ERK Pathway Positively Regulates the Expression of Sprouty Genes

Ozaki, Kei-ichi; Kadomoto, Ryoji; Asato, Keita; Tanimura, Susumu; Itoh, Nobuyuki; Kohno, Michiaki

doi:10.1006/bbrc.2001.5295

Cited by 102 publications

(93 citation statements)

References 22 publications

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“…BDNF and other neurotrophins or growth factors (like FGF) have been implicated in the differentiation of cultured CGN through regulation of the Ras/MAPK pathway. 2,21 As spry expression is regulated by growth factors and is involved in a negative-feedback loop in various contexts, 22,23 we investigated whether BDNF regulated Spry2 levels in neurons. Expression of Spry2 was clearly detected by Western blot in neurons cultured in presence of serum.…”

Section: Resultsmentioning

confidence: 99%

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Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival

Groß

Armant²,

Benosman

et al. 2007

Cell Death Differ

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Sprouty (Spry) proteins are ligand-inducible inhibitors of receptor tyrosine kinases-dependent signaling pathways, which control various biological processes, including proliferation, differentiation and survival. Here, we investigated the regulation and the role of Spry2 in cells of the central nervous system (CNS). In primary cultures of immature neurons, the neurotrophic factor BDNF (brain-derived neurotrophic factor) regulates spry2 expression. We identified the transcription factors CREB and SP1 as important regulators of the BDNF activation of the spry2 promoter. In immature neurons, we show that overexpression of wildtype Spry2 blocks neurite formation and neurofilament light chain expression, whereas inhibition of Spry2 by a dominantnegative mutant or small interfering RNA favors sprouting of multiple neurites. In mature neurons that exhibit an extensive neurite network, spry2 expression is sustained by BDNF and is downregulated during neuronal apoptosis. Interestingly, in these differentiated neurons, overexpression of Spry2 induces neuronal cell death, whereas its inhibition favors neuronal survival. Together, our results imply that Spry2 is involved in the development of the CNS by inhibiting both neuronal differentiation and survival through a negative-feedback loop that downregulates neurotrophic factors-driven signaling pathways.

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Section: Resultsmentioning

confidence: 99%

“…Similarly, Osaki reported that growth factor-induced activation of spry1 transcription was dependent on the Erk1/2 pathway. 23 Finally, we identified CREB and SP1 as two transcription factors that cooperate to regulate spry2 promoter activity in neurons in response to BDNF (Figures 3, 10).…”

Section: Discussionmentioning

confidence: 98%

Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival

Groß

Armant²,

Benosman

et al. 2007

Cell Death Differ

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“…One mechanism of Cbl regulation is through Erk inhibition via expression of Sprouty2. Erk signaling leads to increased transcription of Sprouty2, which binds to and inhibits Cbl, thereby decreasing its ability to promote the degradation of EGFR (35)(36)(37)(38)(39)(40). Thus, through negative regulation of Cbl, Sprouty2 functions to increase EGFR protein stability.…”

Section: Erbb2 Maintains Egfr Expression After Ecm Detachment Throughmentioning

confidence: 99%

ErbB2 Stabilizes Epidermal Growth Factor Receptor (EGFR) Expression via Erk and Sprouty2 in Extracellular Matrix-detached Cells

