Gelsolin-induced epithelial cell invasion is dependent on Ras-Rac signaling.
Gelsolin is a widely distributed actin binding protein involved in controlling cell morphology, motility, signaling and apoptosis. The role of gelsolin in tumor progression, however, remains poorly understood. Here we show that expression of green fluorescent protein (GFP)-tagged gelsolin in MDCK-AZ, MDCKtsSrc or HEK293T cells promotes invasion into collagen type I. In organ culture assays, MDCK cells expressing gelsolin-GFP invaded pre-cultured chick heart fragments. Gelsolin expression inhibited E-cadherin-mediated cell aggregation but did not disrupt the E-cadherin-catenin complex. Co-expression of dominant-negative Rac1N17, but not RhoAN19 or Cdc42N17, counteracted gelsolin-induced invasion, suggesting a requirement for Rac1 activity. Increased ARF6, PLD or PIP5K 1alpha activity canceled out gelsolin-induced invasion. Furthermore, we found that invasion induced by gelsolin is dependent on Ras activity, acting through the PI3K-Rac pathway via the Ras guanine nucleotide exchange factor Sos-1. These findings establish a connection between gelsolin and the Ras oncogenic signaling pathway.
De Corte
Veerle
V
Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Rommelaere Institute, Albert Baertsoenkaai 3, B-9000 Gent, Belgium.
Bruyneel
Erik
E
Boucherie
Ciska
C
Mareel
Marc
M
Vandekerckhove
Joël
J
Gettemans
Jan
J
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D003001:Cloning, Molecular; D003094:Collagen / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology*; D018260:Gelsolin / Q000494:pharmacology*; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009924:Organ Culture Techniques; D011233:Precipitin Tests; D011485:Protein Binding; D020837:SOS1 Protein / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D000089982:ADP-Ribosylation Factor 6; D000199:Actins; D015820:Cadherins; D018076:DNA, Complementary; D018260:Gelsolin; D008164:Luminescent Proteins; D020837:SOS1 Protein; D049452:Green Fluorescent Proteins; D003094:Collagen; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins