title: Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development.
abstract: 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-β superfamily receptors are broader than previously appreciated.
authors.affiliation: 1Duke University Medical Center, 450 Research Drive, LSRC B354, Box 91004, Durham, NC 27708, USA. gerard.blobe@duke.edu.
authors.forename: Alisha
authors.initials: A
authors.lastname: Holtzhausen
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.forename: Tam
authors.initials: T
authors.lastname: How
authors.forename: Yong-Hun
authors.initials: YH
authors.lastname: Lee
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein
keywords: TGF-β; dorsoventral axis; invasion; tumorigenesis