IL-17R-EGFR axis links wound healing to tumorigenesis in Lrig1+ stem cells
IL-17R-EGFR axis links wound healing to tumorigenesis in Lrig1+ stem cells
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DOI：
10.1084/jem.20171849
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发表时间：
2019-01-01
影响因子：
15.3
通讯作者：
Li, Xiaoxia
中科院分区：
文献类型：
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作者：
Chen, Xing;Cai, Gang;Li, Xiaoxia
Lrig1标志着正常表皮中局限于上毛囊皮脂腺单位的一个独特的干细胞群体。在这里，我们报道了il - 17a介导的EGFR激活在Lrig1（+）干细胞及其后代对损伤反应的扩张和迁移中起关键作用，从而促进伤口愈合和皮肤肿瘤发生。小鼠中IL-17R接头Act1或EGFR的lrig1特异性缺失会损害伤口愈合并减少肿瘤形成。在机制上，IL-17R在Lrig1（+）干细胞中招募EGFR参与il - 17a介导的信号传导。在Lrig1（+）干细胞中富集的TRAF4可以拴住IL-17RA和EGFR，而Act1可以募集c-Src用于il - 17a诱导的EGFR反式活化和ERK5的下游活化，从而促进Lrig1（+）干细胞的增殖和迁移。本研究表明，IL-17A激活Lrig1（+）干细胞中的IL-17R-EGFR轴，将伤口愈合与肿瘤发生联系起来。
Lrig1 marks a distinct population of stem cells restricted to the upper pilosebaceous unit in normal epidermis. Here we report that IL-17A-mediated activation of EGFR plays a critical role in the expansion and migration of Lrig1(+) stem cells and their progenies in response to wounding, thereby promoting wound healing and skin tumorigenesis. Lrig1-specific deletion of the IL-17R adaptor Act1 or EGFR in mice impairs wound healing and reduces tumor formation. Mechanistically, IL-17R recruits EGFR for IL-17A-mediated signaling in Lrig1(+) stem cells. While TRAF4, enriched in Lrig1(+) stem cells, tethers IL-17RA and EGFR, Act1 recruits c-Src for IL-17A-induced EGFR transactivation and downstream activation of ERK5, which promotes the expansion and migration of Lrig1(+) stem cells. This study demonstrates that IL-17A activates the IL-17R-EGFR axis in Lrig1(+) stem cells linking wound healing to tumorigenesis.