Premium
YAP and TAZ drive matrix stiffness‐dependent fibroblast activation (1180.6)
Author(s) -
Tschumperlin Daniel,
Varelas Xaralabos,
Liu Fei
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1180.6
Subject(s) - extracellular matrix , fibroblast , hippo signaling pathway , gene knockdown , microbiology and biotechnology , focal adhesion , chemistry , fibrosis , signal transduction , cancer research , biology , gene , pathology , in vitro , biochemistry , medicine
Fibroblasts actively respond to changes in extracellular matrix mechanical properties, and positive feedback between matrix stiffness and fibroblast activation may play a pivotal role in fibrosis. Microarray analysis of matrix‐stiffness regulated genes in human lung fibroblasts identified significant overrepresentation of transcriptional targets of YAP (yes‐associated protein) and TAZ (transcriptional coactivator with PDZ‐binding motif), consistent with a prominent role for these factors in fibroblast mechanoresponsiveness. Immunofluorescence imaging demonstrated that YAP and TAZ transitioned from primarily nuclear localization on relatively stiff matrices (25.6 kPa) to cytoplasmic on soft matrices (0.4 kPa). RNAi‐mediated knockdown of YAP/TAZ significantly reduced the cell spreading, focal adhesion length, traction forces, proliferation, pro‐fibrotic gene expression and collagen synthesis observed on stiff matrices, but exerted negligible effects on soft matrices. Conditional overexpression of YAP overcame soft matrix limitations on proliferation, while overexpression of either YAP or TAZ promoted pro‐fibrotic gene expression on both soft and stiff matrices. Taken together, these results support a central role for YAP and TAZ in matrix stiffness‐dependent activation of fibroblasts to a proliferative, contractile and matrix synthetic state implicated in the pathogenesis of fibrosis. Grant Funding Source : Supported by NIH RO1 HL092961