IL-17R–EGFR axis links wound healing to tumorigenesis in Lrig1 + stem cells

Xing Chen, Gang Cai, Caini Liu, Junjie Zhao, Chunfang Gu, Ling Wu, Thomas A. Hamilton, Cun jin Zhang, Jennifer Ko, Liang Zhu, Jun Qin, Allison Vidimos, Shlomo Koyfman, Brian R. Gastman, Kim B. Jensen, Xiaoxia Li*

*Corresponding author af dette arbejde

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Abstract

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.

OriginalsprogEngelsk
TidsskriftJournal of Experimental Medicine
Vol/bind216
Udgave nummer1
Sider (fra-til)195-214
Antal sider20
ISSN0022-1007
DOI
StatusUdgivet - 1 jan. 2019

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