Premium
Filamin a mediates HGF/c‐MET signaling in tumor cell migration
Author(s) -
Zhou AlexXianghua,
Toylu Aslı,
Nallapalli Rajesh K.,
Nilsson Gisela,
Atabey Neşe,
Heldin CarlHenrik,
Borén Jan,
Bergo Martin O.,
Akyürek Levent M.
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25417
Subject(s) - flna , filamin , hepatocyte growth factor , cancer research , c met , cell migration , protein kinase b , biology , signal transduction , microbiology and biotechnology , cell , cytoskeleton , receptor , genetics
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.