Filamin a mediates HGF/c-MET signaling in tumor cell migration.
Deregulated hepatocyte growth factor (HGF)/c-MET axis has been correlated with poor clinical outcome and drug resistance in many human cancers. Identification of novel regulatory mechanisms influencing HGF/c-MET signaling may therefore be necessary to develop more effective cancer therapies. In our study, we show that multiple human cancer tissues and cells express filamin A (FLNA), a large cytoskeletal actin-binding protein, and expression of c-MET is significantly reduced in human tumor cells deficient for FLNA. The FLNA-deficient tumor cells exhibited poor migrative and invasive ability in response to HGF. On the other hand, the anchorage-dependent and independent tumor cell proliferation was not altered by HGF. The FLNA-deficiency specifically attenuated the activation of the c-MET downstream signaling molecule AKT in response to HGF stimulation. Furthermore, FLNA enhanced c-MET promoter activity by its binding to SMAD2. The impact of FLNA deficiency on c-MET expression and HGF-mediated cell migration in human tumor cells was confirmed in primary mouse embryonic fibroblasts deficient for Flna. These data suggest that FLNA is one of the important regulators of c-MET signaling and HGF-induced tumor cell migration.
Zhou
Alex-Xianghua
AX
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
Toylu
Aslı
A
Nallapalli
Rajesh K
RK
Nilsson
Gisela
G
Atabey
Neşe
N
Heldin
Carl-Henrik
CH
Borén
Jan
J
Bergo
Martin O
MO
Akyürek
Levent M
LM
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D003285:Contractile Proteins / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D064448:Filamins; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
D003285:Contractile Proteins; D064448:Filamins; C529499:FlnA protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D008156:Luciferases; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt