A role for extracellular and transmembrane domains of Sef in Sef-mediated inhibition of FGF signaling

Коваленко, Д. В.; Yang, Xuehui; Chen, Pei-Yu; Nadeau, Robert J.; Zubanova, Olga; Pigeon, Kathleen; Friesel, Robert

doi:10.1016/j.cellsig.2006.03.001

Cited by 35 publications

(39 citation statements)

References 35 publications

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“…These results suggest that in prostate cancer cells hSef exerts an effect at the level of the FGFR or at Ras. Functionality at this level is further supported by the consistent finding of Sef interaction (colocalisation and immunoprecipitation) with the FGFR across different species and cell types and its ability to inhibit both FGFR as well as FRS phosphorylation (Tsang et al, 2002;Kovalenko et al, 2003Kovalenko et al, , 2006Xiong et al, 2003;Yang et al, 2003;Ren et al, 2007). The ability of hSef to act upstream or at Ras would imply that it should also inhibit alternate pathways activated by FGFR/Ras interaction, which include PI3 kinase (Gioeli, 2005).…”

Section: Discussionmentioning

confidence: 64%

“…In contrast, the short isoform of hSef inhibited MAPK activation in both cell types. Work with the full-length mouse homologue, however, showed that Sef was capable of blocking FGF-induced cell proliferation in fibroblast cells and that this was associated with decreased phosphorylation of Raf, MEK and ERK (Kovalenko et al, 2006). In this study we were only able to focus on the function of full-length Sef and therefore cannot currently comment on the role of the short isoform in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 70%

“…The exact mechanism of how hSef might inhibit FGFR/Ras activation of MAPK signalling in prostate cancer cells is currently unclear. Kovalenko et al (2006) have proposed that mSef may act by interfering with FGFR dimerisation and hence prevent receptor phosphorylation and downstream signalling. An alternative mechanism is that hSef interacts directly with and inhibits Ras activation by FGFR at the plasma membrane .…”

Section: Discussionmentioning

confidence: 99%

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Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease

et al. 2009

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The fibroblast growth factor (FGF) axis is an important mitogenic stimulus in prostate carcinogenesis. We have previously reported that transcript level of human similar expression to FGF (hSef), a key regulator of this pathway, is downregulated in clinical prostate cancer. In this study we further analysed the role of hSef in prostate cancer. METHODS: hSef function was studied in in vitro and in vivo prostate cancer models using stable over-expression clones. Protein expression of hSef was studied in a comprehensive tissue microarray. RESULTS: Stable over-expression of hSef resulted in reduced in vitro cancer cell proliferation, migration and invasive potential. In an in vivo xenograft model, the expression of hSef significantly retarded prostate tumour growth as compared with empty vector (P ¼ 0.03) and non-transfected (P ¼ 0.0001) controls. Histological examination further showed a less invasive tumour phenotype and reduced numbers of proliferating cells (P ¼ 0.0002). In signalling studies, hSef inhibited FGF-induced ERK phosphorylation, migration to the nucleus and activation of a reporter gene. Constitutively active Ras, however, was able to reverse these effects, suggesting that hSef exerts an effect either above or at the level of Ras in prostate cancer cells. In a large tissue microarray, we observed a significant loss of hSef protein in high-grade (Po0.0001) and metastatic (Po0.0001) prostate cancer. CONCLUSION: Considered together, the role of hSef in attenuating FGF signalling and evidence of downregulation in advanced tumours argue strongly for a tumour suppressor function in human prostate cancer.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease

et al. 2009

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“…In vitro, Sef overexpression induces apoptosis, whereas knockdown of Sef promotes cell migration in response to FGF ligand, but in vivo roles for Sef have not yet been described (Darby et al, 2006;Kovalenko et al, 2006). FGF2 independently affects both the proliferation and migration of cochlear nucleus precursors in vitro (Zhou et al, 1996;Hossain et al, 2006), whereas FGF8 contributes to tissue morphogenesis, proliferation, and survival in the hindbrain but is surprisingly dispensible for specific cell fate decisions here (Foucher et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Changes in Sef Levels Influence Auditory Brainstem Development and Function

Abraira¹,

Hyun²,

Tucker³

et al. 2007

J. Neurosci.

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During development of the CNS, secreted morphogens of the fibroblast growth factor (FGF) family have multiple effects on cell division, migration, and survival depending on where, when, and how much FGF signal is received. The consequences of misregulating the FGF pathway were studied in a mouse with decreased levels of the FGF antagonist Sef. To uncover effects in the nervous system, we focused on the auditory system, which is accessible to physiological analysis. We found that the mitogen-activated protein kinase pathway is active in the rhombic lip, a germinal zone that generates diverse types of neurons, including the cochlear nucleus complex of the auditory system. Sef is expressed immediately adjacent to the rhombic lip, overlapping with FGF15 and FGFR1, which is also present in the lip itself. This pattern suggests that Sef may normally function in non-rhombic lip cells and prevent them from responding to FGF ligand in the vicinity. Consistent with this idea, overexpression of Sef in chicks decreased the size of the auditory nuclei. Cochlear nucleus defects were also apparent in mice with reduced levels of Sef, with 13% exhibiting grossly dysmorphic cochlear nuclei and 26% showing decreased amounts of GFAP in the cochlear nucleus. Additional evidence for cochlear nucleus defects was obtained by electrophysiological analysis of Sef mutant mice, which have normal auditory thresholds but abnormal auditory brainstem responses. These results show both increases and decreases in Sef levels affect the assembly and function of the auditory brainstem.

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“…2B). In addition, SEF, Sprouty2, PEA3 and ERM, all members of the FGF synexpression group (Brent and Tabin, 2004;Kovalenko et al, 2006), were downregulated by BMP4 treatment in AHF explants ( Fig. 2B; see Fig.…”

Section: Bmp4 Induces the Expression Of Its Synexpression Group And Smentioning

confidence: 99%

BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors

et al. 2010

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SUMMARYThe anterior heart field (AHF) encompasses a niche in which mesoderm-derived cardiac progenitors maintain their multipotent and undifferentiated nature in response to signals from surrounding tissues. Here, we investigate the signaling mechanism that promotes the shift from proliferating cardiac progenitors to differentiating cardiomyocytes in chick embryos. Genomic and systems biology approaches, as well as perturbations of signaling molecules, in vitro and in vivo, reveal tight crosstalk between the bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signaling pathways within the AHF niche: BMP4 promotes myofibrillar gene expression and cardiomyocyte contraction by blocking FGF signaling. Furthermore, inhibition of the FGF-ERK pathway is both sufficient and necessary for these processes, suggesting that FGF signaling blocks premature differentiation of cardiac progenitors in the AHF. We further revealed that BMP4 induced a set of neural crest-related genes, including MSX1. Overexpression of Msx1 was sufficient to repress FGF gene expression and cell proliferation, thereby promoting cardiomyocyte differentiation. Finally, we show that BMP-induced cardiomyocyte differentiation is diminished following cranial neural crest ablation, underscoring the key roles of these cells in the regulation of AHF cell differentiation. Hence, BMP and FGF signaling pathways act via inter-and intra-regulatory loops in multiple tissues, to coordinate the balance between proliferation and differentiation of cardiac progenitors.

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A role for extracellular and transmembrane domains of Sef in Sef-mediated inhibition of FGF signaling

Cited by 35 publications

References 35 publications

Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease

Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease

Changes in Sef Levels Influence Auditory Brainstem Development and Function

BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors

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