DISTINCT ENDOCYTIC RESPONSES OF HETEROMERIC AND HOMOMERIC TRANSFORMING-GROWTH-FACTOR-BETA RECEPTORS

Transforming growth factor beta (TGF beta) family ligands initiate a c ascade of events capable of modulating cellular growth and differentia tion. The receptors responsible for transducing these cellular signals are referred to as the type I and type II TGF beta receptors. Ligand binding to the type II receptor results in the transphosphorylation an d activation of the type I receptor. This heteromeric complex then pro pagates the signal(s) to downstream effectors. There is presently litt le data concerning the fate of TGF beta receptors after ligand binding , with conflicting reports indicating no change or decreasing cell sur face receptor numbers. To address the fate of ligand-activated recepto rs, we have used our previously characterized chimeric receptors consi sting of the ligand binding domain from the granulocyte/macrophage col ony-stimulating factor alpha or beta receptor fused to the transmembra ne and cytoplasmic domain of the type I or type II TGF beta receptor. This system not only provides the necessary sensitivity and specificit y to address these types of questions but also permits the differentia tion of endocytic responses to either homomeric or heteromeric intrace llular TGF beta receptor oligomerization. Data are presented that show , within minutes of ligand binding, chimeric TGF beta receptors are in ternalized. However, although all the chimeric receptor combinations s how similar internalization rates, receptor down-regulation occurs onl y after activation of heteromeric TGF beta receptors. These results in dicate that effective receptor down-regulation requires cross-talk bet ween the type I and type II TGF beta receptors and that TGF beta recep tor heteromers and homomers show distinct trafficking behavior.