IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation

Yipeng Sui, Zun Liu, Se Hyung Park, Sean E. Thatcher, Beibei Zhu, Joseph P. Fernandez, Henrik Molina, Philip A. Kern, Changcheng Zhou

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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

Original languageEnglish
JournalJCI insight
Volume3
Issue number2
DOIs
StatePublished - Jan 25 2018

Keywords

  • Adipose tissue
  • Adult stem cells
  • Cell Biology
  • NF-kappaB
  • Stem cells

ASJC Scopus subject areas

  • Medicine (all)

Fingerprint

Dive into the research topics of 'IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation'. Together they form a unique fingerprint.

Cite this