cPLA2 is phosphorylated and activated by MAP kinase

We have examined the potential role of MAP kinase in the regulation of endothelial cell PGI2 synthesis, vWF secretion and E-selectin expression using the specific MEK inhibitor PD98059. PD98059 dose-dependently attenuated the tyrosine phosphorylation and activation of !}42 mapk in response to thrombin or inflammatory cytokines. Inhibition of thrombinmapk induced p42 activation was paralleled by an inhibitory effect of PD98059 on thrombin-driven PGI2 generation but not on vWF secretion or IL-lo0TNF~-induced E-selectin expression. These results provide evidence for a key role for !142 mapk in the acute regulation of PGI2 synthesis in human endothelial cells and suggest that activation of the MAP kinase cascade is not obligatory for cytokine-stimulated E-selectin expression.

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“…Further studies are required to determine whether this results from p42mapk-mediated phosphorylation of cytosolic phospholipase A2 [16,27].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

et al. 1996

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“…MKK1 and MKK2 in turn activate their respective ERKs through phosphorylation of speci®c Thr-and Tyr-residues within the characteristic TPY motif. The phosphorylated ERKs activate other signaling proteins such as cPLA 2 (Nemeno et al, 1993;Lin et al, 1993) as well as other kinases (Boulton et al, 1991;Sturgill et al, 1988;Stokoe et al, 1992). In addition, the phosphorylated ERKs translocate to nucleus (Chen et al, 1992;Seth et al, 1992;Sanghera et al, 1992;Lenormand et al, 1993) where they activate transcription factors such as TCFs through phosphorylation (Alvarez et al, 1991;Pulverer et al, 1991;Baker et al, 1992;Gille et al, 1992) which leads to the activation of speci®c genes involved in cell proliferation (Davis, 1992;Johnson and Vaillancourt, 1994).…”

Section: Map Kinase Kinase-1 and Map Kinase Kinase-2mentioning

confidence: 99%

Signaling by dual specificity kinases

1998

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Dual speci®city kinases that phosphorylate the Thr-and Tyr-residues within the TXY motif of MAP-kinases of play a central role in the regulation of various processes of cell growth. These dual speci®city kinases also known as MAP kinase kinases are constituents of the sequential kinase signaling modules. Seven distinct mammalian MAP kinases kinases have been identi®ed. Some of the unique signaling properties of these kinases are discussed here.

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“…Raf activity mediates the activation of the MAPK cascade through the Raf-dependent activation of MEK1 (Macdonald et al, 1993;Moodie et al, 1993Moodie et al, , 1994Van Aelst et al, 1993), the regulatory kinase for the p42 and p44 MAPKs. MAPK regulates the activity of cytosolic kinases, including PLA 2 (Lin et al, 1993, andRSK2 (Xing et al, 1996) and, upon translocation of active MAPK to the nucleus, the activity of transcription factors including Elk1 (reviewed by Hill and Treisman, 1995). Ras activity is critical for proliferation since both the microinjection of neutralizing Ras antibodies (Mulcahy et al, 1985) or the ectopic expression of a dominant negative (S17N)Ras protein (Feig and Cooper, 1988;Okuda et al, 1994) block cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo

Hamilton

Wolfman

1998

Oncogene

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The Ras GTPases function as molecular switches, regulating a multiplicity of biological events. However the contribution, if any, of a speci®c c-Ras isoform (Ha-, N-, or Ki-ras A or B) in the regulation of a given biological or biochemical process, is unknown. Murine C3H10T1/2 ®broblasts transformed with activated (G12V)Ha-ras or (Q61K)N-ras proliferate in serum-free media and have constitutive MAPK activity. The growth factor antagonist, suramin, inhibited the serum-independent proliferation of Ha-ras transformed ®broblasts, but not the serum-independent proliferation of N-ras transformed cells. The inhibition of cell proliferation was concomitant with the abrogation of the constitutive MAPK activity in the Ha-ras transformed ®broblasts. Analysis of the Ras-signalling complexes in immunoprecipitates from Ha-ras transformed cells revealed that Raf-1 co-immunoprecipitated with endogenous c-N-ras but not (G12V)Ha-ras. Pretreatment with suramin resulted in the loss of Raf-1 from c-N-ras immunoprecipitates. A c-N-ras antisense oligonucleotide, which down-regulated c-N-ras protein levels, abrogated the constitutive MAPK activity and serum-independent proliferation of (G12V)Ha-ras transformed cells. The data suggest that Raf-1 has a higher a nity for N-ras then Ha-ras in vivo, and c-N-ras function is required for the serum-independent proliferation of Ha-ras transformed cells.

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cPLA2 is phosphorylated and activated by MAP kinase

Cited by 1,790 publications

References 54 publications

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

Signaling by dual specificity kinases

Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo

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cPLA2 is phosphorylated and activated by MAP kinase

Cited by 1,790 publications

References 54 publications

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI2 release but has no effect on von Willebrand factor secretion or E‐selectin expression

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI2 release but has no effect on von Willebrand factor secretion or E‐selectin expression

Signaling by dual specificity kinases

Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo

Contact Info

Product

Resources

About

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression

Inhibition of MAP kinase kinase (MEK) blocks endothelial PGI₂ release but has no effect on von Willebrand factor secretion or E‐selectin expression