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J. Biol. Chem., Vol. 281, Issue 25, 17212-17219, June 23, 2006

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LIM Mineralization Protein-1 Potentiates Bone Morphogenetic Protein Responsiveness via a Novel Interaction with Smurf1 Resulting in Decreased Ubiquitination of Smads^*

From the Atlanta Veterans Affairs Medical Center and the Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia 30329

Development and repair of the skeletal system and other organs is highly dependent on precise regulation of bone morphogenetic proteins (BMPs), their receptors, and their intracellular signaling proteins known as Smads. The use of BMPs clinically to induce bone formation has been limited in part by the requirement of much higher doses of recombinant proteins in primates than were needed in cell culture or rodents. Therefore, control of cellular responsiveness to BMPs is now a critical area that is poorly understood. We determined that LMP-1, a LIM domain protein capable of inducing de novo bone formation, interacts with Smurf1 (Smad ubiquitin regulatory factor 1) and prevents ubiquitination of Smads. In the region of LMP responsible for bone formation, there is a motif that directly interacts with the Smurf1 WW2 domain and can effectively compete with Smad1 and Smad5 for binding. We have shown that small peptides containing this motif can mimic the ability to block Smurf1 from binding Smads. This novel interaction of LMP-1 with the WW2 domain of Smurf1 to block Smad binding results in increased cellular responsiveness to exogenous BMP and demonstrates a novel regulatory mechanism for the BMP signaling pathway.

Received for publication, October 11, 2005 , and in revised form, March 13, 2006.

^* This work was supported in part by a Veterans Affairs Merit Award (to L. T.) and a Veterans Affairs Merit Award (to S. D. B.). S. D. Boden is a consultant for Medtronic Sofamor Danek. Emory University School of Medicine and some of the authors have received/may receive royalties in the future related to LMP-1. 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: 59 Executive Park South, Suite 3000, Atlanta, GA 30329. Tel.: 404-778-7143; Fax: 404-778-7117; E-mail: Scott_boden{at}emory.org.

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