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

J Exp Med. 2019 Jan 7;216(1):195-214. doi: 10.1084/jem.20171849. Epub 2018 Dec 21.

Authors

Xing Chen¹, Gang Cai^{1

2}, Caini Liu¹, Junjie Zhao¹, Chunfang Gu^{1

3}, Ling Wu^{1

4}, Thomas A Hamilton¹, Cun-Jin Zhang¹, Jennifer Ko^{1

5}, Liang Zhu⁶, Jun Qin⁶, Allison Vidimos⁷, Shlomo Koyfman⁸, Brian R Gastman^{1

7

9}, Kim B Jensen^{10

11}, Xiaoxia Li¹²

Affiliations

¹ Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH.
² Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
³ National Institute of Environmental Health Sciences, Research Triangle Park, NC.
⁴ Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH.
⁵ Department of Anatomical Pathology, Cleveland Clinic, Cleveland, OH.
⁶ Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH.
⁷ Department of Dermatology, Cleveland Clinic, Cleveland, OH.
⁸ Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH.
⁹ Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH.
¹⁰ Novo Nordisk Foundation Center for Stem Cell Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹ Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
¹² Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH [email protected].

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
CSK Tyrosine-Protein Kinase
Carcinogenesis / genetics
Carcinogenesis / metabolism*
Carcinogenesis / pathology
Epidermis / metabolism*
Epidermis / pathology
ErbB Receptors / genetics
ErbB Receptors / metabolism*
HeLa Cells
Humans
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Mice
Mice, Knockout
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Receptors, Interleukin-17 / genetics
Receptors, Interleukin-17 / metabolism*
Signal Transduction*
Stem Cells / metabolism*
Stem Cells / pathology
Wound Healing*
src-Family Kinases / genetics
src-Family Kinases / metabolism

Substances

Adaptor Proteins, Signal Transducing
Il17ra protein, mouse
Lrig1 protein, mouse
Membrane Glycoproteins
Nerve Tissue Proteins
Receptors, Interleukin-17
Traf3ip2 protein, mouse
EGFR protein, mouse
ErbB Receptors
CSK Tyrosine-Protein Kinase
src-Family Kinases
CSK protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding