Hyaluronan facilitates transforming growth factor-β1-dependent proliferation via CD44 and epidermal growth factor receptor interaction

Meran, Soma ORCID: https://orcid.org/0000-0003-3408-3978, Luo, Dong Dong, Simpson, Russell M. L., Martin, John, Wells, Alan, Steadman, Robert ORCID: https://orcid.org/0000-0002-1303-2496 and Phillips, Aled Owain ORCID: https://orcid.org/0000-0001-9744-7113 2011. Hyaluronan facilitates transforming growth factor-β1-dependent proliferation via CD44 and epidermal growth factor receptor interaction. Journal of Biological Chemistry 286 (20) , pp. 17618-17630. 10.1074/jbc.M111.226563

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Abstract

Fibroblast proliferation is an early feature of progressive tissue fibrosis and is largely regulated by the cytokine transforming growth factor-β1 (TGF-β1). In the oral mucosa, fibroblasts have a unique phenotype and demonstrate healing with no fibrosis/scarring. Our previous studies show that whereas dermal fibroblasts proliferate in response to TGF-β1, oral fibroblasts have an antiproliferative response to this cytokine. Hyaluronan (HA) was directly linked to this TGF-β1-dependent response. The aim of this study was to understand the underlying mechanism through which HA regulates TGF-β-dependent responses. Using patient-matched oral and dermal fibroblasts, we show that TGF-β1-dependent proliferation is mediated through the HA receptor CD44, whereas the TGF-β1-mediated antiproliferative response is CD44-independent. Furthermore, overexpression of HAS2 (HA synthase-2) in oral cells modifies their response, and they subsequently demonstrate a proliferative, CD44-dependent response to TGF-β1. We also show that epidermal growth factor (EGF) and its receptor (EGFR) are essential for TGF-β1/HA/CD44-dependent proliferation. Increased HA levels promote EGFR and CD44 coupling, potentiating signal transduction through the MAPK/ERK pathway. Thus, in a HA-rich environment, late ERK1/2 activation results from EGFR/CD44 coupling and leads to a proliferative response to TGF-β1. In comparison, in a non-HA-rich environment, only early ERK1/2 activation occurs, and this is associated with an antiproliferative response to TGF-β1. In summary, HA facilitates TGF-β1-dependent fibroblast proliferation through promoting interaction between CD44 and EGFR, which then promotes specific MAPK/ERK activation, inducing cellular proliferation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Subjects:	Q Science > QH Natural history > QH301 Biology R Medicine > RZ Other systems of medicine
Uncontrolled Keywords:	ERK; Fibroblast; Hyaluronate; MAP Kinases (MAPKs); Transforming Growth Factor beta (TGFbeta;) CD44; Epidermal Growth Factor Receptor; Proliferation
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Last Modified:	06 Oct 2023 06:19
URI:	https://orca.cardiff.ac.uk/id/eprint/25747

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