A Novel Function of p38-Regulated/Activated Kinase in Endothelial Cell Migration and Tumor Angiogenesis

Yoshizuka, Naoto; Chen, Rebecca M.; Xu, Zhiwei; Long, Rong; Hong, Lian; Hu, Wen-Yuan; Yu, Guoliang; Han, Jiahuai; Chen, Longchuan; Sun, Peiqing

doi:10.1128/mcb.06301-11

Cited by 63 publications

(75 citation statements)

References 50 publications

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“…MAPKAPK5 is a protein kinase that functions downstream of p38 in the MAPK pathway, a mediator of infl ammatory response ( 36 ). Studies have shown that it is active in endothelial cells, where it mediates EC migration and angiogenesis ( 37 ). Little is known regarding a role for TCTN1 in cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Identification of CAD candidate genes in GWAS loci and their expression in vascular cells

Erbilgin

Civelek²,

Romanoski³

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org provided insight into the many different genetic factors that contribute to the disease ( 3-7 ). Using data acquired from thousands of patients and healthy controls, these studies have collectively identifi ed 35 genetic loci associated with CAD ( 8, 9 ). Although 10 of the recently identifi ed CAD risk loci work through known risk factors, such as lipids and blood pressure, this is not the case for the majority of loci ( 3 ), implying that key pathways leading to coronary atherosclerosis are yet to be discovered. Given their fi rm association with disease risk, novel CAD loci provide a solid foundation to unravel disease networks.As GWAS results do not provide functional information on the loci identifi ed, additional studies are needed to determine the candidate genes and their role in disease. The immediate challenges associated with the validation of GWAS candidate genes include identifying the likely cell types in which the risk variants and genes function, determining which of the multiple candidate genes represented by each CAD locus contribute to disease, and defi ning the functions of poorly annotated candidate genes. Expression analyses of candidate genes under defi ned conditions in model organisms and their associations with risk variants in human samples provide a powerful way to address these issues and predict the causal candidate genes.It is likely that at least some of the novel genes (that is, those not affecting known risk factors, such as plasma lipids or blood pressure) are perturbing vessel wall or infl ammatory cell functions. Endothelial cells (EC) play a critical role in the initiation and progression of atherosclerosis. Abstract Recent genome-wide association studies (GWAS)have identifi ed 35 loci that signifi cantly associate with coronary artery disease (CAD) susceptibility. The majority of the genes represented in these loci have not previously been studied in the context of atherosclerosis. To characterize the roles of these candidate genes in the vessel wall, we determined their expression levels in endothelial, smooth muscle, and macrophage cells isolated from healthy, prelesioned, and lesioned mouse aortas. We also performed expression quantitative locus (eQTL) mapping of these genes in human endothelial cells under control and proatherogenic conditions. Of the 57 genes studied, 31 were differentially expressed in one or more cell types in disease state in mice, and the expression levels of 8 were signifi cantly associated with the CAD SNPs in human cells, 7 of which were also differentially expressed in mice. By integrating human and mouse results, we predict that PPAP2B , GALNT4 , MAPKAPK5 , TCTN1 , SRR , SNF8 , and ICAM1 play a causal role in the susceptibility to atherosclerosis through a role in the vasculature. Additionally, we highlight the genetic complexity of a subset of CAD loci through the differential expression of multiple candidate genes per locus and the involvement of genes that lie outside linkage disequilib...

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Section: Discussionmentioning

confidence: 99%

Identification of CAD candidate genes in GWAS loci and their expression in vascular cells

Erbilgin

Civelek²,

Romanoski³

et al. 2013

Journal of Lipid Research

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“…Mitogen-activated protein kinases (MAPKs), including extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK), and p38, are a family of central signaling molecules that respond to numerous stimuli and are known to participate in cell survival and death decisions (Hardie 2011;Kanaji et al 2013). Moreover, the activation of JNK and p38 MAPK phosphorylation can induce apoptotic responses in endothelial cells (Yoshizuka et al 2012). Evidence has been demonstrated that reactive oxygen species (ROS) can activate JNK/p38 MAPK signaling and trigger subsequent apoptosis (Ong et al 2015;Tormos et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Probucol Protects Against Asymmetric Dimethylarginine-Induced Apoptosis in the Cultured Human Brain Microvascular Endothelial Cells

Zhao

Gao

et al. 2015

J Mol Neurosci

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Asymmetric dimethylarginine (ADMA) is emerging as a key contributor to endothelial dysfunction. The drug probucol was reported to have an anti-lipid peroxidation effect and improve endothelial dilation function. But little is known about the protective effect of probucol on ADMA-induced human brain microvascular endothelial cell (HBMEC) injury and its underlying mechanisms. Therefore, in this study, we investigated the effect of probucol on ADMA-induced HBMEC injury and its potential mechanisms. Results showed that probucol protected against ADMA-induced HBMEC injury in a dose-dependent manner; probucol pretreatment also significantly reduced the level of reactive oxygen species (ROS) and malondialdehyde (MDA), downregulated the expression of pro-apoptotic gene Bax and caspase-3 activity, as well as increased the brain-derived neurotrophic factor (BDNF) release and promoted anti-apoptotic gene Bcl-2 and eNOS expression in the cultured HBMECs. Furthermore, we found that ADMA significantly increased the phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38, while probucol pretreatment effectively inhibited ADMA-induced JNK and p38 phosphorylation in HBMECs. In conclusion, our present results demonstrated that probucol protected against ADMA-induced HBMEC injury and suppressed oxidative stress through the JNK/p38 MAPK pathway, which was the potential underlying mechanism of HBMEC injury in ischemic cerebrovascular disease.

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“…Yoshizuka and collaborators showed that MK5 mediates cytoskeletal reorganization during migration of endothelial cells in response to vascular endothelial growth factor (VEGF) and, maybe, additional factors secreted by the skin tumor epithelium ( Figure 5 ; Yoshizuka et al , 2012a ). VEGF binds predominantly VEGF receptor 2 (VEGFR2), and this triggers MK5 Thr-182 phosphorylation through a cascade involving the p38 MAPK isoforms α and β , but not ERK3 and ERK4.…”

Section: Mk5 and Angiogenesismentioning

confidence: 99%

“…The exact mechanism for MK5-mediated FAK phosphorylation and activation remains to be solved. A striking finding by Yoshizuka and colleagues is that VEGF-induced HSP27 phosphorylation in human vascular umbilical veil endothelial cells was not mediated by MK5 because VEGF-provoked HSP27 phosphorylation was not affected in MK5-depleted cells (Yoshizuka et al , 2012a ). Thus, although HSP27 is a genuine substrate of MK5, and MK5 can be activated by p38 MAPK (reviewed in Shiryaev and Moens , 2010 ), VEGF-induced HSP27 phosphorylation occurs in a MK5-independent manner.…”

Section: Mk5 and Angiogenesismentioning

confidence: 99%

Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

Moens

Kostenko²

2013

Biological Chemistry

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Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases.

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A Novel Function of p38-Regulated/Activated Kinase in Endothelial Cell Migration and Tumor Angiogenesis

Cited by 63 publications

References 50 publications

Identification of CAD candidate genes in GWAS loci and their expression in vascular cells

Identification of CAD candidate genes in GWAS loci and their expression in vascular cells

Probucol Protects Against Asymmetric Dimethylarginine-Induced Apoptosis in the Cultured Human Brain Microvascular Endothelial Cells

Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

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