Chang H. et al. (Endocr Rev. 2002) extensively addressed the transforming growth factor-beta superfamily, from ligand and receptor diversity to signal transducing.

Chang H. et al. (Endocr Rev. 2002) extensively addressed the transforming growth factor-beta superfamily, from ligand and receptor diversity to signal transducing.

Yamashita H, et al. (J Cell Biol. 1995) found that ActR-II can act as a functional type II receptor for OP-1.

The signalling pathway of Nodal was investigated with the use of a Nodal-responsive assay system based on frog animal caps. Expression of dominant negative mutants of various receptors indicated that ALK4, and either ActRIIA or ActRIIB, function as type I and type II receptors for Nodal, respectively. A soluble form of Cripto lacking the COOH-terminal region interacted with Nodal but failed to mediate Nodal signalling, indicating that the native Cripto protein functions as a membrane-bound co-receptor for Nodal. Processed forms of Lefty proteins, both smaller and larger forms, inhibited Nodal signalling. Such Lefty-induced inhibition was rescued by excess ActRIIA or ActRIIB, suggesting that Lefty antagonizes Nodal signalling through competitive binding to the common receptor ActRIIA or ActRIIB. This idea was supported by the demonstration of a genetic interaction between lefty2 and ActRIIB in mouse. Behaviours of GFP-Nodal and GFP-Lefty2 proteins were also investigated in chick embryos. Both proteins could diffuse over a long distance, but the latter diffused faster than the former Sakuma et al. 2002.

Truncated activin type II receptors inhibit bioactivity by the formation of heteromeric complexes with activin type I. receptors. Exp Cell Res. 1996

Inhibin is an antagonist of bone morphogenetic protein signaling. Wiater E, Vale W. Inhibins are endogenous antagonists of activin signaling, long recognized as important regulators of gonadal function and pituitary FSH release. Inhibin, in concert with its co-receptor, betaglycan, can compete with activin for binding to type II activin receptors and, thus, prevent activin signaling. Because bone morphogenetic proteins (BMPs) also utilize type II activin receptors, we hypothesized that BMP signaling might also be sensitive to inhibin blockade. Here we show that inhibin blocks cellular responses to diverse BMP family members in a variety of BMP-responsive cell types. Inhibin abrogates BMP-induced Smad signaling and transcription responses. Inhibin competes with BMPs for type II activin receptors, and this competition is facilitated by betaglycan. Betaglycan also enables inhibin to bind to and compete with BMPs for binding to the BMP-specific type II receptor BMPRII, which does not bind inhibin in the absence of betaglycan. Betaglycan can confer inhibin responsiveness on cells that are otherwise insensitive to inhibin. These findings demonstrate that inhibin, acting through betaglycan, can function as an antagonist of BMP responses, suggesting a broader role for inhibin and betaglycan in restricting and refining a wide spectrum of transforming growth factor beta superfamily signals.

Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5193-8. .

Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning.GDF11 binds to both ActRIIA and ActRIIB, and induces phosphorylation of Smad2. It is interesting to note that activin type IIA was only weakly coprecipitated with ALK4 in the absence of Gdf11, whereas IIB was coprecipitated with ALK4 regardless of Gdf11, suggesting a different binding property of IIA and IIB to ALK4 (Oh et al 2002).

Identification of receptors and signaling pathways for orphan BMP/GDF ligands based on genomic analyses. J Biol Chem. 2005 .

Identification of receptors and signaling pathways for orphan BMP/GDF ligands based on genomic analyses. J Biol Chem. 2005 .