[Functional analysis of transforming growth factor-beta type I receptor].
Proteins in the transforming growth factor-beta (TGF-beta) superfamily exert their effects by forming heteromeric complexes of their type I and type II serine/threonine kinase receptors. Binding of TGF-beta to its constitutively active type II receptor (T beta R-II) recruits the type I receptor (T beta R-I) into the complex; T beta R-I is thereafter phosphorylated in GS domain located just N-terminal to the kinase domain and activated, which is necessary for TGF-beta signaling. Here we investigated the role of cytoplasmic juxtamembrane region located between the transmembrane domain and the GS domain of T beta R-I by mutational analyses using mutant lung epithelial cells which lack endogenous T beta R-I. Upon transfection, wild-type T beta R-I restored the TGF-beta signals for growth inhibition and production of plasminogen activator inhibitor 1 (PAI)-1 and fibronectin. A deletion-mutant, T beta R-I/JD 1 (delta 150-181), which lacks the juxtamembrane region preceding the GS domain bound TGF-beta in concert with T beta R-II and transduced a signal leading to production of PAI-1 but not growth inhibition. Recombinant receptors with mutations that change serine172 to alanine (S172A) or threonine176 to valine (T176V) were similar to wild-type T beta R-I in their abilities to bind TGF-beta, formed complexes with T beta R-II, and transduced a signal for PAI-1 and fibronectin. Similar to T beta R-I/JD1 (delta 150-181), however, these missense mutant receptors were impaired to mediate a growth inhibitory signal. These observations indicate that serine172 and threonine176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta.
Saitoh
M
M
Department of Maxillo-facial Surgery, Tokyo Medical and Dental University, Japan.
D001483:Base Sequence; D002455:Cell Division; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D016326:Extracellular Matrix Proteins; D018125:Receptors, Transforming Growth Factor beta