GS domain mutations that constitutively activate TβR-I, the downstream signaling component in the TGF-β receptor complex Journal Article
| Authors: | Wieser, R.; Wrana, J. L.; Massagué, J. |
| Article Title: | GS domain mutations that constitutively activate TβR-I, the downstream signaling component in the TGF-β receptor complex |
| Abstract: | The TGF-β type II receptor (TβR-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, TβR-I, as a requirement for signal transduction. TβR-I is phosphorylated by TβR-II in the GS domain, a 30 amino acid region preceding the kinase domain and conserved in type I receptors for other TGF-β-related factors. The functional role of seven serines and threonines in the TβR-I GS domain was investigated by mutational analysis. Five of these residues are clustered (TTSGSGSG) in the middle of the GS domain. Mutation of two or more of these residues impairs phosphorylation and signaling activity. Two additional threonines are located near the canonical start of the kinase domain, and their individual mutation to valine strongly inhibits receptor phosphorylation and signaling activity. Replacement of one of these residues, Thr204, with aspartic acid yields a product that has elevated in vitro kinase activity and signals anti-proliferative and transcriptional responses in the absence of ligand and TβR-II. The identification of constitutively active TβR-I forms confirms the hypothesis that this kinase acts as a downstream signaling component in the TGF-β receptor complex, and its activation by TβR-II or by mutation is necessary and sufficient for propagation of anti-proliferative and transcriptional responses. |
| Keywords: | signal transduction; controlled study; mutation; nonhuman; mutant protein; protein domain; cell proliferation; animal cell; cells, cultured; amino acid substitution; serine; transforming growth factor beta; enzyme activation; dose-response relationship, drug; protein serine threonine kinase; structure activity relation; phosphorylation; enzyme phosphorylation; transcription regulation; amino acid sequence; molecular sequence data; recombinant proteins; transforming growth factor beta receptor; receptors, transforming growth factor beta; threonine; receptor; dna mutational analysis; enzyme structure; aspartic acid; valine; receptors, growth factor; peptide mapping; phosphopeptides; tgf-β; membrane enzyme; priority journal; article; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; serine threonine kinases |
| Journal Title: | EMBO Journal |
| Volume: | 14 |
| Issue: | 10 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 1995-05-15 |
| Start Page: | 2199 |
| End Page: | 2208 |
| Language: | English |
| PUBMED: | 7774578 |
| PROVIDER: | scopus |
| PMCID: | PMC398326 |
| DOI: | 10.1002/j.1460-2075.1995.tb07214.x |
| DOI/URL: | |
| Notes: | Article -- Export Date: 28 August 2018 -- Source: Scopus |
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