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J. Biol. Chem., Vol. 283, Issue 13, 8412-8422, March 28, 2008

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Structural Coupling of Smad and Runx2 for Execution of the BMP2 Osteogenic Signal^*

From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655

Two regulatory pathways, bone morphogenetic protein (BMP)/transforming growth factor-β (TGFβ) and the transcription factor RUNX2, are required for bone formation in vivo. Here we show the interdependent requirement of these pathways to induce an osteogenic program. A panel of Runx2 deletion and point mutants was used to examine RUNX2-SMAD protein-protein interaction and the biological consequences on BMP2-induced osteogenic signaling determined in Runx2 null cells. These cells do not respond to BMP2 signal in the absence of Runx2. We established that a triple mutation in the C-terminal domain of RUNX2, HTY (426-428), disrupts the RUNX2-SMAD interaction, is deficient in its ability to integrate the BMP2/TGFβ signal on promoter reporter assays, and is only marginally functional in promoting early stages of osteoblast differentiation. Furthermore, the HTY mutation overlaps the unique nuclear matrix targeting signal of Runx factors and exhibits reduced subnuclear targeting. Thus, formation of a RUNX2-SMAD osteogenic complex and subnuclear targeting are structurally and functionally inseparable. Our results establish the critical residues of RUNX2 for execution and completion of BMP2 signaling for osteoblastogenesis through a mechanism that requires RUNX2-SMAD transcriptional activity.

Received for publication, July 6, 2007 , and in revised form, December 5, 2007.

^* This work is supported by National Institutes of Health Grants P01 AR48818 and DE012528. 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 Current address: Inst. of Oral Health Research, School of Dentistry, University of Alabama, Birmingham, AL 35294.

² Current address: Dept. of Biochemistry, School of Medicine, Saint Louis University, 1402 S. Grand, St. Louis, MO 63104.

³ Current address: Dept. Biología Molecular, Universidad de Concepción, Concepción 4079100, Chile.

⁴ To whom correspondence should be addressed: Dept. of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Tel.: 508-856-5941; Fax: 508-856-6800; E-mail: jane.lian{at}umassmed.edu.

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