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

J Clin Invest. 2016 Dec 1;126(12):4482-4496. doi: 10.1172/JCI87802. Epub 2016 Oct 31.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cherubism / genetics
  • Cherubism / metabolism
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Osteoblasts / metabolism*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Core Binding Factor Alpha 1 Subunit
  • PPAR gamma
  • Runx2 protein, mouse
  • Sh3bp2 protein, mouse
  • Wwtr1 protein, mouse
  • Proto-Oncogene Proteins c-abl