Sef Interacts with TAK1 and Mediates JNK Activation and Apoptosis

Yang, Xuehui; Коваленко, Д. В.; Nadeau, Robert J.; Harkins, Lauren K.; Mitchell, Jane; Zubanova, Olga; Chen, Pei-Yu; Friesel, Robert

doi:10.1074/jbc.c400318200

Cited by 50 publications

(27 citation statements)

References 18 publications

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“…Besides Ras-Erk signaling, overexpression of Sef has also been shown to induce apoptosis through the activation of c-jun amino-terminal kinase (JNK). Sef was demonstrated to activate JNK through a TAK-MKK4-JNK pathway, and to associate with TAK1 in a coimmunoprecipitated complex [11].…”

Section: Introductionmentioning

confidence: 99%

hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

Ren

Cheng

Rong

et al. 2008

Cellular Signalling

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Sef (similar expression to fgf genes) was identified as an effective antagonist of fibroblast growth factor (FGF) in vertebrates. Previous reports have demonstrated that Sef interacts with FGF receptors (FGFRs) and inhibits FGF signaling, however, its role in regulating epidermal growth factor receptor (EGFR) signaling remains unclear. In this report, we found that hSef localizes to the plasma membrane (PM) and is subjected to rapid internalization and well localizes in early/ recycling endosomes while poorly in late endosomes/lysosomes. We observed that hSef interacts and functionally colocalizes with EGFR in early endosomes in response to EGF stimulation. Importantly, we demonstrated that overexpression of hSef attenuates EGFR degradation and potentiates EGF-mediated mitogen-activated protein kinase (MAPK) signaling by interfering EGFR trafficking. Finally, our data showed that, with overexpression of hSef, elevated levels of Erk phosphorylation and differentiation of rat pheochromocytoma (PC12) cells occur in response to EGF stimulation. Taken together, these data suggest that hSef plays a positive role in the EGFRmediated MAPK signaling pathway. This report, for the first time, reveals opposite roles for Sef in EGF and FGF signalings.

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Section: Introductionmentioning

confidence: 99%

hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

Ren

Cheng

Rong

et al. 2008

Cellular Signalling

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“…Besides FGFs, Sef has also been implicated as a regulator of both nerve growth factor and epidermal growth factor signalling (Xiong et al, 2003;Torii et al, 2004). Overexpression of Sef has also been shown to induce apoptosis through the activation of JNK (Yang et al, 2004). More recently, Sef has been implicated in the regulation of Gbx2, itself a key modulator of IL6, a potent mitogen in androgenindependent prostate cancer (Gao et al, 2000;Lin et al, 2005).…”

Section: Loss Of Sef In Prostate Cancermentioning

confidence: 99%

Loss of Sef (similar expression to FGF) expression is associated with high grade and metastatic prostate cancer

et al. 2006

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Fibroblast growth factors (FGF), and in particular FGF8, have been strongly implicated in prostate carcinogenesis. This study investigated the expression of Sef, a key inhibitory regulator of FGF signalling, in prostate cancer. In a panel of cell lines, hSef was detected in both androgen-dependent and independent cells but was significantly reduced in highly metastatic derivative clones. hSef expression was not influenced by androgenic stimulation. Forced downregulation of hSef by siRNA increased FGF8b induced cell migration (P ¼ 0.02) and invasion (P ¼ 0.007). Reduced hSef levels also enhanced FGF8b stimulated expression of MMP9 (P ¼ 0.005). mRNA in situ hybridization revealed hSef expression in 80% (8/10) of benign biopsies but in only 69% (23/33) of Gleason sum 4-7 and 35% (10/28) of Gleason sum 8-10 cancer biopsies (P ¼ 0.004). Quantitative PCR of microdissected glands confirmed this trend (P ¼ 0.001). hSef was expressed in 69% (27/39) of non-metastatic tumours but in only 18% (2/11) of metastatic tumours (P ¼ 0.004, n ¼ 50). hSef expression was next correlated with earlier data on FGF8b expression in a subgroup of cancers. In this cohort, 86% (19/22) of high-grade cancers expressed FGF8 but only 31% (7/22) expressed hSef. Positive FGF8 expression but a loss of hSef was observed in 88% (7/8) of metastatic tumours. In contrast, metastasis was evident in only 10% (1/10) of tumours, which co-expressed both FGF8 and hSef (Po0.001). These results suggest evidence that hSef is downregulated in advanced prostate cancer and might facilitate an enhanced tumorigenic response to FGFs. Further research into the role of hSef in cancer cell signalling and the mechanism of its downregulation may contribute to more effective targeting of growth factors in prostate cancer.

