Ordered phosphorylation of p42<sup>mapk</sup> by MAP kinase kinase

Haystead, Timothy A.J.; Dent, Paul; Wu, Jie; Haystead, Clare M.M.; Sturgill, Thomas W.

doi:10.1016/0014-5793(92)80828-5

Cited by 149 publications

(109 citation statements)

References 17 publications

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“…MAPKK-1 phosphorylates Tyr-185 of p42 MAPK preferentially [19], and the present work shows that GST-XMEK2(E286, E290) also phosphorylates the Xenopus RK homologue XMpk2 much more rapidly at Tyr-183 than at Thr-181 in vitro. Indeed, we cannot be certain that GST-XMEK2 phosphorylates Thr-181 at all, because phosphorylation of Tyr-183 by XMEK2 may then permit MalE-XMpk2 to slowly phosphorylate itself at Thr-181.…”

Section: Discussionsupporting

confidence: 58%

Activation of the MAP kinase homologue RK requires the phosphorylation of Thr‐180 and Tyr‐182 and both residues are phosphorylated in chemically stressed KB cells

et al. 1995

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Section: Discussionsupporting

confidence: 58%

Activation of the MAP kinase homologue RK requires the phosphorylation of Thr‐180 and Tyr‐182 and both residues are phosphorylated in chemically stressed KB cells

et al. 1995

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“…[37][38][39][40] In vitro, ECs activate this pathway on stimulation of multiple proangiogenic EC receptors including, VEGFR2, FGFR2, Tie2, integrins (␣ v ␤ 3 and ␣ v ␤ 5 ), and EDG1, 17,18,21,[41][42][43][44] and EC activation of this pathway is necessary for angiogenesis. 22,[25][26][27] Inhibition of EC signaling through Raf-MEK-ERK was shown in tumors treated with sorafenib by decreased immunohistochemical staining for p-ERK.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Tumor Endothelial ERK Activation, Angiogenesis, and Tumor Growth by Sorafenib (BAY43-9006)

Murphy

Makonnen

Lassoued

et al. 2006

The American Journal of Pathology

137

102

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Activation of the Raf-MEK-ERK signal transduction pathway in endothelial cells is required for angiogenesis. Raf is the kinase most efficiently inhibited by the multikinase inhibitor sorafenib, which has shown activity against certain human cancers in clinical trials. To understand the mechanisms underlying this activity, we studied how it controlled growth of K1735 murine melanomas. Therapy caused massive regional tumor cell death accompanied by severe tumor hypoxia, decreased microvessel density, increased percentage of pericyte-covered vessels, and increased caliber and decreased arborization of vessels. These signs of K1735 angiogenesis inhibition, along with its ability to inhibit Matrigel neovascularization, showed that sorafenib is an effective antiangiogenic agent. Extracellular signal-regulated kinase (ERK) activation in tumor endothelial cells, revealed by immunostaining for phospho-ERK and CD34, was inhibited, whereas AKT activation, revealed by phospho-AKT immunostaining, was not inhibited in K1735 and two other tumor types treated with sorafenib. Treatment decreased endothelial but not tumor cell proliferation and increased both endothelial cell and tumor cell apoptosis. These data indicate that sorafenib's anti-tumor efficacy may be primarily attributable to angiogenesis inhibition resulting from its inhibition of Raf-MEK-ERK signaling in endothelial cells. Assessing endothelial cell ERK activation in tumor biopsies may provide mechanistic insights into and allow monitoring of sorafenib's activity in patients in clinical trials.

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“…p42 / p44 MAPK are activated by phosphorylation within their activation lip at Thr 183 -Glu-Tyr 185 (21). p38 MAPK is activated by the phosphorylation at a Thr-GlyTyr motif (22 -24).…”

Section: Discussionmentioning

confidence: 99%

p38 Mitogen-Activated Protein Kinase Regulates Vasoconstriction in Spontaneously Hypertensive Rats

Kwon

Fang

et al. 2004

J Pharmacol Sci

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Abstract. We investigated whether p42 / p44 mitogen-activated protein kinase (MAPK) and / or p38 MAPK participates in the regulation of vascular smooth muscle contraction by endothelin-1 (ET-1) in Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR). ET-1 (10 nM) induced a sustained contraction in WKY and SHR aortas. PD98059 (100 m M), an inhibitor of p42/ p44 MAPK kinase, partially attenuated the ET-1-induced contraction in WKY and SHR. However, SB203580 (10 m M), an inhibitor of p38 MAPK, relaxed the ET-1-induced contraction to the resting levels in SHR, but not in WKY. ET-1 (10 nM) increased phosphorylation of both p42 / p44 MAPK and p38 MAPK in WKY and SHR. However, in SHR, p38 MAPK phosphorylation in response to ET-1 stimulation was increased more than in WKY. PD98059 (100 m M) and SB203580 (10 m M) abolished the phosphorylation of p42 / p44 MAPK and p38 MAPK in response to ET-1 stimulation in WKY and SHR, respectively. On the other hand, SB203580 (10 mM) did not affect myosin light chain (MLC) phosphorylation in response to ET-1 (10 nM) stimulation in WKY and SHR. From these results, it is concluded that p42 / p44 MAPK and/ or p38 MAPK partially regulates the ET-1-induced vasoconstriction in WKY. However, p38 MAPK, rather than p42 / p44 MAPK, activation plays an important role for the maintenance of ET-1-induced vasoconstriction in SHR through a MLC phosphorylationindependent pathway.

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Ordered phosphorylation of p42^mapk by MAP kinase kinase

Cited by 149 publications

References 17 publications

Activation of the MAP kinase homologue RK requires the phosphorylation of Thr‐180 and Tyr‐182 and both residues are phosphorylated in chemically stressed KB cells

Activation of the MAP kinase homologue RK requires the phosphorylation of Thr‐180 and Tyr‐182 and both residues are phosphorylated in chemically stressed KB cells

Inhibition of Tumor Endothelial ERK Activation, Angiogenesis, and Tumor Growth by Sorafenib (BAY43-9006)

p38 Mitogen-Activated Protein Kinase Regulates Vasoconstriction in Spontaneously Hypertensive Rats

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Ordered phosphorylation of p42mapk by MAP kinase kinase

Cited by 149 publications

References 17 publications

Activation of the MAP kinase homologue RK requires the phosphorylation of Thr‐180 and Tyr‐182 and both residues are phosphorylated in chemically stressed KB cells

Activation of the MAP kinase homologue RK requires the phosphorylation of Thr‐180 and Tyr‐182 and both residues are phosphorylated in chemically stressed KB cells

Inhibition of Tumor Endothelial ERK Activation, Angiogenesis, and Tumor Growth by Sorafenib (BAY43-9006)

p38 Mitogen-Activated Protein Kinase Regulates Vasoconstriction in Spontaneously Hypertensive Rats

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Ordered phosphorylation of p42^mapk by MAP kinase kinase