Abstract
Smads transmit signals from transmembrane ser/thr kinase receptors to the nucleus. We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. Phosphorylation of Smad2 induces dissociation from SARA with concomitant formation of Smad2/Smad4 complexes and nuclear translocation. Furthermore, mutations in SARA that cause mislocalization of Smad2 inhibit TGFbeta-dependent transcriptional responses, indicating that the regulation of Smad localization is important for TGFbeta signaling. These results thus define SARA as a component of the TGFbeta pathway that brings the Smad substrate to the receptor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Adult
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Amino Acid Sequence
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Animals
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Binding Sites
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COS Cells
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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DNA-Binding Proteins / metabolism*
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Humans
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Intracellular Signaling Peptides and Proteins*
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Mice
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Molecular Sequence Data
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Nerve Growth Factors
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Phosphorylation
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Protein Serine-Threonine Kinases
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Rabbits
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / metabolism*
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Recombinant Fusion Proteins / metabolism
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Serine Endopeptidases*
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Signal Transduction
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Smad Proteins
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Smad2 Protein
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Smad3 Protein
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Smad4 Protein
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Subcellular Fractions
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Trans-Activators / metabolism*
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Transforming Growth Factor beta / metabolism*
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Tumor Cells, Cultured
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Xenopus
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Xenopus Proteins*
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Zinc Fingers*
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Nerve Growth Factors
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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SMAD2 protein, human
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SMAD3 protein, human
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SMAD4 protein, human
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Smad Proteins
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Smad2 Protein
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Smad2 protein, Xenopus
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Smad2 protein, mouse
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Smad3 Protein
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Smad3 protein, mouse
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Smad4 Protein
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Smad4 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta
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Xenopus Proteins
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ZFYVE9 protein, Xenopus
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madh3 protein, Xenopus
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smad4.1 protein, Xenopus
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smad4.2 protein, Xenopus
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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ZFYVE16 protein, human
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Serine Endopeptidases
Associated data
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GENBANK/AF104304
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GENBANK/AF104305