Pin1-mediated Modification Prolongs the Nuclear Retention of β-Catenin in Wnt3a-induced Osteoblast Differentiation

• Published in: The Journal of biological chemistry Vol. 291; no. 11; pp. 5555 - 5565
• Main Authors: Shin, Hye-Rim, Islam, Rabia, Yoon, Won-Joon, Lee, Taegyung, Cho, Young-Dan, Bae, Han-sol, Kim, Bong-Su, Woo, Kyung-Mi, Baek, Jeong-Hwa, Ryoo, Hyun-Mo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-03-2016; American Society for Biochemistry and Molecular Biology
• Subjects: adenomatous polyposis coli (APC); Animals; beta Catenin - metabolism; Cell Differentiation; Cell Line; Cell Nucleus - genetics; Cell Nucleus - metabolism; HEK293 Cells; Humans; Mice; Mice, Knockout; NIMA-Interacting Peptidylprolyl Isomerase; nuclear translocation; osteoblast; Osteoblasts - cytology; Osteoblasts - metabolism; Osteogenesis; peptidyl prolyl cis-trans isomerization; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1); Peptidylprolyl Isomerase - genetics; Peptidylprolyl Isomerase - metabolism; Proteolysis; Signal Transduction; Wnt signaling; Wnt3A Protein - metabolism; β-catenin; β-catenin; cell differentiation; Wnt signaling; nuclear translocation; peptidyl prolyl cis-trans isomerization; adenomatous polyposis coli (APC); peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1); osteoblast; osteogenesis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.698563

The canonical Wnt signaling pathway, in which β-catenin nuclear localization is a crucial step, plays an important role in osteoblast differentiation. Pin1, a prolyl isomerase, is also known as a key enzyme in osteogenesis. However, the role of Pin1 in canonical Wnt signal-induced osteoblast differentiation is poorly understood. We found that Pin1 deficiency caused osteopenia and reduction of β-catenin in bone lining cells. Similarly, Pin1 knockdown or treatment with Pin1 inhibitors strongly decreased the nuclear β-catenin level, TOP flash activity, and expression of bone marker genes induced by canonical Wnt activation and vice versa in Pin1 overexpression. Pin1 interacts directly with and isomerizes β-catenin in the nucleus. The isomerized β-catenin could not bind to nuclear adenomatous polyposis coli, which drives β-catenin out of the nucleus for proteasomal degradation, which consequently increases the retention of β-catenin in the nucleus and might explain the decrease of β-catenin ubiquitination. These results indicate that Pin1 could be a critical target to modulate β-catenin-mediated osteogenesis.