TGF beta receptor internalization into EEA1-enriched early endosomes: role in signaling to Smad2
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Program in Molecular Medicine and Interdisciplinary Graduate Program
Medical Subject Headings
Animals; Binding Sites; COS Cells; Carrier Proteins; Cricetinae; DNA-Binding Proteins; Dynamins; Endosomes; Fluorescent Antibody Technique; Genes, Dominant; Hela Cells; Humans; *Intracellular Signaling Peptides and Proteins; Membrane Proteins; Phosphorylation; Potassium; Protein Transport; Receptors, Transforming Growth Factor beta; *Serine Endopeptidases; Signal Transduction; Smad2 Protein; Subcellular Fractions; Trans-Activators; Transfection; Transferrin; Transforming Growth Factor beta; Tumor Cells, Cultured; Vesicular Transport Proteins; *Zinc Fingers
Life Sciences | Medicine and Health Sciences
Transforming growth factor (TGF)beta is an important physiological regulator of cellular growth and differentiation. It activates a receptor threonine/serine kinase that phosphorylates the transcription factor Smad2, which then translocates into the nucleus to trigger specific transcriptional events. Here we show that activated type I and II TGF beta receptors internalize into endosomes containing the early endosomal protein EEA1. The extent of TGF beta-stimulated Smad2 phosphorylation, Smad2 nuclear translocation, and TGF beta-stimulated transcription correlated closely with the extent of internalization of the receptor. TGF beta signaling also requires SARA (Smad anchor for receptor activation), a 135-kD polypeptide that contains a FYVE Zn(++) finger motif. Here we show that SARA localizes to endosomes containing EEA1, and that disruption of this localization inhibits TGF beta-induced Smad2 nuclear translocation. These results indicate that traffic of the TGF beta receptor into the endosome enables TGF beta signaling, revealing a novel function for the endosome as a compartment specialized for the amplification of certain extracellular signals.
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Citation: J Cell Biol. 2002 Sep 30;158(7):1239-49.