title: FGF2-induced Ras-MAPK signalling maintains lymphatic endothelial cell identity by upregulating endothelial-cell-specific gene expression and suppressing TGFβ signalling through Smad2.
abstract: The lymphatic endothelial cell (LEC) fate decision program during development has been described. However, the mechanism underlying the maintenance of differentiated LEC identity remains largely unknown. Here, we show that fibroblast growth factor 2 (FGF2) plays a fundamental role in maintaining a differentiated LEC trait. In addition to demonstrating the appearance of LECs expressing α-smooth muscle actin in mouse lymphedematous skin in vivo, we found that mouse immortalised LECs lose their characteristics and undergo endothelial-to-mesenchymal transition (EndMT) when cultured in FGF2-depleted medium. FGF2 depletion acted synergistically with transforming growth factor (TGF) β to induce EndMT. We also found that H-Ras-overexpressing LECs were resistant to EndMT. Activation of H-Ras not only upregulated FGF2-induced activation of the Erk mitogen activated protein kinases (MAPK3 and MAPK1), but also suppressed TGFβ-induced activation of Smad2 by modulating Smad2 phosphorylation by MAPKs. These results suggest that FGF2 regulates LEC-specific gene expression and suppresses TGFβ signalling in LECs through Smad2 in a Ras-MAPK-dependent manner. Taken together, our findings provide a new insight into the FGF2-Ras-MAPK-dependent mechanism that maintains and modulates the LEC trait.
authors.affiliation: Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Ichise
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshida
authors.forename: Hirotake
authors.initials: H
authors.lastname: Ichise
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D015870:Gene Expression; D042601:Lymphatic Vessels / Q000166:cytology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051899:Smad2 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
chemical_list: D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D018631:ras Proteins
keywords: Endothelial–mesenchymal transition; FGF2; Lymphatic endothelial cell; MAPK; Ras; Smad