Bone morphogenetic proteins signal through the transforming growth factor-beta type III receptor.
The bone morphogenetic protein (BMP) family, the largest subfamily of the structurally conserved transforming growth factor-beta (TGF-beta) superfamily of growth factors, are multifunctional regulators of development, proliferation, and differentiation. The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor. Here we demonstrate that TbetaRIII functions as a BMP cell surface receptor. TbetaRIII directly and specifically binds to multiple members of the BMP subfamily, including BMP-2, BMP-4, BMP-7, and GDF-5, with similar kinetics and ligand binding domains as previously identified for TGF-beta. TbetaRIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous TbetaRIII attenuates BMP-mediated Smad1 phosphorylation. Using a biologically relevant model for TbetaRIII function, we demonstrate that BMP-2 specifically stimulates TbetaRIII-mediated epithelial to mesenchymal cell transformation. The ability of TbetaRIII to serve as a cell surface receptor and mediate BMP, inhibin, and TGF-beta signaling suggests a broader role for TbetaRIII in orchestrating TGF-beta superfamily signaling.
Kirkbride
Kellye C
KC
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27708, USA.
Townsend
Todd A
TA
Bruinsma
Monique W
MW
Barnett
Joey V
JV
Blobe
Gerard C
GC
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007265:Inhibins / Q000378:metabolism*; D007700:Kinetics; D010766:Phosphorylation; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D016212:Transforming Growth Factor beta; C071736:betaglycan; D007265:Inhibins