title: Fas ligand enhances malignant behavior of tumor cells through interaction with Met, hepatocyte growth factor receptor, in lipid rafts.
abstract: Many late-stage cancer cells express Fas ligand (FasL) and show high malignancy with metastatic potential. We report here a novel signaling mechanism for FasL that hijacks the Met signal pathway to promote tumor metastasis. FasL-expressing human tumor cells express a significant amount of phosphorylated Met. The down-regulation of FasL in these cells led to decreased Met activity and reduced cell motility. Ectopic expression of human FasL in NIH3T3 cells significantly stimulated their migration and invasion. The inhibition of Met and Stat3 activities reverted the FasL-associated phenotype. Notably, FasL variants activated the Met pathway, even though most of their intracellular domain or Fas binding sites were deleted. FasL interacted with Met through the FasL(105-130) extracellular region in lipid rafts, which consequently led to Met activation. Knocking down Met gene expression by RNAi technology reverted the FasL-associated motility to basal levels. Furthermore, treatment with synthetic peptides corresponding to FasL(117-126) significantly reduced the FasL/Met interaction, Met phosphorylation, and cell motility of FasL(+) transfectants and tumor cells. Finally, the transfectants of truncated FasL showed strong anchorage-independent growth and lung metastasis potential in null mice. Collectively, our results establish the FasL-Met-Stat3 signaling pathway and explains the metastatic phenotype of FasL-expressing tumors.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Huan-Ching
authors.initials: HC
authors.lastname: Lin
authors.forename: Po-Yin
authors.initials: PY
authors.lastname: Lai
authors.forename: Yu-ping
authors.initials: YP
authors.lastname: Lin
authors.forename: Jyun-Yuan
authors.initials: JY
authors.lastname: Huang
authors.forename: Bei-Chang
authors.initials: BC
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met