Bone Morphogenetic Proteins Signal through the Transforming Growth Factor-β Type III Receptor

Abstract

The bone morphogenetic protein (BMP) family, the largest subfamily of the structurally conserved transforming growth factor-␤ (TGF-␤) superfamily of growth factors, are multifunctional regulators of development, proliferation, and differentiation. The TGF-␤ type III receptor (T␤RIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-␤ and inhibin receptor. Here we demonstrate that T␤RIII functions as a BMP cell surface receptor. T␤RIII 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-␤. T␤RIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous T␤RIII attenuates BMP-mediated Smad1 phosphorylation. Using a biologically relevant model for T␤RIII function, we demonstrate that BMP-2 specifically stimulates T␤RIII-mediated epithelial to mesenchymal cell transformation. The ability of T␤RIII to serve as a cell surface receptor and mediate BMP, inhibin, and TGF-␤ signaling suggests a broader role for T␤RIII in orchestrating TGF-␤ superfamily signaling.

Signaling Receptors for TGF-β Family Members

“…Betaglycan-deficient mouse embryo fibroblasts show reduced Smad2 nuclear translocation and reduced growth suppression in response to TGF-b2 stimulation, but not in response to TGF-b1 and TGF-b3 (Stenvers et al 2003). Betaglycan also binds and promotes signaling by inhibin (Lewis et al 2000;Wiater et al 2006) and BMPs (Kirkbride et al 2008;Lee et al 2009). …”

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

“…These data indicate that T␤RIII inhibits the intrinsic ability of epithelial cells to migrate. Because reduced T␤RIII expression in NOSE007 cells increased cell migration, and T␤RIII has previously defined roles in regulating epithelial to mesenchymal transition (EMT) during development (11,12) and in cancer models (21), we investigated whether reduced T␤RIII expression induced EMT in NOSE007 cells. Consistent with a role in inducing EMT, shRNAmediated silencing of T␤RIII expression in NOSE007 cells resulted in an increase in expression of mesenchymal markers, including N-cadherin and Vimentin (Fig.…”

“…T␤RIII null embryos die on embryonic day 13.5, exhibiting hepatic and cardiovascular defects (10). An essential role for T␤RIII has also been demonstrated in mesenchymal transformation during chick embryonic heart development (11,12) and in mediating TGF-␤ resistance in intestinal goblet cells (13). We have defined essential roles for the cytoplasmic domain of T␤RIII in mediating TGF-␤ signaling independent of the ligand presentation role (14), along with regulating cell-surface levels of T␤RIII and T␤RII through interactions with G␣-interacting protein-interacting protein, C terminus (GIPC) (15) and ␤-arrestin2 (16).…”

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

“…For example, BMP2 and TGFβ2 can bind to Betaglycan to induce EMT in chick ventricular and AVC explant assays [174,175], which suggests this interaction plays an important role in AVC cushion formation. Loss of ALK2 in endothelium leads to reduced phosphorylation of TGFβ and BMP Smads [45] and indicates either that loss of BMP signalling reduces TGFβs expression (as mentioned earlier) or that BMP signalling can induce TGFβ Smads specifically via different combinations of receptor-ligand complexes or vice versa.…”