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 o f ligand binding and phosphorylates the cytoplasmic domain of the type I receptor. Using a chimeric receptor strategy, we and others have sh own previously that a functional TGF-beta receptor complex requires he teromerization of both extracellular and intracellular domains of type I and type II receptors. In the current study, we show that overexpre ssion of two receptors carrying a heteromeric combination of cytoplasm ic domains resulted in ligand-independent responses, fur ther supporti ng the functional requirement of the two heterologous cytoplasmic doma ins in TGF-beta signaling. Furthermore, coexpression of only the cytop lasmic domains of both the type I and II receptors or tethering the ty pe II to the type I cytoplasmic domain activated TGF-beta responses in a ligand-independent manner. In cotransfected COS-1 cells, both cytop lasmic domains are associated with each other. Our results indicate th at the cytoplasmic domains of the type I and type II TGF-beta receptor s physically and functionally interact with each other in the heterome ric complex.