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J. Biol. Chem., Vol. 280, Issue 9, 8300-8308, March 4, 2005

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The Role of Internalization in Transforming Growth Factor 1-induced Smad2 Association with Smad Anchor for Receptor Activation (SARA) and Smad2-dependent Signaling in Human Mesangial Cells^*

Constance E. Runyan, H. William Schnaper, and Anne-Christine Poncelet

From the Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Recent data investigating the role of the Smad anchor for receptor activation (SARA) in TGF- signaling have suggested that it has a crucial function in both aiding the recruitment of Smad to the TGF- receptor, and ensuring appropriate subcellular localization of the activated receptor-bound complex. The FYVE domain in SARA directs its localization to early endosomal compartments where it can interact with both the TGF- receptors and Smads. However, the necessity of endocytosis in the TGF- response remains controversial. We sought to examine the role of internalization in TGF-/Smad signaling in human kidney mesangial cells. Using co-immunoprecipitation studies, we show that endogenous Smad2 interacts with SARA after TGF-1 stimulation. Inhibition of clathrin-mediated internalization only slightly affects TGF-1-stimulated association between SARA and Smad2, Smad2 phosphorylation, or Smad2 interaction with Smad4. However, endocytosis inhibition decreases TGF-1-induced Smad2 nuclear translocation and thus abrogates Smad2-dependent transcriptional responses. The TGF-1-stimulated association between SARA and Smad2 peaks at 30 min followed by separation of the complex components. However, under conditions of inhibited endocytosis, Smad2 remains bound to SARA for at least 6 h without a significant decline in associated levels. This lack of complex dissociation correlates with a lack of Smad2 nuclear accumulation and reduction of Smad2-dependent ARE-Luc reporter activity. Our data therefore suggest that endocytosis plays a critical role in TGF- signaling in mesangial cells, and that internalization enhances the dissociation of Smad2 from the TGF- receptor-SARA complex, allowing Smad2 to accumulate in the nucleus and modulate target gene transcription.

Received for publication, July 14, 2004 , and in revised form, December 9, 2004.

^* This work was supported in part by a Young Investigator Research Grant from the National Kidney Foundation of Illinois (to A.-C. P.), Grants KO1-DK64074-01 (to A.-C. P.) and R01-DK49362 (to H. W. S.) from the NIDDK, National Institutes of Health, and the Children's Memorial Institute for Education and Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Northwestern University Feinberg School of Medicine, Dept. of Pediatrics, WARD 12-110, 303 East Chicago Ave., Chicago, IL 60611. Tel.: 312-503-0089; Fax: 312-503-1181; E-mail: c-runyan{at}northwestern.edu.

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