TY - JOUR
T1 - Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2
AU - Matsumoto, Yoshinori
AU - Rose, Jose La
AU - Kent, Oliver A.
AU - Wagner, Melany J.
AU - Narimatsu, Masahiro
AU - Levy, Aaron D.
AU - Omar, Mitchell H.
AU - Tong, Jiefei
AU - Krieger, Jonathan R.
AU - Riggs, Emily
AU - Storozhuk, Yaryna
AU - Pasquale, Julia
AU - Ventura, Manuela
AU - Yeganeh, Behzad
AU - Post, Martin
AU - Moran, Michael F.
AU - Grynpas, Marc D.
AU - Wrana, Jeffrey L.
AU - Superti-Furga, Giulio
AU - Koleske, Anthony J.
AU - Pendergast, Ann Marie
AU - Rottapel, Robert
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI87802
DO - 10.1172/JCI87802
M3 - Article
C2 - 27797343
AN - SCOPUS:85002549261
VL - 126
SP - 4482
EP - 4496
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -