ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish

Ren, Bin; Deng, Yong; Mukhopadhyay, Arpita; Lanahan, Anthony A.; Zhuang, Zhen W.; Moodie, Karen L; Mulligan-Kehoe, Mary Jo; Byzova, Tatiana V.; Peterson, Randall T.; Simons, Michael

doi:10.1172/jci39837

Cited by 142 publications

(170 citation statements)

References 49 publications

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“…Until recently, no interactions between these two signaling cascades have been appreciated. We have previously demonstrated that under normal conditions in the adult vasculature, AKT inhibits ERK signaling via phosphorylation of RAF1, and that inhibition of PI3K leads to ERK activation (9). The importance of PI3K/ERK interaction is further suggested by studies demonstrating that mice lacking the of RAF1 S259A causes a lymphatic phenotype similar to that observed in Noonan and LEOPARD syndrome patients.…”

Section: Discussionmentioning

confidence: 87%

“…Primary mouse ECs were isolated from mouse embryos or lungs using a protocol similar to that previously described (9). Briefly, embryos or lungs were harvested, minced finely with scissors, and then digested in 25 ml collagenase 0.2% (w/v) at 37°C for 20 minutes (embryo) or 45 minutes (lung).…”

Section: Methodsmentioning

confidence: 99%

“…The molecular basis of the lymphatic defects in these diseases is still unknown. Previously, we have demonstrated that under normal conditions, the PI3K/AKT signaling pathway inhibits ERK signaling via AKT1-dependent phosphorylation of RAF1 on Ser259 (Figure 1, A and B) in endothelial cells (ECs) (9). Gain-of-function mutations of RAF1 at Ser259 have been frequently identified in Noonan syndrome patients (10)(11)(12).…”

Section: Introductionmentioning

confidence: 93%

See 2 more Smart Citations

Endothelial ERK signaling controls lymphatic fate specification

Deng

Atri²,

Eichmann³

et al. 2013

J. Clin. Invest.

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117

103

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Section: Discussionmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

See 1 more Smart Citation

Endothelial ERK signaling controls lymphatic fate specification

Deng

Atri²,

Eichmann³

et al. 2013

J. Clin. Invest.

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117

103

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“…To study the involvement of Erk1/2 in regulation of VEGFR2 expression, we used Ad vectors encoding Erk2 fused to the low-activity form of its upstream regulator, Mek1. Whereas the Mek1-Erk2 (ME) hybrid protein is retained in the cytoplasm because of the presence of a nuclear export sequence, mutation of the 4 leucines in the export sequence to alanines (Mek1-Erk2-LA [ME-LA]) dramatically increases its catalytic activity with concomitant nuclear translocation (11,12). Transduction of Ad-ME-LA, but not Ad-GFP or Ad-ME, into FGFR1DN-expressing BAECs restored Vegfr2 mRNA and protein expression to control levels (Figure 1, F and G), which indicates that regulation of VEGFR2 expression by FGF is mediated through an Erk1/2-dependent signaling mechanism.…”

