A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis.
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.
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.
Ling
L
Wu
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.
Xing
X
Chen
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.
Junjie
J
Zhao
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.
Bradley
B
Martin
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.
Jarod A
JA
Zepp
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.
Jennifer S
JS
Ko
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.
Chunfang
C
Gu
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.
Gang
G
Cai
Department of Immunology, Genentech, South San Francisco, CA 94080.
Wenjun
W
Ouyang
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.
Ganes
G
Sen
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.
George R
GR
Stark
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.
Bing
B
Su
University of Texas at El Paso, El Paso, TX 79968.
Charlotte M
CM
Vines
University of Manchester, Manchester M13 9PL, England, UK.
Cathy
C
Tournier
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.
Thomas A
TA
Hamilton
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.
Allison
A
Vidimos
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.
Brian
B
Gastman
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.
Caini
C
Liu
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.
Xiaoxia
X
Li
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D025461:Feedback, Physiological; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology*; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D053449:TNF Receptor-Associated Factor 4 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D020381:Interleukin-17; D008565:Membrane Proteins; D010750:Phosphoproteins; D053722:Receptors, Interleukin-17; D053449:TNF Receptor-Associated Factor 4; C436323:Tiarp protein, mouse; C515963:Traf3ip2 protein, mouse; C506368:Traf4 protein, mouse; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D048054:Mitogen-Activated Protein Kinase 7; D048748:MAP Kinase Kinase Kinase 3; C482626:Map3k3 protein, mouse