Activated Ras induces a proangiogenic phenotype in primary endothelial cells

Meadows, Kafi N.; Bryant, Patrick; Vincent, Peter; Pumiglia, Kevin

doi:10.1038/sj.onc.1206921

Cited by 81 publications

(63 citation statements)

References 60 publications

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“…For example, MAPK signaling is considered one of the critical molecular events in the growth, survival, and migration of vascular endothelial cells in angiogenesis (5,6). Also, the AKT kinases are activated in endothelial cells by a variety of stimuli (33), and they regulate multiple critical steps by phosphorylating different downstream substrates, such as mTOR (34).…”

Section: Discussionmentioning

confidence: 99%

Hesperidin Inhibits Vascular Formation by Blocking the AKT/mTOR Signaling Pathways

Kim

2015

JFN

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ABSTRACT:Hesperidin has been shown to possess a potential inhibitory effect on vascular formation in endothelial cells. However, the fundamental mechanism for the anti-angiogenic activity of hesperidin is not fully understood. In the present study, we evaluated whether hesperidin has anti-angiogenic effects in mouse embryonic stem cell (mES)-derived endothelial-like cells, and human umbilical vascular endothelial cells (HUVECs), and evaluated their mechanism via the AKT/mammalian target of rapamycin (mTOR) signaling pathway. The endothelial cells were treated with several doses of hesperidin (12.5, 25, 50, and 100 M) for 24 h. Cell viability and vascular formation were analyzed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and tube formation assay, respectively. Alteration of the AKT/mTOR signaling in vascular formation was analyzed by western blot. In addition, a mouse aortic ring assay was used to determine the effect of hesperidin on vascular formation. There were no differences between the viability of mES-derived endothelial-like cells and HUVECs after hesperidin treatment. However, hesperidin significantly inhibited cell migration and tube formation of HUVECs (P＜0.05) and suppressed sprouting of microvessels in the mouse aortic ring assay. Moreover, hesperidin suppressed the expression of AKT and mTOR in HUVECs. Taken together, these findings suggest that hesperidin inhibits vascular formation by blocking the AKT/mTOR signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Hesperidin Inhibits Vascular Formation by Blocking the AKT/mTOR Signaling Pathways

Kim

2015

JFN

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“…As it has been reported that the JNK signaling plays a role in cell migration or motility (Huang et al, 2004;Kawauchi et al, 2003;Meadows et al, 2004;Pedram et al, 2001), we hypothesized that the suppressed migration of ENCCs in the homozygous S697A mice is due to the impaired JNK signaling by the S697 mutant form of RET. To test whether JNK signaling was required for the chemoattractant response to GDNF, explant experiments were carried out in the presence of the JNK inhibitor SP600125.…”

Section: Jnk Signal Is Impaired In the Ret S697a Mutant Mice And Requmentioning

confidence: 99%

Targeted mutation of serine 697 in theRettyrosine kinase causes migration defect of enteric neural crest cells

Asai

Fukuda

et al. 2006

Development

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The RET receptor tyrosine kinase plays a critical role in the development of the enteric nervous system (ENS) and the kidney. Upon glial-cell-line-derived neurotrophic factor (GDNF) stimulation, RET can activate a variety of intracellular signals, including the Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)/AKT, and RAC1/JUN NH 2 -terminal kinase (JNK) pathways. We recently demonstrated that the RAC1/JNK pathway is regulated by serine phosphorylation at the juxtamembrane region of RET in a cAMP-dependent manner. To determine the importance of cAMP-dependent modification of the RET signal in vivo, we generated mutant mice in which serine residue 697, a putative protein kinase A (PKA) phosphorylation site, was replaced with alanine (designated S697A mice). Homozygous S697A mutant mice lacked the ENS in the distal colon, resulting from a migration defect of enteric neural crest cells (ENCCs). In vitro organ culture showed an impaired chemoattractant response of the mutant ENCCs to GDNF. JNK activation by GDNF but not ERK, AKT and SRC activation was markedly reduced in neurons derived from the mutant mice. The JNK inhibitor SP600125 and the PKA inhibitor KT5720 suppressed migration of the ENCCs in cultured guts from wild-type mice to comparable degrees. Thus, these findings indicated that cAMP-dependent modification of RET function regulates the JNK signaling responsible for proper migration of the ENCCs in the developing gut.

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“…Cell Proliferation and Cell Migration-These experiments were conducted essentially as described previously by us (10,15,24).…”

Section: Methodsmentioning

confidence: 99%

Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

McMullen

Bryant

Glembotski

et al. 2005

Journal of Biological Chemistry

135

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Pathological conditions such as hypertension and hyperglycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.

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Activated Ras induces a proangiogenic phenotype in primary endothelial cells

Cited by 81 publications

References 60 publications

Hesperidin Inhibits Vascular Formation by Blocking the AKT/mTOR Signaling Pathways

Hesperidin Inhibits Vascular Formation by Blocking the AKT/mTOR Signaling Pathways

Targeted mutation of serine 697 in theRettyrosine kinase causes migration defect of enteric neural crest cells

Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

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