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Hgs and SARA Recruit Smads

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Science's STKE  05 Dec 2000:
Vol. 2000, Issue 61, pp. tw7
DOI: 10.1126/stke.2000.61.tw7

Smads 1, 2, 3, 5, and 8 are transcription factors that transmit the signal generated by activation of members of the transforming growth factor-β (TGF-β) receptor family. When activated, these receptor-regulated Smads form complexes with Smad4 and then translocate to the nucleus. Miura et al. investigated how the receptor-regulated Smads are anchored to the receptors. Their data suggest that two FYVE domain-containing proteins, Hgs and SARA, cooperate to recruit Smads to inactive receptors and that this interaction is essential for viability in mice. FYVE domains interact with phosphatidylinositol 3-phosphate and function in various signaling pathways (see Corvera). In a yeast two-hybrid screen, Hgs was identified as a binding partner for Smad 2. These results were confirmed by coimmunoprecipitation experiments in which Hgs interacted with Smads 1, 2, and 3 in the absence of ligand stimulation, but not with Smad 4 or 6. Cotransfection experiments with wild-type or mutated Hgs and Smad 2 or 3 showed that these interactions depended on the COOH-terminal domain of Hgs, but not the FYVE domain. Overexpression of Hgs increased recruitment of Smads to the activin receptor, increased phosphorylation of Smads, and was essential for activin-simulated signaling to reporter genes. The effect of Hgs was enhanced if a second FYVE-domain protein, SARA, was also cotransfected into the cells. Expression of a COOH-terminally truncated version of Hgs in "knockin" mice was lethal by embryonic day 10 (E10). Mutant cells isolated before E10 demonstrated a decreased responsiveness to TGF-β and activin A, which could be restored if SARA or Hgs or both proteins were overexpressed in the cells.

Miura, S., Takeshita, T., Asao, H., Kimura, Y., Murata, K., Sasaki, Y., Hania, J.-I., Beppu, H., Tsukazaki, T., Wrana, J.L., Miyazono, K., and Sugamura, K. (2000) Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol. Cell. Biol. 20: 9346-9355. [Abstract] [Full Text]

Corvera, S. (2000) Signal transduction: Stuck with FYVE domains.Science's STKE: http://www.stke.org/cgi/content/full/OC_sigtrans;2000/37/pe1. [Full Text]

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