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

doi:10.1084/jem.20171849

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 for this work

The Danish Stem Cell Center

37 Citations (Scopus)

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.

Original language	English
Journal	Journal of Experimental Medicine
Volume	216
Issue number	1
Pages (from-to)	195-214
Number of pages	20
ISSN	0022-1007
DOIs	https://doi.org/10.1084/jem.20171849
Publication status	Published - 1 Jan 2019

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10.1084/jem.20171849Licence: CC BY-NC-SA

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Chen, X., Cai, G., Liu, C., Zhao, J., Gu, C., Wu, L., Hamilton, T. A., Zhang, C. J., Ko, J., Zhu, L., Qin, J., Vidimos, A., Koyfman, S., Gastman, B. R., Jensen, K. B., & Li, X. (2019). IL-17R–EGFR axis links wound healing to tumorigenesis in Lrig1 ⁺ stem cells. Journal of Experimental Medicine, 216(1), 195-214. https://doi.org/10.1084/jem.20171849

Chen, X, Cai, G, Liu, C, Zhao, J, Gu, C, Wu, L, Hamilton, TA, Zhang, CJ, Ko, J, Zhu, L, Qin, J, Vidimos, A, Koyfman, S, Gastman, BR, Jensen, KB & Li, X 2019, 'IL-17R–EGFR axis links wound healing to tumorigenesis in Lrig1 ⁺ stem cells', Journal of Experimental Medicine, vol. 216, no. 1, pp. 195-214. https://doi.org/10.1084/jem.20171849

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

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. ",

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

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AU - Chen, Xing

AU - Cai, Gang

AU - Liu, Caini

AU - Zhao, Junjie

AU - Gu, Chunfang

AU - Wu, Ling

AU - Hamilton, Thomas A.

AU - Zhang, Cun jin

AU - Ko, Jennifer

AU - Zhu, Liang

AU - Qin, Jun

AU - Vidimos, Allison

AU - Koyfman, Shlomo

AU - Gastman, Brian R.

AU - Jensen, Kim B.

AU - Li, Xiaoxia

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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DO - 10.1084/jem.20171849

M3 - Journal article

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AN - SCOPUS:85059926688

SN - 0022-1007

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SP - 195

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JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 1

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

Abstract

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