Functional analysis of human Smad1: Role of the amino-terminal domain

Ren He Xu, Robert J. Lechleider, Hsiu Ming Shih, Chen Fei Hao, Dvora Sredni, Anita B. Roberts, Hsiang Fu Kung

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10 Scopus citations


The signals originating from transforming growth factor β/activin/bone morphogenetic proteins (BMPs) are transduced by a set of evolutionarily conserved family of Smad proteins which, upon activation, directly translocate to the nucleus where they may activate transcription. Smad proteins of different species contain conserved amino- (N) and carboxy- (C) terminal domains separated by a proline-rich linker. Human, Drosophila, and Xenopus Smad1 all have been shown to mediate the biological effects of BMP-4 in Xenopus embryos. We have investigated the functional domains of human Smad1 (hSmad1) using the Xenopus embryo system. Dorsal injection of hsmad1 RNA into the 4-cell-stage embryos results in embryonic ventralization. Since the C-terminus of Smads has been shown to mediate the transcriptional activity, whereas this activity is masked by the presence of the N-terminus, we tested the effect of a hSmad1 construct lacking the C-terminal domain [hSmad1(N)] in the Xenopus embryo system. Surprisingly, we found that hSmad1(N) not only synergizes with hSmad1 in embryonic ventralization, but induces ventralization by itself. Ectopic expression of a dominant negative BMP receptor (DN-BR) as well as neural inducers noggin and chordin induce neurogenesis in the animal cap, which is inhibited by co-expression of either hSmad1 or hSmad1(N). Ventral expression of DN-BR induces formation of a second body axis at tailbud stage, which is also prevented by hSmad1 and hSmad1(N). It has recently been reported that calmodulin interacts with the N-terminal domain of Smad proteins. We demonstrate that the ventralizing activity of hsmad1 and hSmad1(N) is markedly inhibited by calmodulin. Thus, calmodulin acts as a Smad1 inhibitor. A model is proposed to accomodate these findings.

Original languageEnglish
Pages (from-to)366-373
Number of pages8
JournalBiochemical and Biophysical Research Communications
Issue number2
StatePublished - 10 May 1999

Bibliographical note

Funding Information:
We thank Drs. D. A. Melton, R. M. Harland, Y. Sasai, and E. M. De Robertis for the valuable cDNAs. We also appreciate Mrs. Annie Rogers for editing the manuscript. This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-56000, and partly supported by the Shiffman Program for Clinical and Basic Research between Bar Ilan University of Israel and the National Cancer Institute of the United States. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.


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