Grassian

Schafer

Brugge

2011

Journal of Biological Chemistry

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Epithelial cells are dependent on extracellular matrix (ECM) attachment for maintenance of metabolic activity and suppression of apoptosis. Here we show that loss of ECM attachment causes down-regulation of epidermal growth factor receptor (EGFR) and ␤1 integrin protein and mRNA expression and that ErbB2, which is amplified in 25% of breast tumors, reverses these effects of ECM deprivation. ErbB2 rescue of ␤1 integrin mRNA and protein in suspended cells is dependent on EGFR, however, the rescue of EGFR expression does not require ␤1 integrin. We show that there is a significant decrease in the stability of EGFR in ECM-detached cells that is reversed by ErbB2 overexpression. Rescue of both EGFR and ␤1 integrin protein by ErbB2 is dependent on Erk activity and induction of its downstream target Sprouty2, a protein known to regulate EGFR protein stability. Interestingly, expression of EGFR and ␤1 integrin protein is more dependent on Erk/ Sprouty2 in ECM-detached ErbB2-overexpressing cells when compared with ECM-attached cells. These results provide further insight into the ErbB2-driven anchorage independence of tumor cells and provide a new mechanism for regulation of EGFR and ␤1 integrin expression in ECM-detached cells.One of the hallmarks of tumor cells is the ability to survive without attachment to the extracellular matrix (ECM) 3 (1). Detachment of normal epithelial cells from ECM leads to metabolic impairment and induction of apoptotic death (anoikis) (2-5). However, tumor cells are generally able to survive without ECM attachment, a property known as "anchorage independence" (2, 3). This is believed to allow tumor cells to invade and proliferate outside their natural ECM niches. For example, one early feature of breast cancer is the proliferation of cells into the ECM-deficient hollow lumen of the glandular epithelium (6). These premalignant cells are able to survive despite the lack of contact to the basement membrane. Additionally, it is believed that anchorage independence is an important aspect of the metastatic process, both for survival in the vasculature and lymphatic system and also for survival in distant sites with altered matrix environments (2). Thus, elucidation of the mechanisms responsible for tumor cell anchorage independence is critical for understanding of the tumorigenic processes and may lead to identification of novel drug targets.ECM detachment of mammary epithelial cells results in a decrease of growth factor signaling through the Mek/Erk and PI3K/Akt pathways (2, 4, 5, 7). This leads to decreased cell viability, both through the induction of anoikis and through a caspase-independent metabolic impairment (2, 4). We have previously found that decreased Erk activation in ECM-detached cells leads to increased expression of the pro-apoptotic protein, Bim (7-9). In addition, the lack of Akt signaling in the ECM-detached cells results in a dramatic decrease in glucose uptake and ATP levels, causing a severe energy deficiency (4). Therefore, survival of mammary epithelial cells under ECM-de...

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“…As miRNAs have been shown to regulate mRNAs by binding to their 3 0 -UTRs and enhancing degradation or preventing translation, 34 we reason that miR-21 affects Spry1 expression by degrading mRNA transcript and thereby repressing translation. Spry1 expression is dependent on the ERK signaling Transcriptional and post-transcriptional regulation of Sprouty1 M Darimipourain et al pathway; 35 we therefore used phosphor-ERK1/2 as a marker for monitoring changes in Spry1 function that would be regulated by changes in its levels. As shown in Figure 4c, increased expression of Spry1 in prostate cells in response to anti-miR-21 treatment led to a marked decrease in basal phosphor-ERK1/2 normalized to the total ERK.…”

Section: The Role Of Mir-21 Expression and Spry1mentioning

confidence: 99%

Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer

Darimipourain

Wang

Ittmann

et al. 2011

Prostate Cancer Prostatic Dis

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Sprouty1 (Spry1) is a negative regulator of fibroblast growth factor signaling with a potential tumor suppressor function in prostate cancer (PCa). Spry1 is downregulated in human PCa, and Spry1 expression can markedly inhibit PCa proliferation in vitro. We have reported DNA methylation as a mechanism for controlling Spry1 expression. However, promoter methylation does not seem to explain gene silencing in all PCa cases studied to suggest other mechanisms of gene inactivation, such as alterations in trans-acting factors and/or post-transcriptional activity may be responsible for the decreased expression in those cases. Binding sites for Wilm's tumor (WT1) transcription factors EGR1, EGR3 and WTE are highly conserved between the mouse and human Spry1 promoter regions, suggesting an evolutionary conserved mechanism(s) involving WT1 and EGR in Spry1 regulation. Spry1 mRNA contains multiple microRNA (miRNA) binding sites in its 3 0 UTR region suggesting post-transcriptional control. We demonstrate that Spry1 is a target for miR-21-mediated gene silencing. miRNA-based therapeutic approaches to treat cancer are emerging. Spry1 is highly regulated by miRNAs and could potentially be an excellent candidate for such approaches.

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ERK Pathway Positively Regulates the Expression of Sprouty Genes

Cited by 102 publications

References 22 publications

Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival

Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival

ErbB2 Stabilizes Epidermal Growth Factor Receptor (EGFR) Expression via Erk and Sprouty2 in Extracellular Matrix-detached Cells

Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer

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