Flt3 is a target of coumestrol in protecting against UVB-induced skin photoaging

Biochem Pharmacol. 2015 Dec 1;98(3):473-83. doi: 10.1016/j.bcp.2015.08.104. Epub 2015 Sep 2.


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.

Keywords: Coumestrol; FLT3 kinase; Matrix metalloproteinase 1; Photoaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Coumestrol / chemistry
  • Coumestrol / pharmacology*
  • Humans
  • Matrix Metalloproteinase 1 / biosynthesis
  • Matrix Metalloproteinase 1 / drug effects
  • Molecular Conformation
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Skin / radiation effects*
  • Skin Aging / drug effects*
  • Ultraviolet Rays / adverse effects*
  • fms-Like Tyrosine Kinase 3 / drug effects*


  • Protease Inhibitors
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Matrix Metalloproteinase 1
  • Coumestrol