Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin.
Transforming growth factor beta (TGF-beta) and activin bind to receptor complexes that contain two distantly related transmembrane serine/threonine kinases known as receptor types I and II. The type II receptors determine ligand binding specificity, and each interacts with a distinct repertoire of type I receptors. Here we identify a new type I receptor for activin, ActR-IB, whose kinase domain is nearly identical to that of the recently cloned TGF-beta type I receptor, T beta R-I. ActR-IB has the structural and binding properties of a type I receptor: it binds activin only in the presence of an activin type II receptor and forms a heteromeric noncovalent complex with activin type II receptors. In Mv1Lu lung epithelial cells, ActR-IB and T beta R-I signal a common set of growth-inhibitory and transcriptional responses in association with their corresponding ligands and type II receptors. The transcriptional responses include elevated expression of fibronectin and plasminogen activator inhibitor 1. Although T beta R-I and ActR-IB are nearly identical in their kinase domains (90% amino acid sequence identity), their corresponding type II receptor kinase domains are very different from each other (42% amino acid sequence identity). Therefore, signaling of a specific set of responses by TGF-beta and activin correlates with the presence of similar type I kinases in their complex. Indeed, other TGF-beta and activin type I receptors (TSR-I and ActR-I) whose kinase domains significantly diverge from those of T beta R-I and ActR-IB do not substitute as mediators of these growth-inhibitory and extracellular matrix transcriptional responses. Hence, we conclude that the type I receptor subunits are primary specifiers of signals sent by TGF-beta and activin receptor complexes.
Cárcamo
J
J
Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Weis
F M
FM
Ventura
F
F
Wieser
R
R
Wrana
J L
JL
Attisano
L
L
Massagué
J
J
D029404:Activin Receptors; D030201:Activin Receptors, Type I; D028341:Activins; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D017931:DNA Primers; D018076:DNA, Complementary / Q000302:isolation & purification / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007265:Inhibins / Q000378:metabolism / Q000494:pharmacology*; D007668:Kidney; D008156:Luciferases / Q000096:biosynthesis / Q000378:metabolism; D008168:Lung; D008907:Mink; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016133:Polymerase Chain Reaction; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013552:Swine; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
D017931:DNA Primers; D018076:DNA, Complementary; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D028341:Activins; D007265:Inhibins; D008156:Luciferases; D029404:Activin Receptors; D030201:Activin Receptors, Type I