Phosphoproteomic profiling reveals a defined genetic program for osteoblastic lineage commitment of human bone marrow–derived stromal stem cells
- Inigo Barrio-Hernandez1,
- Abbas Jafari2,3,
- Kristoffer T.G. Rigbolt1,
- Philip Hallenborg1,
- Virginia Sanchez-Quiles1,
- Ida Skovrind1,
- Vyacheslav Akimov1,
- Irina Kratchmarova1,
- Joern Dengjel4,
- Moustapha Kassem2,3 and
- Blagoy Blagoev1
- 1Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark;
- 2Department of Endocrinology and Metabolism, University Hospital of Odense and University of Southern Denmark, 5000 Odense C, Denmark;
- 3Department of Cellular and Molecular Medicine, The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark;
- 4Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland
Abstract
Bone marrow–derived mesenchymal stem cells (MSCs) differentiate into osteoblasts upon stimulation by signals present in their niche. Because the global signaling cascades involved in the early phases of MSCs osteoblast (OB) differentiation are not well-defined, we used quantitative mass spectrometry to delineate changes in human MSCs proteome and phosphoproteome during the first 24 h of their OB lineage commitment. The temporal profiles of 6252 proteins and 15,059 phosphorylation sites suggested at least two distinct signaling waves: one peaking within 30 to 60 min after stimulation and a second upsurge after 24 h. In addition to providing a comprehensive view of the proteome and phosphoproteome dynamics during early MSCs differentiation, our analyses identified a key role of serine/threonine protein kinase D1 (PRKD1) in OB commitment. At the onset of OB differentiation, PRKD1 initiates activation of the pro-osteogenic transcription factor RUNX2 by triggering phosphorylation and nuclear exclusion of the histone deacetylase HDAC7.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.248286.119.
- Received January 10, 2019.
- Accepted November 5, 2019.
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