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

Journal Article

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 PPARγ-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.

Full Text

Duke Authors

Cited Authors

  • Matsumoto, Y; La Rose, J; Kent, OA; Wagner, MJ; Narimatsu, M; Levy, AD; Omar, MH; Tong, J; Krieger, JR; Riggs, E; Storozhuk, Y; Pasquale, J; Ventura, M; Yeganeh, B; Post, M; Moran, MF; Grynpas, MD; Wrana, JL; Superti-Furga, G; Koleske, AJ; Pendergast, AM; Rottapel, R

Published Date

  • December 2016

Published In

Volume / Issue

  • 126 / 12

Start / End Page

  • 4482 - 4496

PubMed ID

  • 27797343

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci87802

Language

  • eng