IKK? is a ?-catenin kinase that regulates mesenchymal stem cell differentiation.

ABSTRACT: Mesenchymal stem cells (MSCs) can give rise to both adipocytes and osteoblasts, but the molecular mechanisms underlying MSC fate determination remain poorly understood. I?B kinase ? (IKK?), a central coordinator of inflammation and immune responses through activation of NF-?B, has been implicated as a critical molecular link between obesity and metabolic disorders. Here, we show that IKK? can reciprocally regulate adipocyte and osteoblast differentiation of murine and human MSCs through an NF-?B-independent mechanism. IKK? is a ?-catenin kinase that phosphorylates the conserved degron motif of ?-catenin to prime it for ?-TrCP-mediated ubiquitination and degradation, thereby increasing adipogenesis and inhibiting osteogenesis in MSCs. Animal studies demonstrated that deficiency of IKK? in BM mesenchymal stromal cells increased bone mass and decreased BM adipocyte formation in adult mice. In humans, IKK? expression in adipose tissue was also positively associated with increased adiposity and elevated ?-catenin phosphorylation. These findings suggest IKK? as a key molecular switch that regulates MSC fate, and they provide potentially novel mechanistic insights into the understanding of the cross-regulation between the evolutionarily conserved IKK? and Wnt/?-catenin signaling pathways. The IKK?-Wnt axis we uncovered may also have important implications for development, homeostasis, and disease pathogenesis.

SUBMITTER: Sui Y 

PROVIDER: S-EPMC5821193 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other