The MEK/ERK signalling cascade is required for sonic hedgehog signalling pathway‐mediated enhancement of proliferation and inhibition of apoptosis in normal keratinocytes

Keratinocytes (KCs) play a critical role in maintaining the cutaneous structure and are involved in various physiological and pathologic processes of the skin. Many inflammatory skin diseases and skin cancers result from excessive proliferation and insufficient apoptosis of KCs. Recent data suggested that the sonic hedgehog (Shh) signalling pathway plays an essential role in the proliferation and apoptosis of normal KCs. However, the mechanism remains poorly defined. Here, we provide evidence that Shh signalling induces proliferation and inhibits apoptosis in normal KCs via cyclin D1 and Bcl2 in an extracellular signal-regulatedkinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent manner. In addition, the effect is independent of phosphoinositide-3 kinase (PI3K)/AKT or Janus kinase/signal transducer and activator of transcription (JAK/STAT) 1/3 pathways. Furthermore, we observed that epidermal growth factor receptor (EGFR) signalling modulates the activity of Shh signalling pathway; besides, Shh and EGFR signalling act additively to induce the ERK activation and the increases in cyclin D1 and Bcl2 thereby affecting proliferation and apoptosis in KCs in vitro. The present study suggests that the MEK/ERK1/2 activation is part of the mechanism of Shh signal-mediated proliferation and apoptosis in normal KCs. Our results may help to elucidate the regulatory mechanisms of the Shh pathway in normal KCs and the pathogenesis of related skin disorders.