Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal

Amjad Javed, Jong Sup Bae, Faiza Afza, Soraya Gutierrez, Jitesh Pratap, Sayyed K. Zaidi, Yang Lou, Andre J van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8412-8422
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number13
DOIs
StatePublished - Mar 28 2008
Externally publishedYes

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Transforming Growth Factors
Nuclear Matrix
Null Lymphocytes
Mutation
Bone Morphogenetic Proteins
Osteoblasts
Osteogenesis
Assays
Bone
Proteins
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Javed, A., Bae, J. S., Afza, F., Gutierrez, S., Pratap, J., Zaidi, S. K., ... Lian, J. B. (2008). Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal. Journal of Biological Chemistry, 283(13), 8412-8422. https://doi.org/10.1074/jbc.M705578200

Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal. / Javed, Amjad; Bae, Jong Sup; Afza, Faiza; Gutierrez, Soraya; Pratap, Jitesh; Zaidi, Sayyed K.; Lou, Yang; van Wijnen, Andre J; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.

In: Journal of Biological Chemistry, Vol. 283, No. 13, 28.03.2008, p. 8412-8422.

Research output: Contribution to journalArticle

Javed, A, Bae, JS, Afza, F, Gutierrez, S, Pratap, J, Zaidi, SK, Lou, Y, van Wijnen, AJ, Stein, JL, Stein, GS & Lian, JB 2008, 'Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal', Journal of Biological Chemistry, vol. 283, no. 13, pp. 8412-8422. https://doi.org/10.1074/jbc.M705578200
Javed, Amjad ; Bae, Jong Sup ; Afza, Faiza ; Gutierrez, Soraya ; Pratap, Jitesh ; Zaidi, Sayyed K. ; Lou, Yang ; van Wijnen, Andre J ; Stein, Janet L. ; Stein, Gary S. ; Lian, Jane B. / Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 13. pp. 8412-8422.
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