by TGF-beta in malignant MECs and suggest that antagonizing this signaling axis may one day prove beneficial in treating patients with metastatic breast cancers.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
