5-Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor-induced cell migration through Tiam1 upregulation and Rac1 activation.
Bottom Line: In this study, we found that 5-lipoxygenase (5-LOX) is activated in the process of EGF-induced cell migration, and that leukotriene C4 (LTC4 ) produced by 5-LOX mediated the second wave of Rac1 activation, as well as cell migration.Furthermore, these effects caused by LTC4 were found to be blocked in the presence of the antagonist of cysteinyl leukotriene receptor 1 (CysLT1).We also found that 5-LOX inhibitors, CysLT1 antagonists and the knockdown of CysLT1 inhibited EGF-induced T cell lymphoma invasion and metastasis-inducing protein 1 (Tiam1) expression.
Affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.Show MeSH
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Mentions: We previously demonstrated that Tiam1 might function as the RacGEF responsible for the second EGF-induced wave of Rac1 activation by interacting with 14-3-3ζ. As shown in Figure4(a) and in our previous report,6 the intracellular expression levels of Tiam1 were quite low in unstimulated A431 cells, but gradually increased within 9 h after EGF stimulation. Furthermore, an elevated level of the Tiam1 mRNA was detected by real time RT-PCR analysis in EGF-stimulated A431 cells (Fig.4b); this observation suggests that Tiam1 expression was increased at the level of transcription. However, the regulatory mechanisms underlying EGF-increased Tiam1 expression have not yet been discovered. Therefore, we examined the possibility that CysLT1 signaling regulates the expression level of Tiam1. As shown in Figure4(c,d), the CysLT1 antagonists MK-571 and montelukast suppressed the EGF-induced increase in Tiam1 expression at both the mRNA and protein levels. Similar results were obtained when TT cells (a human thyroid cancer cell line) or EC109 cells (a human esophageal cancer cell line), were used in place of A431 cells (Fig. S3). The 5-LOX inhibitors BU-4664L and AA-861 also inhibited expression, and addition of LTD4 ified this inhibition (Figs4e,S4). Taken together, 5-LOX/LTC4(D4)/CysLT1 signaling regulates the second EGF-induced wave of Rac1 activation and lamellipodia formation by modulating the expression level of Tiam1 protein.
Affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.