A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis

Ling Wu; Xing Chen; Junjie Zhao; Bradley Martin; Jarod A Zepp; Jennifer S Ko; Chunfang Gu; Gang Cai; Wenjun Ouyang; Ganes Sen; George R Stark; Bing Su; Charlotte M Vines; Cathy Tournier; Thomas A Hamilton; Allison Vidimos; Brian Gastman; Caini Liu; Xiaoxia Li

doi:10.1084/jem.20150204

A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis

J Exp Med. 2015 Sep 21;212(10):1571-87. doi: 10.1084/jem.20150204. Epub 2015 Sep 7.

Authors

Ling Wu¹, Xing Chen², Junjie Zhao¹, Bradley Martin¹, Jarod A Zepp¹, Jennifer S Ko², Chunfang Gu², Gang Cai³, Wenjun Ouyang⁴, Ganes Sen², George R Stark², Bing Su⁵, Charlotte M Vines⁶, Cathy Tournier⁷, Thomas A Hamilton², Allison Vidimos², Brian Gastman⁸, Caini Liu⁹, Xiaoxia Li⁹

Affiliations

¹ Department of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Pathology and Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
² Department of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
³ Department of Laboratory Medicine, Ruijin Hospital, Shanghai Institute of Immunology, and Department of Immunobiology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁴ Department of Immunology, Genentech, South San Francisco, CA 94080.
⁵ Department of Laboratory Medicine, Ruijin Hospital, Shanghai Institute of Immunology, and Department of Immunobiology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Department of Laboratory Medicine, Ruijin Hospital, Shanghai Institute of Immunology, and Department of Immunobiology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Department of Immunobiology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520 Department of Immunobiology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520.
⁶ University of Texas at El Paso, El Paso, TX 79968.
⁷ University of Manchester, Manchester M13 9PL, England, UK.
⁸ Department of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 Department of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195.
⁹ Department of Immunology, Department of Anatomical Pathology and Clinical Pathology, Department of Cancer Biology, Department of Dermatology, and Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH 44195 lix@ccf.org liuc@ccf.org.

Abstract

Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17-induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17-induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17-dependent sustained activation of the TRAF4-ERK5 axis for keratinocyte proliferation and tumor formation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / pathology
Cell Proliferation / genetics
Feedback, Physiological
Humans
Interleukin-17 / genetics
Interleukin-17 / metabolism*
Keratinocytes / metabolism*
Keratinocytes / pathology*
MAP Kinase Kinase Kinase 3 / genetics
MAP Kinase Kinase Kinase 3 / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mitogen-Activated Protein Kinase 7 / genetics
Mitogen-Activated Protein Kinase 7 / metabolism*
Phosphoproteins / genetics
Phosphoproteins / metabolism
Receptors, Interleukin-17 / genetics
Receptors, Interleukin-17 / metabolism
Signal Transduction
Skin Neoplasms / metabolism
Skin Neoplasms / pathology
TNF Receptor-Associated Factor 4 / genetics
TNF Receptor-Associated Factor 4 / metabolism*
Trans-Activators / genetics
Trans-Activators / metabolism

Substances

Adaptor Proteins, Signal Transducing
Interleukin-17
Membrane Proteins
Phosphoproteins
Receptors, Interleukin-17
TNF Receptor-Associated Factor 4
Tiarp protein, mouse
Traf3ip2 protein, mouse
Traf4 protein, mouse
Trans-Activators
Trp63 protein, mouse
Mitogen-Activated Protein Kinase 7
MAP Kinase Kinase Kinase 3
Map3k3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding