Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2

Yoshinori Matsumoto, Jose La Rose, Oliver A. Kent, Melany J. Wagner, Masahiro Narimatsu, Aaron D. Levy, Mitchell H. Omar, Jiefei Tong, Jonathan R. Krieger, Emily Riggs, Yaryna Storozhuk, Julia Pasquale, Manuela Ventura, Behzad Yeganeh, Martin Post, Michael F. Moran, Marc D. Grynpas, Jeffrey L. Wrana, Giulio Superti-Furga, Anthony J. KoleskeAnn Marie Pendergast, Robert Rottapel

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22 Citations (Scopus)

Abstract

Cellular identity in metazoan organisms is frequently established through lineage-specifying transcription factors, which control their own expression through transcriptional positive feedback, while antagonizing the developmental networks of competing lineages. Here, we have uncovered a distinct positive feedback loop that arises from the reciprocal stabilization of the tyrosine kinase ABL and the transcriptional coactivator TAZ. Moreover, we determined that this loop is required for osteoblast differentiation and embryonic skeletal formation. ABL potentiated the assembly and activation of the RUNX2-TAZ master transcription factor complex that is required for osteoblastogenesis, while antagonizing PPAR?-mediated adipogenesis. ABL also enhanced TAZ nuclear localization and the formation of the TAZ-TEAD complex that is required for osteoblast expansion. Last, we have provided genetic data showing that regulation of the ABL-TAZ amplification loop lies downstream of the adaptor protein 3BP2, which is mutated in the craniofacial dysmorphia syndrome cherubism. Our study demonstrates an interplay between ABL and TAZ that controls the mesenchymal maturation program toward the osteoblast lineage and is mechanistically distinct from the established model of lineage-specific maturation.

Original languageEnglish
Pages (from-to)4482-4496
Number of pages15
JournalJournal of Clinical Investigation
Volume126
Issue number12
DOIs
Publication statusPublished - Dec 1 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Matsumoto, Y., Rose, J. L., Kent, O. A., Wagner, M. J., Narimatsu, M., Levy, A. D., Omar, M. H., Tong, J., Krieger, J. R., Riggs, E., Storozhuk, Y., Pasquale, J., Ventura, M., Yeganeh, B., Post, M., Moran, M. F., Grynpas, M. D., Wrana, J. L., Superti-Furga, G., ... Rottapel, R. (2016). Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2. Journal of Clinical Investigation, 126(12), 4482-4496. https://doi.org/10.1172/JCI87802