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“…However, contrary to Sprouty and SPRED proteins that are dedicated inhibitors of the MAP kinase (ERK/MAPK) pathway (Christofori 2003, Dikic & Giordano 2003, Guy et al 2009), SEF modulates multiple signaling pathways including the inhibition of ERK/MAPK activation in response to various RTK ligands and suppression of FGF-mediated activation of AKT, a downstream effector of phosphatidylinositol 3-OH kinase (Kovalenko et al 2003, Ziv et al 2006. SEF also augments the activity of stress kinases (Yang et al 2004, Ziv et al 2006. Moreover, our recent study has expanded the inhibitory activity of SEF to include the pro-inflammatory cytokines interleukin 1 (IL1) and tumor necrosis factor (TNF), in which SEF interacts physically with the master transcription factor NFkB and inhibits its nuclear translocation upon cytokine stimulation (Fuchs et al 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Among the Spry proteins, SPRY2 has been explored in the ovary, and its expression in GC is regulated by gonadotropins (Haimov-Kochman et al 2005, Sugiura et al 2009, Jiang et al 2011. Similar to the Sprouty and SPRED proteins, SEF antagonizes the activity of a number of RTKs, including the FGF and EGF receptors in mammals (Kovalenko et al 2003, Xiong et al 2003, Torii et al 2004, Yang et al 2004, Ziv et al 2006. However, contrary to Sprouty and SPRED proteins that are dedicated inhibitors of the MAP kinase (ERK/MAPK) pathway (Christofori 2003, Dikic & Giordano 2003, Guy et al 2009), SEF modulates multiple signaling pathways including the inhibition of ERK/MAPK activation in response to various RTK ligands and suppression of FGF-mediated activation of AKT, a downstream effector of phosphatidylinositol 3-OH kinase (Kovalenko et al 2003, Ziv et al 2006.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the dual function of SEF distinguishes it from other RTK and NFkB inhibitors and furnishes SEF with the capacity to impact many physiological and pathological processes. Accordingly, and depending on cellular context, mammalian SEF orthologs can attenuate cell proliferation, differentiation, migration, or can induce apoptosis in response to growth factors (Kovalenko et al 2003, Xiong et al 2003, Torii et al 2004, Yang et al 2004, Darby et al 2006, Ziv et al 2006. Sef inactivation in mice induces inflammation in several organs (Tang et al 2010, http://www.mmrrc.org/strains/32387/032387.html).…”

Section: Introductionmentioning

confidence: 99%

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Expression and regulation of the tumor suppressor, SEF, during folliculogenesis in humans and mice

et al. 2014

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Similar expression to FGF (SEF or IL17RD), is a tumor suppressor and an inhibitor of growth factors as well as of pro-inflammatory cytokine signaling. In this study, we examined the regulation of Sef expression by gonadotropins during ovarian folliculogenesis. In sexually immature mice, in situ hybridization (ISH) localized Sef gene expression to early developing oocytes and granulosa cells (GC) but not to theca cells. Sef was also expressed in mouse ovarian endothelial cells, in the fallopian tube epithelium as well as in adipose tissue venules. SEF protein expression, determined by immunohistochemistry (IHC), correlated well with Sef mRNA expression in GC, while differential expression was noticed in oocytes. High Sef mRNA but undetectable SEF protein levels were observed in the oocytes of primary/secondary follicles, while an inverse correlation was found in the oocytes of preantral and small antral follicles. Sef mRNA expression dropped after pregnant mare's serum gonadotropin (PMSG) administration, peaked at 6-8 h after human chorionic gonadotropin (hCG) treatment, and declined by 12 h after this treatment. ISH and IHC localized the changes to oocytes and mural GC following PMSG treatment, whereas Sef expression increased in mural GC and declined in granulosa-lutein cells upon hCG treatment. The ovarian expression of SEF was confirmed using human samples. ISH localized SEF transcripts to human GC of antral follicles but not to corpora lutea. Furthermore, SEF mRNA was detected in human GC recovered from preovulatory follicles. These results are the first to demonstrate Sef expression in a healthy ovary during folliculogenesis. Hormonal regulation of its expression suggests that Sef may be an important factor involved in intra-ovarian control mechanisms.

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Sef Interacts with TAK1 and Mediates JNK Activation and Apoptosis

Cited by 50 publications

References 18 publications

hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

Loss of Sef (similar expression to FGF) expression is associated with high grade and metastatic prostate cancer

Expression and regulation of the tumor suppressor, SEF, during folliculogenesis in humans and mice

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