Disruption of transforming growth factor β signaling by a mutation that prevents transphosphorylation within the receptor complex Journal Article
| Authors: | Cárcamo, J.; Zentella, A.; Massagué, J. |
| Article Title: | Disruption of transforming growth factor β signaling by a mutation that prevents transphosphorylation within the receptor complex |
| Abstract: | TβR-II (transforming growth factor β [TGF-β] type II receptor) is a transmembrane serine/threonine kinase that acts as the primary TGF-β receptor. Ligand binding tn TβR-II leads tn the recruitment and phosphorylation of TβR-I, a distantly related transmembrane kinase that acts as a downstream signaling component. TβR-1 phosphorylation by TβR-II is shown here to be essential fur signaling. A mutant TβR-II that binds ligand but lacks signaling activity was identified. This mutant was identified by screening with a TGF-β-inducible vector a series of mink lung epithelial cell clones that have normal TGF-β binding activity but have lost antiproliferative and transcriptional responses to TGF-β. When transiently cotransfected with TβR-II, one of these cell lines, S-21, recovered TGF-β, responsiveness. cDNA cloning and sequencing of TβR-II from S-21 cells revealed a point mutation that changes proline 525 to leucine in kinase subdomain X1. A recombinant receptor containing this mutation, TβR- II(P525L), is similar to wild-type TβR-II in its abilities to bind ligand, support ligand binding to TβR-I, and form a complex with TβR-I in vivo. TβR-II(P525L) has autophosphorylating activity in vitro and in vivo; however, unlike the wild-type receptor, it fails to phosphorylate an associated TβR-I. These results suggest that TβR-II(P525L) is a catalytically active receptor that cannot recognize TβR-I as a substrate. The close link between TβR-I transphosphorylation and signaling activity argues that transphosphorylation is essential for signal propagation via TβR-I. |
| Keywords: | signal transduction; controlled study; nonhuman; comparative study; dna replication; polymerase chain reaction; animal cell; animal; amino acid substitution; transforming growth factor beta; cell line; luciferase; dose-response relationship, drug; transfection; protein serine threonine kinase; autophosphorylation; cercopithecus aethiops; phosphorylation; cloning, molecular; kidney; amino acid sequence; molecular sequence data; sequence homology, amino acid; recombinant proteins; recombinant protein; lung; transforming growth factor beta receptor; transforming growth factor beta1; receptors, transforming growth factor beta; epithelium cell; mutagenesis, site-directed; receptor affinity; point mutation; mammals; ligand binding; complementary dna; plasminogen activator inhibitor 1; mink; fibronectin; phorbol 13 acetate 12 myristate; tetradecanoylphorbol acetate; peptide mapping; phosphopeptide; phosphopeptides; consensus sequence; lung alveolus epithelium; fibronectins; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s. |
| Journal Title: | Molecular and Cellular Biology |
| Volume: | 15 |
| Issue: | 3 |
| ISSN: | 0270-7306 |
| Publisher: | American Society for Microbiology |
| Date Published: | 1995-03-01 |
| Start Page: | 1573 |
| End Page: | 1581 |
| Language: | English |
| PUBMED: | 7862150 |
| PROVIDER: | scopus |
| PMCID: | PMC230381 |
| DOI: | 10.1128/MCB.15.3.1573 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 28 August 2018 -- Source: Scopus |
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