Specific residues of RUNX2 are obligatory for formation of BMP2-induced RUNX2-SMAD complex to promote osteoblast differentiation

Amjad Javed, Faiza Afzal, Jong Sup Bae, Soraya Gutierrez, Kaleem Zaidi, Jitesh Pratap, Andre J. Van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

BMP2 signaling and RUNX2 regulatory pathways converge for transcriptional control of bone formation in vivo. SMAD proteins are recruited to RUNX2 regulatory complexes via an overlapping nuclear matrix targeting signal/Smad interacting domain sequence (391-432) in Runx2. To establish the contribution of RUNX2-SMAD interaction to osteoblastogenesis, we characterized a number of point mutants. Only a triple mutation of amino acids 426-428 (HTY-AAA) results in loss of RUNX2 interactions with either BMP2- or TGF-β- responsive SMADs and fails to integrate the BMP2/TGF-β signal on target gene promoters. In a Runx2 null cell reconstitution assay, the HTY mutant did not activate the program of osteoblast differentiation (alkaline phosphatase, collagen type 1, osteopontin, bone sialoprotein and osteocalcin) in response to BMP2 signaling. Thus, subnuclear targeting function and formation of a RUNX2-SMAD osteogenic complex are functionally inseparable. Taken together, these studies provide direct evidence that RUNX2 is essential for execution and completion of BMP2 signaling for osteoblast differentiation.

Original languageEnglish (US)
Pages (from-to)133-137
Number of pages5
JournalCells Tissues Organs
Volume189
Issue number1-4
DOIs
StatePublished - Dec 1 2008

Keywords

  • BMP2 osteogenic signaling
  • RUNX2
  • SMAD coregulatory proteins
  • Transcriptional regulation

ASJC Scopus subject areas

  • Anatomy
  • Histology

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    Javed, A., Afzal, F., Bae, J. S., Gutierrez, S., Zaidi, K., Pratap, J., Van Wijnen, A. J., Stein, J. L., Stein, G. S., & Lian, J. B. (2008). Specific residues of RUNX2 are obligatory for formation of BMP2-induced RUNX2-SMAD complex to promote osteoblast differentiation. Cells Tissues Organs, 189(1-4), 133-137. https://doi.org/10.1159/000151719