Abstract
The earlier step of cutaneous wound healing process, re-epithelialization of the wounded skin, is triggered by a variety of growth factors. However, molecular mechanisms through which growth factors trigger skin wound healing are less understood. Here, we demonstrate that hepatocyte growth factor (HGF)/c-Met signaling-induced expression of the small G protein Arf6 mRNA in keratinocytes is essential for the skin wound healing. Arf6 mRNA expression was dramatically induced in keratinocytes at the wounded skin, which was specifically suppressed by the c-Met inhibitor. Wound healing of the skin was significantly delayed in keratinocyte-specific Arf6 conditional knockout mice. Furthermore, Arf6 deletion from keratinocytes remarkably suppressed HGF-stimulated cell migration and peripheral membrane ruffle formation, but did not affect skin morphology and proliferation/differentiation of keratinocytes. These results are consistent with the notion that Arf6 expressed in skin keratinocytes through the HGF/c-Met signaling pathway in response to skin wounding plays an important role in skin wound healing by regulating membrane dynamics-based motogenic cellular function of keratinocytes.
Highlights
The results obtained in this study provide evidence for the first time that expression of Arf[6] mRNA in keratinocytes is induced via hepatocyte growth factor (HGF)/c-Met signaling when the skin is wounded, and upregulated Arf[6] at least in part plays an important role in skin wound healing by regulating the membrane dynamics-based motogenic function of keratinocytes
It has been reported that expression of HGF and c-Met mRNAs is elicited in keratinocytes at wound edge when the skin is injured[7], the HGF protein is expressed only in hair follicle mesenchyme of normal skin, but not in epidermis, and c-Met exists in neighboring hair bulb keratinocytes[28]
Similar to HGF and c-Met mRNA expression, expression of Arf[6] mRNA in keratinocyte was induced in response to skin wound (Fig. 1B–D), which was inhibited by the c-Met inhibitor PHA665752 in a dose-dependent manner (Fig. 3D–G), suggesting that HGF/c-Met axis is a key signaling pathway for the induction of Arf[6] mRNA expression
Summary
Endosomes regulates membrane dynamics-based cellular events such as actin cytoskeleton reorganization[12,13], membrane trafficking[14,15], membrane ruffling[16], epithelial cell migration[17] and wound healing in vitro[18] by controlling the membrane lipid composition of these organelles through lipid-metabolizing enzymes: Arf[6] directly activates phosphatidylinositol 4-phosphate 5-kinase (PIP5K), which generates the versatile membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PI4,5P2)[16], and phospholipase D (PLD), which produces the signaling lipid phosphatidic acid (PA)[19]. It has been reported that Arf[6] is activated upon cell stimulation by several growth factors, including EGF20 and HGF21,22. These reports led us to speculate that Arf[6] plays an important role in growth factor-promoted skin wound healing. Results obtained indicate that expression of Arf[6] mRNA is drastically induced in keratinocytes at the wound site after injury of the skin through the HGF/c-Met-mediated signaling to regulate the membrane dynamics-based motogenic cellular function, which is responsible for promotion of skin wound healing in vivo
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