Holtzhausen, A., Golzio, C., How, T., Lee, Y.H., Schiemann, W.P., Katsanis, N., and Blobe, G.C. (2014) Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 28(3):1248-67.
The bone morphogenetic protein (BMP) signaling pathways have important roles in embryonic development and cellular homeostasis,
with aberrant BMP signaling resulting in a broad spectrum of human disease. We report that BMPs unexpectedly signal through
the canonical transforming growth factor β (TGF-β)-responsive Smad2 and Smad3. BMP-induced Smad2/3 signaling occurs preferentially
in embryonic cells and transformed cells. BMPs signal to Smad2/3 by stimulating complex formation between the BMP-binding
TGF-β superfamily receptors, activin receptor-like kinase (ALK)3/6, and the Smad2/3 phosphorylating receptors ALK5/7. BMP
signaling through Smad2 mediates, in part, dorsoventral axis patterning in zebrafish embryos, whereas BMP signaling through
Smad3 facilitates cancer cell invasion. Consistent with increased BMP-mediated Smad2/3 signaling during cancer progression,
Smad1/5 and Smad 2/3 signaling converge in human cancer specimens. Thus, the signaling mechanisms used by BMPs and TGF-&beta superfamily
receptors are broader than previously appreciated.—Holtzhausen, A., Golzio, C., How, T., Lee, Y.-H., Schiemann, W. P., Katsanis,
N., Blobe, G. C. Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development.