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Src Phosphorylates Tyr²⁸⁴ in TGF-ß Type II Receptor and Regulates TGF-ß Stimulation of p38 MAPK during Breast Cancer Cell Proliferation and Invasion

Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado

Requests for reprints: William P. Schiemann, Department of Pharmacology, University of Colorado Health Sciences Center, Room L18-6110, RC1 South Tower, 12801 East 17th Avenue, P.O. Box 6511, Aurora, CO 80045. Phone: 303-724-1541; Fax: 303-724-3663; E-mail: Bill.Schiemann{at}uchsc.edu.

Genetic and epigenetic events often negate the cytostatic function of transforming growth factor-ß (TGF-ß) in mammary epithelial cells (MEC), which ultimately enables malignant MECs to proliferate, invade, and metastasize when stimulated by TGF-ß. The molecular mechanisms underlying this phenotypic conversion of TGF-ß function during mammary tumorigenesis remain poorly defined. We previously established _vß₃ integrin and Src as essential mediators of mitogen-activated protein kinase (MAPK) activation, invasion, and epithelial-to-mesenchymal transition stimulated by TGF-ß in normal and malignant MECs. Mechanistically, ß₃ integrin interacted physically with the TGF-ß type II receptor (TßR-II), leading to its tyrosine phosphorylation by Src and the initiation of oncogenic signaling by TGF-ß. We now show herein that Src phosphorylated TßR-II on Y284 both in vitro and in vivo. Interestingly, although the expression of Y284F-TßR-II mutants in breast cancer cells had no effect on TGF-ß stimulation of Smad2/3, this TßR-II mutant completely abrogated p38 MAPK activation by TGF-ß. 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) TßR-II, thereby associating these adapter proteins to MAPK activation by TGF-ß. Importantly, Y284F-TßR-II mutants also abrogated breast cancer cell invasion induced by _vß₃ integrin and TGF-ß as well as partially restored their cytostatic response to TGF-ß. Our findings have identified a novel _vß₃ integrin/Src/Y284/TßR-II signaling axis that promotes oncogenic signaling by TGF-ß in malignant MECs and suggest that antagonizing this signaling axis may one day prove beneficial in treating patients with metastatic breast cancers. [Cancer Res 2007;67(8):3752–8]

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