The ternary complex factor Net regulates cell migration through inhibition of PAI-1 expression.
Net, Elk-1, and Sap-1 are members of the ternary complex factor (TCF) subfamily of Ets transcription factors. They form ternary complexes with serum response factor (SRF) on serum response elements of immediate early genes such as c-fos and egr-1 and mediate responses to growth factors and mitogen-activated protein kinase signaling. Although the TCFs have been extensively studied as intermediates in signaling cascades, surprisingly little is known about their different target genes and physiological functions. We report that Net homozygous mutant mouse embryonic fibroblasts have a defect in cell migration. This defect results at least in part from increased expression of plasminogen activator inhibitor type 1 (PAI-1), a serine protease inhibitor (serpin) that controls extracellular proteolysis and cell matrix adhesion. The defect in cell migration can be reverted by the addition of a PAI-1 blocking antibody. Net represses PAI-1 promoter activity and binds to a specific region of the promoter containing Ets binding sites in the absence of SRF. We conclude that Net is a negative regulator of PAI-1 expression and is thereby involved in cell migration.
Buchwalter
Gilles
G
Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS, INSERM, ULP, Illkirch, France.
Gross
Christian
C
Wasylyk
Bohdan
B
D000199:Actins / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001483:Base Sequence; D002465:Cell Movement / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D027602:Serum Response Element / Q000235:genetics; D050801:Ternary Complex Factors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics
D000199:Actins; D019138:Antibodies, Blocking; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C491779:Elf4 protein, mouse; C086924:Elk3 protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D050783:Proto-Oncogene Proteins c-ets; D050801:Ternary Complex Factors; D014157:Transcription Factors