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Published 30 September 2002. doi:10.1083/jcb.200204088
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© The Rockefeller University Press, 0021-9525/2002/9/1239 $5.00
The Journal of Cell Biology, Volume 158, Number 7, September 30, 2002 1239-1249

Article

TGFß receptor internalization into EEA1-enriched early endosomes

: role in signaling to Smad2



Susan Hayes1,2, Anil Chawla1 and Silvia Corvera1,2

1 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
2 Interdisciplinary Graduate Program, University of Massachusetts Medical School, Worcester, MA 01605

Address correspondence to Silvia Corvera, Program in Molecular Medicine, 373 Plantation St., Worcester, MA 01605. Tel.: (508) 856-6898. Fax: (508) 856-4289. E-mail: silvia.corvera{at}umassmed.edu

Transforming growth factor (TGF)ß 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 TGFß receptors internalize into endosomes containing the early endosomal protein EEA1. The extent of TGFß-stimulated Smad2 phosphorylation, Smad2 nuclear translocation, and TGFß-stimulated transcription correlated closely with the extent of internalization of the receptor. TGFß 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 TGFß-induced Smad2 nuclear translocation. These results indicate that traffic of the TGFß receptor into the endosome enables TGFß signaling, revealing a novel function for the endosome as a compartment specialized for the amplification of certain extracellular signals.

Key Words: FYVE; PI 3-kinase; transforming growth factor; SARA; endocytosis


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