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J. Biol. Chem., Vol. 281, Issue 39, 29349-29356, September 29, 2006

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BMP4 Activation and Secretion Are Negatively Regulated by an Intracellular Gremlin-BMP4 Interaction^*

Jianping Sun, Feng-Feng Zhuang, Jerald E. Mullersman^¶, Hui Chen, Elizabeth J. Robertson^||, David Warburton, Yi-Hsin Liu, and Wei Shi¹

From the Developmental Biology Program, The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, the Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California 90033, the ^¶Department of Pathology, East Tennessee State University, Johnson City, Tennessee 37614, and the ^||Wellcome Trust Center for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom

Bone morphogenetic protein 4 (BMP4) is a potent growth factor that is involved in many important biological processes. Regulation of the level of secreted mature BMP4 determines the biological effects of BMP4 on cells in the local microenvironment. Previous studies suggested that Gremlin, a member of DAN family proteins, antagonizes BMP4 activity by sequestering extracellular BMP4. Herein, we report a novel intracellular regulatory mechanism by which Gremlin interacts with BMP4 precursor, prevents secretion of mature BMP4, and therefore inhibits BMP4 activity more efficiently. Furthermore, we also defined a 30-amino acid peptide sequence within the Gremlin DAN domain that is essential for BMP4 interaction. This novel Gremlin-mediated BMP4 posttranslational regulatory mechanism implies that the level of BMP4 mRNA expression does not truly reflect BMP4 activity when Gremlin and BMP4 are coexpressed within the same cell. Similar regulatory mechanisms may be utilized by other DAN family proteins.

Received for publication, April 21, 2006 , and in revised form, July 28, 2006.

^* This work was supported by National Institutes of Health Grants HL68597 and HL61286, American Heart Association grant-in-aid, and Childrens Hospital Los Angeles Research Career Developmental Award. 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.

¹ To whom correspondence should be addressed: Developmental Biology Program, Dept. of Surgery, Childrens Hospital Los Angeles, 4650 Sunset Blvd., MS 35, Los Angeles, CA 90027. Tel.: 323-669-5430; Fax: 323-671-3613; E-mail: wshi{at}chla.usc.edu.

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