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

ABSTRACT: The canonical Wnt signaling pathway, in which ?-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 ?-catenin in bone lining cells. Similarly, Pin1 knockdown or treatment with Pin1 inhibitors strongly decreased the nuclear ?-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 ?-catenin in the nucleus. The isomerized ?-catenin could not bind to nuclear adenomatous polyposis coli, which drives ?-catenin out of the nucleus for proteasomal degradation, which consequently increases the retention of ?-catenin in the nucleus and might explain the decrease of ?-catenin ubiquitination. These results indicate that Pin1 could be a critical target to modulate ?-catenin-mediated osteogenesis.

SUBMITTER: Shin HR 

PROVIDER: S-EPMC4786698 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other