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Transforming growth factor-β1 (TGF-β1)-stimulated fibroblast to myofibroblast differentiation Is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts

Midgley, Adam Christopher, Rogers, Mathew James, Hallett, Maurice Bartlett, Clayton, Aled, Bowen, Timothy, Phillips, Aled Owain and Steadman, Robert 2013. Transforming growth factor-β1 (TGF-β1)-stimulated fibroblast to myofibroblast differentiation Is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. Journal of Biological Chemistry 288 (21) , pp. 14824-14838. 10.1074/jbc.M113.451336

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Abstract

Fibroblast to myofibroblast differentiation drives effective wound healing and is largely regulated by the cytokine transforming growth factor-β1 (TGF-β1). Myofibroblasts express α-smooth muscle actin and are present in granulation tissue, where they are responsible for wound contraction. Our previous studies show that fibroblast differentiation in response to TGF-β1 is dependent on and mediated by the linear polysaccharide hyaluronan (HA). Both the HA receptor, CD44, and the epidermal growth factor receptor (EGFR) are involved in this differentiation response. The aim of this study was to understand the mechanisms linking HA-, CD44-, and EGFR-regulated TGF-β1-dependent differentiation. CD44 and EGFR co-localization within membrane-bound lipid rafts was necessary for differentiation, and this triggered downstream mitogen-activated protein kinase (MAPK/ERK) and Ca2+/calmodulin kinase II (CaMKII) activation. We also found that ERK phosphorylation was upstream of CaMKII phosphorylation, that ERK activation was necessary for CaMKII signaling, and that both kinases were essential for differentiation. In addition, HA synthase-2 (HAS2) siRNA attenuated both ERK and CaMKII signaling and sequestration of CD44 into lipid rafts, preventing differentiation. In summary, the data suggest that HAS2-dependent production of HA facilitates TGF-β1-dependent fibroblast differentiation through promoting CD44 interaction with EGFR held within membrane-bound lipid rafts. This induces MAPK/ERK, followed by CaMKII activation, leading to differentiation. This pathway is synergistic with the classical TGF-β1-dependent SMAD-signaling pathway and may provide a novel opportunity for intervention in wound healing.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Uncontrolled Keywords: CD44; Epidermal Growth Factor Receptor (EGFR); Hyaluronate; Lipid Raft; Myofibroblast
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Last Modified: 14 Mar 2019 21:21
URI: http://orca.cf.ac.uk/id/eprint/49379

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