Pin1-mediated Runx2 modification is critical for skeletal development

Won Joon Yoon, Rabia Islam, Young Dan Cho, Kyung Mi Woo, Jeong Hwa Baek, Takafumi Uchida, Toshihisa Komori, Andre van Wijnen, Janet L. Stein, Jane B. Lian, Gary S. Stein, Je Yong Choi, Suk Chul Bae, Hyun Mo Ryoo

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17 Scopus citations

Abstract

Runx2 is the master transcription factor for bone formation. Haploinsufficiency of RUNX2 is the genetic cause of cleidocranial dysplasia (CCD) that is characterized by hypoplastic clavicles and open fontanels. In this study, we found that Pin1, peptidyl prolyl cis-trans isomerase, is a critical regulator of Runx2 in vivo and in vitro. Pin1 mutant mice developed CCD-like phenotypes with hypoplastic clavicles and open fontanels as found in the Runx2+/- mice. In addition Runx2 protein level was significantly reduced in Pin1 mutant mice. Moreover Pin1 directly interacts with the Runx2 protein in a phosphorylation-dependent manner and subsequently stabilizes Runx2 protein. In the absence of Pin1, Runx2 is rapidly degraded by the ubiquitin-dependent protein degradation pathway. However, Pin1 overexpression strongly attenuated uniquitin-dependent Runx2 degradation. Collectively conformational change of Runx2 by Pin1 is essential for its protein stability and possibly enhances the level of active Runx2 in vivo.

Original languageEnglish (US)
Pages (from-to)2377-2385
Number of pages9
JournalJournal of Cellular Physiology
Volume228
Issue number12
DOIs
StatePublished - Dec 1 2013

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ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Yoon, W. J., Islam, R., Cho, Y. D., Woo, K. M., Baek, J. H., Uchida, T., Komori, T., van Wijnen, A., Stein, J. L., Lian, J. B., Stein, G. S., Choi, J. Y., Bae, S. C., & Ryoo, H. M. (2013). Pin1-mediated Runx2 modification is critical for skeletal development. Journal of Cellular Physiology, 228(12), 2377-2385. https://doi.org/10.1002/jcp.24403