CHIMERIC GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR TRANSFORMING GROWTH-FACTOR-BETA (TGF-BETA) RECEPTORS DEFINE A MODEL SYSTEM FOR INVESTIGATING THE ROLE OF HOMOMERIC AND HETEROMERIC RECEPTORS IN TGF-BETA SIGNALING/

Transforming growth factor-beta (TGF-beta) belongs to a family of liga nds that regulate cell growth and differentiation. The most commonly o bserved receptors are referred to as the type I, type II, and type III (betaglycan) TGF-beta receptors. Two receptor models have been presen ted to account for the various cellular responses to TGF-beta. The fir st proposes that all TGF-beta signaling results from the formation of a heteromeric type I/type II complex, while the second suggests that d istinct type I or type II TGF-beta receptor combinations mediate aspec ts of TGF-beta signaling. We have addressed this general question rela ting to TGF-beta signaling by constructing chimeric receptors consisti ng of the extracellular domain of the granulocyte/macrophage colony-st imulating factor (GM-CSF) alpha or beta receptor fused to the transmem brane and cytoplasmic domain of the type I or type II TGF-beta recepto r. Since high affinity GM-CSF binding requires dimerization of the alp ha and beta ligand binding subunits, the response elicited by defined type I and/or type II TGF-beta receptor cytoplasmic domain homomers or heteromers can be examined. We show in mesenchymal AKR-2B cells that while TGF-beta-dependent transient luciferase activity, endogenous gen e activity, and longterm biological responses are similarly induced by activating the chimeric heteromeric receptors with GM-CSF as the endo genous TGF-beta receptor, chimeric homomeric type I/type I or type II/ type II receptors are signaling-incompetent.