Integrin |[alpha]|6|[beta]|4 promotes expression of autotaxin|[sol]|ENPP2 autocrine motility factor in breast carcinoma cells

摘要

In advanced breast carcinomas, the 64 integrin is associated with a migratory and invasive phenotype. In our current study, we show that expression of the 64 integrin in MDA-MB-435 breast carcinoma cells leads to increased expression of the autocrine motility factor autotaxin, as determined by Affymetrix gene chip, real-time quantitative RT–PCR and immunoblot analyses. We further demonstrate that increased autotaxin secretion from integrin 64 expressing cells acts to enhance chemotaxis through its ability to convert lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) and accounts for 80% of the motogenic activity of the conditioned medium. We determine that integrin 64-dependent overexpression of autotaxin in MDA-MB-435 cells is mediated by NFAT1, but not NFAT5, through the use of siRNAs that specifically target autotaxin, integrin 4, NFAT1 and NFAT5. Finally, we show by electrophoretic mobility shift assays that two consensus NFAT binding sites found in the autotaxin promoter strongly and specifically bind NFAT1 from integrin 64 expressing cells. In summary, we find that the 64 integrin potentiates autotaxin expression through the upregulation and activation of NFAT1. These observations highlight for the first time a mechanism by which NFAT transcription factors can facilitate an invasive and motile phenotype downstream of integrin 64 signaling.