Section: Fgf-induced Erk1/2 Activation Mediates Vegfr2 Expressionmentioning

confidence: 99%

FGF-dependent regulation of VEGF receptor 2 expression in mice

Murakami¹,

Nguyen²,

Hatanaka³

et al. 2011

J. Clin. Invest.

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160

145

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Numerous studies have suggested a link between the angiogenic FGF and VEGF signaling pathways; however, the nature of this link has not been established. To evaluate this relationship, we investigated VEGF signaling in ECs with disrupted FGF signaling in vitro and in vivo. ECs lacking FGF signaling became unresponsive to VEGF, caused by downregulation of VEGF receptor 2 (VEGFR2) expression after reduced Vegfr2 enhancer activation. FGF mediated VEGFR2 expression via activation of Erk1/2. Transcriptional analysis revealed that Ets transcription factors controlled VEGFR2 expression in an FGF-and Erk1/2-dependent manner. Mice with defective FGF signaling exhibited loss of vascular integrity and reduced vascular morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF. IntroductionNew vessel formation is a multistep process requiring integrated actions of a number of angiogenic growth factors. Among them, the FGF and VEGF families are the most potent promoters of angiogenesis. Although synergistic action of FGF and VEGF has been observed and the crosstalk of the 2 families has been suggested as an essential regulatory step in vascular formation, the key details of this mechanism, which have long been a fundamental question in vascular biology, are not understood (1).The FGF family is one of the largest and evolutionarily preserved growth factor families; FGFs are capable of acting on a variety of cell types. They are critical in early embryonic development and precede the appearance of VEGF signaling. In adults, FGFs play key roles in neovascularization, wound healing, and cancer (2-4). One of the characteristic features of FGF signaling is the context specificity of action, producing divergent biological effects depending on the effector cell type and the dose, duration, or timing of action (5). This complex biology of FGFs suggests that they play a regulatory role in many biological settings by influencing multiple cellular components (4).Studies of the biological role of the FGF system have been complicated by the great redundancy among FGFs and by indispensable roles played by FGFR1 and FGFR2 in embryonic development (6). A noteworthy recent discovery has been the demonstration of an essential role played by endothelial FGF signaling in the maintenance of blood vessels (7). At the same time, VEGF and its receptors, VEGF receptor 1 (VEGFR1) and VEGFR2, play a key role in vascular development and maintenance of the adult vasculature.These observations suggest a tight integration of FGF and VEGF signaling in the endothelium. To study this interaction, we used several complementary approaches to block FGF signaling in ECs in vitro and in vivo and observed the effect of this inhibition on VEGF signaling and VEGF-induced biological responses. Suppression of endothelial FGF signaling, either by depletion of exogenous

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“…In another study, anthrax toxin, whose targets include MEK1/2 [22], appeared to reduce vessel lumen size in zebrafish [23]. During earlier developmental stages, MEK1/2 is also involved in artery specification in both zebrafish and mice [24,25]. Together these findings imply that MEK1/2 may cooperate with VEGFR to regulate blood vessel lumen diameter.…”

Section: Combined Action Of Vegfr and Map Kinase Pathways Maintains Vmentioning

confidence: 93%

Combinatory action of VEGFR2 and MAP kinase pathways maintains endothelial-cell integrity

Zhong

Wang

et al. 2011

Cell Res

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Blood vessels normally maintain stereotyped lumen diameters and their stable structures are crucial for vascular function. However, very little is known about the molecular mechanisms controlling the maintenance of vessel diameters and the integrity of endothelial cells. We investigated this issue in zebrafish embryos by a chemical genetics approach. Small molecule libraries were screened using live Tg(kdrl:GRCFP) zn1 transgenic embryos in which endothelial cells are specifically labeled with GFP. By analyzing the effects of compounds on the morphology and function of embryonic blood vessels after lumen formation, PP1, a putative Src kinase inhibitor, was identified as capable of specifically reducing vascular lumen size by interrupting endothelial-cell integrity. The inhibitory effect is not due to Src or general VEGF signaling inhibition because another Src inhibitor and Src morpholino as well as several VEG-FR inhibitors failed to produce a similar phenotype. After profiling a panel of 22 representative mammalian kinases and surveying published data, we selected a few possible new candidates. Combinational analysis of these candidate kinase inhibitors established that PP1 induced endothelial collapse by inhibiting both the VEGFR2 and MAP kinase pathways. More importantly, combinatory use of two clinically approved drugs Dasatinib and Sunitinib produced the same phenotype. This is the first study to elucidate the pathways controlling maintenance of endothelial integrity using a chemical genetics approach, indicating that endothelial integrity is controlled by the combined action of the VEGFR2 and MAP kinase pathways. Our results also suggest the possible side effect of the combination of two anticancer drugs on the circulatory system.

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ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish

Cited by 142 publications

References 49 publications

Endothelial ERK signaling controls lymphatic fate specification

Endothelial ERK signaling controls lymphatic fate specification

FGF-dependent regulation of VEGF receptor 2 expression in mice

Combinatory action of VEGFR2 and MAP kinase pathways maintains endothelial-cell integrity

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