Ligand-independent activation of transforming growth factor (TGF) beta signaling pathways by heteromeric cytoplasmic domains of TGF-beta receptors.

Transforming growth factor beta (TGF-beta) transduces signals through two related serine/threonine kinase receptors, the type I and type II receptors, which have the ability to interact with each other. In the heteromeric complex, the type II receptor is the primary determinant of ligand binding and phosphorylates the cytoplasmic domain of the type I receptor. Using a chimeric receptor strategy, we and others have shown previously that a functional TGF-beta receptor complex requires heteromerization of both extracellular and intracellular domains of type I and type II receptors. In the current study, we show that overexpression of two receptors carrying a heteromeric combination of cytoplasmic domains resulted in ligand-independent responses, further supporting the functional requirement of the two heterologous cytoplasmic domains in TGF-beta signaling. Furthermore, coexpression of only the cytoplasmic domains of both the type I and II receptors or tethering the type II to the type I cytoplasmic domain activated TGF-beta responses in a ligand-independent manner. In cotransfected COS-1 cells, both cytoplasmic domains are associated with each other. Our results indicate that the cytoplasmic domains of the type I and type II TGF-beta receptors physically and functionally interact with each other in the heteromeric complex.