Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38

Lamalice, Laurent; Houle, François; Jourdan, Guillaume; Huot, Jacques

doi:10.1038/sj.onc.1207034

Cited by 194 publications

(167 citation statements)

References 50 publications

(57 reference statements)

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“…Supporting the role of VEGFR2 in p38 phosphorylation, Shay-Salit et al (2002) found that shear stress caused a rapid (1-2 minute) interaction between VEGFR2 and VE-cadherin that was needed for p38 phosphorylation. Other researchers have shown that Y1214 on VEGFR2 regulates the phosphorylation of p38 (Lamalice et al, 2004). Consistent with the findings, we observed phosphorylation of Y1214 in response to shear stress.…”

Section: Discussionsupporting

confidence: 82%

“…Vascular endothelial growth factor receptor 2 (VEGFR2) is implicated as both a ligand activated receptor (Lamalice et al, 2004) and a mechanoreceptor (Jin et al, 2003). Activation of VEGFR2 occurs immediately in response to elevated shear stress, and is not prevented by the presence of a polyclonal anti-VEGF antibody, suggesting that activation is not induced by ligand binding (Chen et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress‐induced angiogenesis

Gee

Milkiewicz

Haas

2009

Journal Cellular Physiology

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Increased capillary shear stress induces angiogenesis in skeletal muscle, but the signaling mechanisms underlying this response are not known. We hypothesize that shear stress-dependent activation of vascular endothelial growth factor receptor 2 (VEGFR2) causes p38 and ERK1/2 phosphorylation, which contribute to shear stress-induced angiogenesis. Skeletal muscle microvascular endothelial cells were sheared (12 dynes/cm 2 , 0.5-24 hours). VEGFR2-Y1214 phosphorylation increased in response to elevated shear stress and VEGF stimulation. p38 and ERK1/2 phosphorylation increased at 2 hours of shear stress, but only p38 remained phosphorylated at 6 and 24 hours of shear stress. VEGFR2 inhibition abrogated p38, but not ERK1/2 phosphorylation. VEGF production was increased in response to shear stress at 6 hours, and this increased production was abolished by p38 inhibition. Male Sprague-Dawley rats were administered prazosin (50 mg/L drinking water, 1, 2, 4 or 7 days) to induce chronically elevated capillary shear stress in skeletal muscle. In some experiments, mini-osmotic pumps were used to dispense p38 inhibitor SB203580 or its inactive analog SB202474, to the extensor digitorum longus (EDL) of control and prazosin treated rats. Immunostaining and Western blotting showed increases in p38 phosphorylation in capillaries from rats treated with prazosin for 2 days but returned to basal levels at 4 and 7 days. p38 inhibition abolished the increase in capillary to muscle fibre ratio seen after 7 days of prazosin treatment. Our data suggest that p38 activation is necessary for shear stress-dependent angiogenesis.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress‐induced angiogenesis

Gee

Milkiewicz

Haas

2009

Journal Cellular Physiology

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“…In fact, our results showed that Cdc42 might be essential for p38MAPK activation and migration induced by LPA (Figures 5e and 6d). This hypothesis was supported by very recent studies showing that Cdc42 could also be important for p38MAPK-dependent T-cell chemotaxis (Shi et al, 2003) and the VEGFinduced formation of stress fibers in endothelial cells (Lamalice et al, 2004). In prostate carcinoma cells (Edlund et al, 2002), Cdc42 as well as RhoA could participate in not only transforming growth factor-binduced formation of stress fibers but also in membrane ruffling.…”

Section: Discussionsupporting

confidence: 71%

Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells

et al. 2005

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A potential role for 1-oleoyl-sn-glycero-3-phosphate or lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) in the regulation of malignant diseases has been widely considered. In this study, we found that in transformed astroglial cells, the expression profile of lysophospholipid receptor mRNA and the action modes of LPA and S1P on cell motility were changed: there was a change in the acquisition of the ability of LPA to stimulate cell migration and a change in the migratory response to S1P from stimulation through S1P 1 to inhibition through S1P 2 . LPA-induced cell migration was almost completely inhibited by either pertussis toxin, LPA 1 receptor antagonists including Ki16425 (3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfonyl)propanoic acid) or an inhibitor of phosphatidylinositol 3-kinase (PI3K) wortmannin. The LPA-induced action was also suppressed, although incompletely, by several specific inhibitors for intracellular signaling pathways including Rac1, Cdc42, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun terminal kinase (JNK), but not extracellular signalregulated kinase. Nearly complete inhibition of migration response to LPA, however, required simultaneous inhibition of both the p38MAPK and JNK pathways. Inhibition of Rac1 suppressed JNK but not p38MAPK, while the activity of p38MAPK was abolished by a dominantnegative form of Cdc42. These findings suggest that, in glioma cells, the PI3K/Cdc42/p38MAPK and PI3K/ Rac1/JNK pathways are equally important for LPA 1 receptor-mediated migration.

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“…Several studies, as well as studies in our laboratory, have shown that inhibiting p38 can inhibit stress fiber formation in adherent cells and lead to decreases in cell permeability in some cell systems (57)(58)(59)(60). However, our data also indicate that no stress fiber formation accompanies the increase in lamellipodia formation observed in MEK6E-expressing cells replated onto gelatin.…”

Section: Fig 9 Mek6e-induced Migration and Actin Reorganization Invcontrasting

confidence: 46%

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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Phosphorylation of tyrosine 1214 on VEGFR2 is required for VEGF-induced activation of Cdc42 upstream of SAPK2/p38

Cited by 194 publications

References 50 publications

p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress‐induced angiogenesis

p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress‐induced angiogenesis

Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells

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

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