A single heteromeric receptor complex is sufficient to mediate biological effects of transforming growth factor-beta ligands.
Transforming growth factor beta (TGF-beta), a multifunctional cytokine that regulates a variety of biological functions, signals through a heteromeric receptor complex of the type I and type II TGF-beta receptors. The type II receptor, a transmembrane serine-threonine kinase, was cloned based on its ability to directly bind TGF-beta. Recently, a number of candidate type I TGF-beta receptors have been isolated. Although only one of these transmembrane kinases (R4) has been shown to mediate TGF-beta-dependent gene activation, others bind TGF-beta when overexpressed in COS cells. Consequently, it has been postulated that the diversity of TGF-beta responses is generated through the association of distinct type I receptors with the type II TGF-beta receptor, thus creating receptor complexes of differential signaling capacities. In contrast to this model, we demonstrate that stable expression of only the R4 type I TGF-beta receptor in a mutant cell line lacking endogenous type I TGF-beta receptor was able to complex with the endogenous type II TGF-beta receptor and restore the effects of TGF-beta on inhibition of cell proliferation and activation of specific genes, regardless of which of the three mammalian isoforms of TGF-beta was used as the ligand. Therefore, R4 acts as a fully functional type I TGF-beta receptor, and the differential effects of TGF-beta are likely mediated by a single receptor complex consisting of R4 and the type II receptor.
Bassing
C H
CH
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Howe
D J
DJ
Segarini
P R
PR
Donahoe
P K
PK
Wang
X F
XF
D000818:Animals; D002460:Cell Line; D008024:Ligands; D008907:Mink; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta