Chimeric granulocyte/macrophage colony-stimulating factor/transforming growth factor-β (TGF-β) receptors define a model system for investigating the role of homomeric and heteromeric receptors in TGF-β signaling

Transforming growth factor-β (TGF-β) belongs to a family of ligands that regulate cell growth and differentiation. The most commonly observed receptors are referred to as the type I, type II, and type III (betaglycan) TGF-β receptors. Two receptor models have been presented to account for the various cellular responses to TGF-β. The first proposes that all TGF-β signaling results from the formation of a heteromeric type I/type II complex, while the second suggests that distinct type I or type II TGF-β receptor combinations mediate aspects of TGF-β signaling. We have addressed this general question relating to TGF-β signaling by constructing chimeric receptors consisting of the extracellular domain of the granulocyte/macrophage colony-stimulating factor (GM-CSF) α or β receptor fused to the transmembrane and cytoplasmic domain of the type I or type II TGF-β receptor. Since high affinity GM-CSF binding requires dimerization of the α and β ligand binding subunits, the response elicited by defined type I and/or type II TGF-β receptor cytoplasmic domain homomers or heteromers can he examined. We show in mesenchymal AKR-2B cells that while TGF-β- dependent transient luciferase activity, endogenous gene activity, and longterm biological responses are similarly induced by activating the chimeric heteromeric receptors with GM-CSF as the endogenous TGF-β receptor, chimeric homomeric type I/type I or type II/type II receptors are signaling- incompetent.