The B56α subunit of PP2A is necessary for mesenchymal stem cell commitment to adipocyte

• Published in: EMBO reports Vol. 22; no. 8; pp. e51910 - n/a
• Main Authors: Hanse, Eric A, Pan, Min, Liu, Wenzhu, Yang, Ying, Ishak Gabra, Mari B, Tran, Thai Q, Lowman, Xazmin H, Ruiz, Bryan, Wang, Qiong A, Kong, Mei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.08.2021; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: adipocyte; Adipocytes; Adipose tissue; B56α; Biomedical materials; Cell differentiation; Depletion; Differentiation; EMBO11; EMBO21; EMBO37; Mesenchymal stem cells; Peroxisome proliferator-activated receptors; Phosphatase; Phosphoprotein phosphatase; Phosphorylation; PP2A; PPARγ; Protein phosphatase; Proteins; Signal transduction; Signaling; Stem cell transplantation; Stem cells; Wnt; Wnt protein; B56α; PP2A; Wnt; PPARγ; adipocyte
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202051910

Adipose tissue plays a major role in maintaining organismal metabolic equilibrium. Control over the fate decision from mesenchymal stem cells (MSCs) to adipocyte differentiation involves coordinated command of phosphorylation. Protein phosphatase 2A plays an important role in Wnt pathway and adipocyte development, yet how PP2A complexes actively respond to adipocyte differentiation signals and acquire specificity in the face of the promiscuous activity of its catalytic subunit remains unknown. Here, we report the PP2A phosphatase B subunit B56α is specifically induced during adipocyte differentiation and mediates PP2A to dephosphorylate GSK3β, thereby blocking Wnt activity and driving adipocyte differentiation. Using an inducible B56α knock-out mouse, we further demonstrate that B56α is essential for gonadal adipose tissue development in vivo and required for the fate decision of adipocytes over osteoblasts. Moreover, we show B56α expression is driven by the adipocyte transcription factor PPARγ thereby establishing a novel link between PPARγ signaling and Wnt blockade. Overall, our results reveal B56α is a necessary part of the machinery dictating the transition from pre-adipocyte to mature adipocyte and provide fundamental insights into how PP2A complex specifically and actively regulates unique signaling pathway in biology. SYNOPSIS PP2A phosphatase subunit B56α is specifically induced to regulate Wnt signaling during adipocyte differentiation. B56α depletion is detrimental to adipocyte development in vitro and gonadal WAT development in vivo . B56α expression is tightly regulated during adipocyte development. B56α knock-out mice have a deficiency in gonadal white adipose development. GSK3b, Axin and b-catenin are found in a complex with B56α protein. B56α binds directly to GSK3b and correlates with its phosphorylation status. B56α protein expression is controlled by the master adipogenic transcriptional activator, PPARg. Graphical Abstract PP2A phosphatase subunit B56α is specifically induced to regulate Wnt signaling during adipocyte differentiation. B56α depletion is detrimental to adipocyte development in vitro and gonadal WAT development in vivo .