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. Koleske, Ann Marie Pendergast, Robert Rottapel
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. Koleske, Ann Marie Pendergast, Robert Rottapel
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Research Article Bone biology Cell biology

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

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.

Authors

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. Koleske, Ann Marie Pendergast, Robert Rottapel

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Figure 8

The ABL-TAZ amplification loop required for osteoblastogenesis is regulated by the adapter protein 3BP2.

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The ABL-TAZ amplification loop required for osteoblastogenesis is regula...
(A) Primary murine osteoblasts from WT or Sh3bp2–/– (KO) mice were cultured in osteogenic medium. Nuclear lysates were probed with the indicated antibodies for Western blot analysis. (B) Primary murine osteoblasts from WT or Sh3bp2–/– (KO) mice were infected with an empty vector control or FKBP-ABL–expressing retroviral vector (WT) and cultured in osteogenic medium. Nuclear lysates were probed with the indicated antibodies for Western blot analysis. (C) Osteoblasts in B were cultured in osteogenic medium and stained with alizarin red S solution. n = 3. (D) NIH3T3 cells infected with an empty vector control or a retroviral vector expressing FKBP-ABL (WT or KD) were cultured in adipogenic medium and stained with oil red O solution. Upper panel: bright-field images; bottom panel: oil red O–stained images; original magnification ×200. n = 3. (E) Culture plate images of the oil red O staining in D. n = 3. (F) qPCR analysis of aP2 mRNA expression in cells in D and E cultured for 3 to 6 days. n = 3. Data are presented as the mean ± SEM. (G) Luciferase activity from an aP2 reporter assay in HEK293T cells cotransfected with the indicated constructs. n = 3. *P < 0.05, by ANOVA with a Tukey-Kramer post-hoc test. (H) Schematic model of reciprocal protein stabilization of ABL and TAZ , which regulates osteoblastogenesis through the activation of RUNX2.