Abstract
Transforming growth factor-beta (TGF-beta) 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-beta receptors. Two receptor models have been presented to account for the various cellular responses to TGF-beta. The first proposes that all TGF-beta 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-beta receptor combinations mediate aspects of TGF-beta signaling. We have addressed this general question relating to TGF-beta signaling by constructing chimeric receptors consisting of the extracellular domain of the granulocyte/macrophage colony-stimulating factor (GM-CSF) alpha or beta receptor fused to the transmembrane and cytoplasmic domain of the type I or type II TGF-beta receptor. Since high affinity GM-CSF binding requires dimerization of the alpha 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 gene activity, and long-term biological responses are similarly induced by activating the chimeric heteromeric receptors with GM-CSF as the endogenous TGF-beta receptor, chimeric homomeric type I/type I or type II/type II receptors are signaling-incompetent.
Highlights
Transforming growth factor- (TGF-)1 is a 25-kDa polypeptide prototypic of a growth factor superfamily involved in events central to cell biology [1,2,3]
Additional data for which the heteromeric model cannot readily account are: (i) type I and type II receptor homomers have been documented in the absence or presence of ligand binding [18, 30, 31]; (ii) the type I and type II receptor kinase domains have been shown to have identical substrate specificity [32], raising the question of whether the two receptors can functionally substitute for each other; (iii) effects on growth inhibition and gene expression have been uncoupled using dominant negative type II receptors and receptor mutants [28, 33]; and (iv) other TGF- family members such as OP-1 and BMP-4 are capable of binding type I receptors in the absence of type II receptor expression [34]
We addressed this question concerning the requirement for TGF- receptor heteromers or homomers by generating stable cell lines expressing chimeric receptors consisting of the ligand binding domain of the granulocyte/macrophage colony stimulating factor (GM-CSF) ␣ or  receptors [36, 37] fused to the transmembrane and cytoplasmic domains of the type I and type II TGF- receptors
Summary
Transforming growth factor- (TGF-)1 is a 25-kDa polypeptide prototypic of a growth factor superfamily involved in events central to cell biology [1,2,3]. We addressed this question concerning the requirement for TGF- receptor heteromers or homomers by generating stable cell lines expressing chimeric receptors consisting of the ligand binding domain of the granulocyte/macrophage colony stimulating factor (GM-CSF) ␣ or  receptors [36, 37] fused to the transmembrane and cytoplasmic domains of the type I and type II TGF- receptors.
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