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E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR

Mesenchymal stem cells (MSCs) are adult stem cell populations and exhibit great potential in regenerative medicine and oncology. Platelet-derived growth factors (PDGFs) are well known to regulate MSC biology through their chemotactic and mitogenic properties. However, their direct roles in the regul...

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Autores principales: Pham, Tri, Najy, Abdo J., Kim, Hyeong-Reh C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133640/
https://www.ncbi.nlm.nih.gov/pubmed/35472332
http://dx.doi.org/10.1016/j.jbc.2022.101981
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author Pham, Tri
Najy, Abdo J.
Kim, Hyeong-Reh C.
author_facet Pham, Tri
Najy, Abdo J.
Kim, Hyeong-Reh C.
author_sort Pham, Tri
collection PubMed
description Mesenchymal stem cells (MSCs) are adult stem cell populations and exhibit great potential in regenerative medicine and oncology. Platelet-derived growth factors (PDGFs) are well known to regulate MSC biology through their chemotactic and mitogenic properties. However, their direct roles in the regulation of MSC lineage commitment are unclear. Here, we show that PDGF D promotes the differentiation of human bone marrow mesenchymal stem cells (hBMSCs) into osteoblasts and inhibits hBMSC differentiation into adipocytes. We demonstrate that PDGF D-induced β-actin expression and polymerization are essential for mediating this differential regulation of osteoblastogenesis and adipogenesis. Interestingly, we found that PDGF D induces massive upward molecular weight shifts of its cognate receptor, PDGF receptor beta (β-PDGFR) in hBMSCs, which was not observed in fibroblasts. Proteomic analysis indicated that the E3 ubiquitin ligase HECT, UBA, and WWE domain–containing protein 1 (HUWE1) associates with the PDGF D-activated β-PDGFR signaling complex in hBMSCs, resulting in β-PDGFR polyubiquitination. In contrast to the well-known role of ubiquitin in protein degradation, we provide evidence that HUWE1-mediated β-PDGFR polyubiquitination delays β-PDGFR internalization and degradation, thereby prolonging AKT signaling. Finally, we demonstrate that HUWE1-regulated β-PDGFR signaling is essential for osteoblastic differentiation of hBMSCs, while being dispensable for PDGF D-induced hBMSC migration and proliferation as well as PDGF D-mediated inhibition of hBMSC differentiation into adipocytes. Taken together, our findings provide novel insights into the molecular mechanism by which PDGF D regulates the commitment of hBMSCs into the osteoblastic lineage.
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spelling pubmed-91336402022-06-04 E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR Pham, Tri Najy, Abdo J. Kim, Hyeong-Reh C. J Biol Chem Research Article Mesenchymal stem cells (MSCs) are adult stem cell populations and exhibit great potential in regenerative medicine and oncology. Platelet-derived growth factors (PDGFs) are well known to regulate MSC biology through their chemotactic and mitogenic properties. However, their direct roles in the regulation of MSC lineage commitment are unclear. Here, we show that PDGF D promotes the differentiation of human bone marrow mesenchymal stem cells (hBMSCs) into osteoblasts and inhibits hBMSC differentiation into adipocytes. We demonstrate that PDGF D-induced β-actin expression and polymerization are essential for mediating this differential regulation of osteoblastogenesis and adipogenesis. Interestingly, we found that PDGF D induces massive upward molecular weight shifts of its cognate receptor, PDGF receptor beta (β-PDGFR) in hBMSCs, which was not observed in fibroblasts. Proteomic analysis indicated that the E3 ubiquitin ligase HECT, UBA, and WWE domain–containing protein 1 (HUWE1) associates with the PDGF D-activated β-PDGFR signaling complex in hBMSCs, resulting in β-PDGFR polyubiquitination. In contrast to the well-known role of ubiquitin in protein degradation, we provide evidence that HUWE1-mediated β-PDGFR polyubiquitination delays β-PDGFR internalization and degradation, thereby prolonging AKT signaling. Finally, we demonstrate that HUWE1-regulated β-PDGFR signaling is essential for osteoblastic differentiation of hBMSCs, while being dispensable for PDGF D-induced hBMSC migration and proliferation as well as PDGF D-mediated inhibition of hBMSC differentiation into adipocytes. Taken together, our findings provide novel insights into the molecular mechanism by which PDGF D regulates the commitment of hBMSCs into the osteoblastic lineage. American Society for Biochemistry and Molecular Biology 2022-04-25 /pmc/articles/PMC9133640/ /pubmed/35472332 http://dx.doi.org/10.1016/j.jbc.2022.101981 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Pham, Tri
Najy, Abdo J.
Kim, Hyeong-Reh C.
E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR
title E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR
title_full E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR
title_fullStr E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR
title_full_unstemmed E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR
title_short E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-PDGFR
title_sort e3 ligase huwe1 promotes pdgf d-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of β-pdgfr
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133640/
https://www.ncbi.nlm.nih.gov/pubmed/35472332
http://dx.doi.org/10.1016/j.jbc.2022.101981
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