Flt3 is a target of coumestrol in protecting against UVB-induced skin photoaging.
While skin aging is a naturally occurring process by senescence, exposure to ultraviolet (UV) radiation accelerates wrinkle formation and sagging of skin. UV induces skin aging by degrading collagen via activating matrix metalloproteinases (MMPs). In this study, we show that coumestrol, a metabolite of the soybean isoflavone daidzein, has a preventive effect on skin photoaging in three-dimensional human skin equivalent model. Coumestrol inhibited UVB-induced MMP-1 expression and activity. Whole human kinase profiling assay identified FLT3 kinase as a novel target protein of coumestrol in UVB-induced signaling pathway in skin. Coumestrol suppresses FLT3 kinase activity, and subsequently, Ras/MEK/ERK and Akt/p70 ribosomal S6 kinase pathway. This suppresses AP-1 activity and in turn, diminishes MMP-1 gene transcription. Using X-ray crystallography, the binding of coumestrol to FLT3 was defined and implied ATP-competitive inhibition. Residues Lys644 and Phe830 showed local changes to accommodate coumestrol in the ATP-binding pocket. 4-APIA, a pharmacological inhibitor of FLT3, inhibited MMP-1 expression and induced signal transduction changes similar to coumestrol. Taken together, coumestrol inhibits UVB-induced MMP-1 expression by suppressing FLT3 kinase activity. These findings suggest that coumestrol is a novel dietary compound with potential application in preventing and improving UVB-associated skin aging.
WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
Gaeun
G
Park
Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea; Max Planck Institute for Biochemistry, Martinsried, Germany; Proteros Biostructures GmbH, Martinsried, Germany.
Sohee
S
Baek
WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
Jong-Eun
JE
Kim
WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea; The Hormel Institute, University of Minnesota, Austin, Minnesota, United States.
Tae-gyu
TG
Lim
Department of Food Science, Cornell University, Ithaca, New York, United States.
Charles C
CC
Lee
WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea.
Hee
H
Yang
Skin Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea.
Young-Gyu
YG
Kang
Skin Research Institute, Amorepacific Corporation R&D Center, Yongin, Republic of Korea.
Jun Seong
JS
Park
Proteros Biostructures GmbH, Martinsried, Germany.
Martin
M
Augustin
Proteros Biostructures GmbH, Martinsried, Germany.
Michael
M
Mrosek
Department of Food Science, Cornell University, Ithaca, New York, United States; Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
Chang Yong
CY
Lee
The Hormel Institute, University of Minnesota, Austin, Minnesota, United States.
Zigang
Z
Dong
Max Planck Institute for Biochemistry, Martinsried, Germany; Department of Chemistry, Technical University of Munich, Garching, Germany; School of Biosciences, Cardiff University, Wales, UK; Center for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany.
Robert
R
Huber
WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea; Institute on Aging, Seoul National University, Seoul, Republic of Korea. Electronic address: kiwon@snu.ac.kr.
Ki Won
KW
Lee
D002478:Cells, Cultured; D003375:Coumestrol / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000187:drug effects; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D012867:Skin / Q000528:radiation effects*; D015595:Skin Aging / Q000187:drug effects*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051941:fms-Like Tyrosine Kinase 3 / Q000187:drug effects*
D011480:Protease Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D020781:Matrix Metalloproteinase 1; D003375:Coumestrol
Coumestrol; FLT3 kinase; Matrix metalloproteinase 1; Photoaging