Hyaluronan Facilitates Transforming Growth Factor-beta 1-dependent Proliferation via CD44 and Epidermal Growth Factor Receptor Interaction

作者：Meran Soma^*; Luo Dong Dong; Simpson Russell; Martin John; Wells Alan; Steadman Robert; Phillips Aled O

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286(20): 17618-17630.

DOI：10.1074/jbc.M111.226563

Fibroblast proliferation is an early feature of progressive tissue fibrosis and is largely regulated by the cytokine transforming growth factor-beta 1 (TGF-beta 1). 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-beta 1, oral fibroblasts have an antiproliferative response to this cytokine. Hyaluronan (HA) was directly linked to this TGF-beta 1-dependent response. The aim of this study was to understand the underlying mechanism through which HA regulates TGF-beta-dependent responses. Using patient-matched oral and dermal fibroblasts, we show that TGF-beta 1-dependent proliferation is mediated through the HA receptor CD44, whereas the TGF-beta 1-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-beta 1. We also show that epidermal growth factor (EGF) and its receptor (EGFR) are essential for TGF-beta 1/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-beta 1. In comparison, in a non-HA-rich environment, only early ERK1/2 activation occurs, and this is associated with an antiproliferative response to TGF-beta 1. In summary, HA facilitates TGF-beta 1-dependent fibroblast proliferation through promoting interaction between CD44 and EGFR, which then promotes specific MAPK/ERK activation, inducing cellular proliferation.

• 出版日期2011-5-20