Involvement of 14-3-3 Proteins in the Second Epidermal Growth Factor-induced Wave of Rac1 Activation in the Process of Cell Migration

Kobayashi, Hiroki; Ogura, Yusuke; Sawada, Masato; Nakayama, Ryoji; Takano, Kei; Minato, Yusuke; Takemoto, Yasushi; Tashiro, Etsu; Watanabe, Hidenobu; Imoto, Masaya

doi:10.1074/jbc.m111.255489

Cited by 40 publications

(38 citation statements)

References 39 publications

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“…This is consistent with the previous reports showing that 14-3-3 binding to Tiam1 is required for Rac1 activation. 44,45 A previous study found S60A mutation was stabilized but with reduced interaction with 14-3-3, while other single mutations (S172 or S231) have no effect on the half-life of Tiam1. 32 It was hypothesized that 14-3-3 binding to different combination of phosphorylation sites resulted in distinct conformational changes, thereby regulating Tiam1 stability.…”

Section: Discussionmentioning

confidence: 96%

An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis

et al. 2015

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Epidermal growth factor receptor (EGFR) signaling regulates cell growth and survival, and its overactivation drives cancer development. One important branch of EGFR signaling is through activation of GTPase Rac1, which further promotes cell proliferation, survival and cancer metastasis. Here, we show that EGFR activates Rac1 via inducing the accumulation of its specific guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 1 (Tiam1) in non-small-cell lung cancer and colon cancer cells. Conversely, elevated Tiam1 is required for EGFR-induced tumorigenesis. In human lung adenocarcinoma and colon cancer specimens, Tiam1 expression strongly correlates with EGFR expression. We further reveal that AKT, a key downstream protein kinase of EGFR, phosphorylates Tiam1 at several consensus sites, facilitates the interaction of Tiam1 with scaffold proteins 14-3-3 and leads to an increase of Tiam1 stability. Subsequently, Tiam1 is dephosporylated and destabilized by PP2A. Together, our study identifies a bidirectional (phosphorylation and dephosphorylation) regulatory mechanism controlling Tiam1 stability and provides new insights on how EGFR signaling triggers Rac1 activation and cancer development.

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Section: Discussionmentioning

confidence: 96%

An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis

et al. 2015

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“…Rac1-GTP pull-down assay was carried out as described previously. (6) Leukotriene C 4 measurement. A431 cells were pretreated with or without drugs for 15 min and then stimulated with 30 ng ⁄ mL EGF.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we reported that epidermal growth factor (EGF) induces biphasic lamellipodia formation, which was observed at 5 min and 12 h, in the process of cell migration of human epidermoid carcinoma A431 cells and human thyroid carcinoma TT cells. These two waves of lamellipodia formation were reflected by two waves of EGF‐induced Rac1 activation, which were observed at 2–5 min and 6–12 h, respectively . The biphasic timing of Rac1 activation mirrors the biphasic formation of lamellipodia.…”

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confidence: 94%

5‐Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor‐induced cell migration through Tiam1 upregulation and Rac1 activation

et al. 2014

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Cell migration is an essential step for tumor metastasis. The small GTPase Rac1 plays an important role in cell migration. Previously, we reported that epidermal growth factor (EGF) induced two waves of Rac1 activation; namely, at 5 min and 12 h after stimulation. A second wave of EGF-induced Rac1 activation was required for EGF-induced cell migration, however, the spatiotemporal regulation of the second wave of EGF-induced Rac1 activation remains largely unclear. 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). This blockage indicates that LTC4-mediated CysLT1 signaling regulates the second EGF-induced wave of Rac1 activation. 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. Tiam1 expression is required for the second wave of EGF-induced Rac1 activation in A431 cells. Therefore, our results indicate that the 5-LOX/LTC4/CysLT1 signaling pathway regulates EGF-induced cell migration by increasing Tiam1 expression, leading to a second wave of Rac1 activation. Thus, CysLT1 may serve as a new molecular target for antimetastatic therapy. In addition, the CysLT1 antagonist, montelukast, which is used clinically for allergy treatment, might have great potential as a novel type of antimetastatic agent.

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“…Based on a chemical genomic-based pathway analysis for EGF-mediated signaling in various migrating cancer cells, we reported that common and cell-type specific pathways existed during EGF-induced cell migration [15,16]. Moreover, we revealed that the 5-lipoxygenase/leukotriene receptor 1/cysteinyl leukotriene receptor 1 signaling pathway-mediated Tiam1 expression is involved in EGF-induced cell migration in A431 cells [17,18]. Through further investigation into the mechanism by which EGF induces cell migration, we found that EGF decreased E-cadherin expression in colorectal carcinoma LoVo cells.…”

Section: Introductionmentioning

confidence: 90%

Involvement of the MEK/ERK pathway in EGF-induced E-cadherin down-regulation

Tashiro

Henmi

Odake

et al. 2016

Biochemical and Biophysical Research Communications

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Involvement of 14-3-3 Proteins in the Second Epidermal Growth Factor-induced Wave of Rac1 Activation in the Process of Cell Migration

Cited by 40 publications

References 39 publications

An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis

An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis

5‐Lipoxygenase and cysteinyl leukotriene receptor 1 regulate epidermal growth factor‐induced cell migration through Tiam1 upregulation and Rac1 activation

Involvement of the MEK/ERK pathway in EGF-induced E-cadherin down-regulation

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