title: TGF-β signalling is mediated by two autonomously functioning TβRI:TβRII pairs.
abstract: Transforming growth factor (TGF)-βs are dimeric polypeptides that have vital roles in regulating cell growth and differentiation. They signal by assembling a receptor heterotetramer composed of two TβRI:TβRII heterodimers. To investigate whether the two heterodimers bind and signal autonomously, one of the TGF-β protomers was substituted to block receptor binding. The substituted dimer, TGF-β3 WD, bound the TβRII extracellular domain and recruited the TβRI with affinities indistinguishable from TGF-β3, but with one-half the stoichiometry. TGF-β3 WD was further shown to retain one-quarter to one-half the signalling activity of TGF-β3 in three established assays for TGF-β function. Single-molecule fluorescence imaging with GFP-tagged receptors demonstrated a measurable increase in the proportion of TβRI and TβRII dimers upon treatment with TGF-β3, but not with TGF-β3 WD. These results provide evidence that the two TβRI:TβRII heterodimers bind and signal in an autonomous manner. They further underscore how the TGF-βs diverged from the bone morphogenetic proteins, the ancestral ligands of the TGF-β superfamily that signal through a RI:RII:RII heterotrimer.
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Laurent
authors.initials: L
authors.lastname: David
authors.forename: Valentín
authors.initials: V
authors.lastname: Mendoza
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Maria
authors.initials: M
authors.lastname: Villarreal
authors.forename: Keya
authors.initials: K
authors.lastname: De
authors.forename: LuZhe
authors.initials: L
authors.lastname: Sun
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Fang
authors.forename: Fernando
authors.initials: F
authors.lastname: López-Casillas
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Hinck
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D053782:Transforming Growth Factor beta3 / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C509044:TGFB3 protein, human; D053782:Transforming Growth Factor beta3; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II