Lipid Phosphate Phosphatase 3 Stabilization of β-Catenin Induces Endothelial Cell Migration and Formation of Branching Point Structures

Humtsoe, Joseph O.; Liu, Mingyao; Malik, Asrar B.; Wary, Kishore K.

doi:10.1128/mcb.00038-09

Cited by 43 publications

(63 citation statements)

References 47 publications

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“…This was consistent with different functions that have been attributed for PPAP2B in ECs and SMCs. In ECs, PPAP2B localizes to adherens junctions and regulates ␤ -catenin signaling, thereby affecting cell migration ( 34 ). In SMCs, it regulates lysophospholipid signaling responses and affects SMC phenotypic plasticity ( 35 ).…”

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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“…Mammalian LPPs have been demonstrated to localize to specific plasma membrane domains. Human (h) LPP1 (PPAP2A -Human Genome Nomenclature Committee) sorts apically, whereas hLPP3 colocalizes with Ecadherin in Madin-Darby canine kidney (MDCK) cells (Jia et al, 2003) and the C-terminal domain of hLPP3 has been shown to bind the AJ protein p120 catenin (catenin 1) (Humtsoe et al, 2010). However, it remains to be confirmed whether specific Wun-GFP localization is crucial for activity.…”

Section: Discussionmentioning

confidence: 99%

“…Catalytically dead forms of mammalian LPP3 can have effects on cells (Escalante-Alcalde et al, 2003;Humtsoe et al, 2010); therefore, we asked whether catalytic activity is required to rescue the tracheal defects. A mutant form of Wun2 in which a predicted catalytic histidine has been converted to lysine, H326K, is incapable of affecting the survival or migration of germ cells and shows no activity in vitro against PA (Starz-Gaiano et al, 2001;Renault et al, 2004).…”

Section: Lpp Activity Is Required Autonomously In Tracheal Cellsmentioning

confidence: 99%

Wunen, a Drosophila lipid phosphate phosphatase, is required for septate junction-mediated barrier function

et al. 2012

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SUMMARYLipid phosphate phosphatases (LPPs) are integral membrane enzymes that regulate the levels of bioactive lipids such as sphingosine 1-phosphate and lysophosphatidic acid. The Drosophila LPPs Wunen (Wun) and Wunen-2 (Wun2) have a well-established role in regulating the survival and migration of germ cells. We now show that wun has an essential tissue-autonomous role in development of the trachea: the catalytic activity of Wun is required to maintain septate junction (SJ) paracellular barrier function, loss of which causes failure to accumulate crucial luminal components, suggesting a role for phospholipids in SJ function. We find that the integrity of the blood-brain barrier is also lost in wun mutants, indicating that loss of SJ function is not restricted to the tracheal system. Furthermore, by comparing the rescue ability of different LPP homologs we show that wun function in the trachea is distinct from its role in germ cell migration.

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“…HUVECs were treated with either control virus or virus encoding KIF13B-specific shRNA and were tested in a TER system for cell migration. (B) VEGF-mediated migration of HUVECs was determined by using the scratch wound healing assay (Humtsoe et al, 2010). HUVECs were treated with scrambled control siRNA or KIF13B-specific siRNA and were subjected to the scratch wound healing assay in the presence of 2.2 nmol/l VEGF.…”

Section: Impaired Kif13b Motor Function Shunts Vegfr2 To Lysosomesmentioning

confidence: 99%

“…In vitro capillary network formation on Matrigel (BD Biosciences, San Jose, CA) was performed as described previously (Humtsoe et al, 2010).…”

Section: Formation Of Capillary Network Structures In Vitromentioning

confidence: 99%

KIF13B regulates angiogenesis through golgi-plasma membrane trafficking of VEGFR2

Yamada

Nakajima

Geyer

et al. 2014

Journal of Cell Science

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Although the trafficking of newly synthesized VEGFR2 to the plasma membrane is a key determinant of angiogenesis, the molecular mechanisms of Golgi to plasma membrane trafficking are unknown. Here, we have identified a key role of the kinesin family plus-end molecular motor KIF13B in delivering VEGFR2 cargo from the Golgi to the endothelial cell surface. KIF13B is shown to interact directly with VEGFR2 on microtubules. We also observed that overexpression of truncated versions of KIF13B containing the binding domains that interact with VEGFR2 inhibited VEGF-induced capillary tube formation. KIF13B depletion prevented VEGFmediated endothelial migration, capillary tube formation and neovascularization in mice. Impairment in trafficking induced by knockdown of KIF13B shunted VEGFR2 towards the lysosomal degradation pathway. Thus, KIF13B is an essential molecular motor required for the trafficking of VEGFR2 from the Golgi, and its delivery to the endothelial cell surface mediates angiogenesis.

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Lipid Phosphate Phosphatase 3 Stabilization of β-Catenin Induces Endothelial Cell Migration and Formation of Branching Point Structures

Cited by 43 publications

References 47 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

Wunen, a Drosophila lipid phosphate phosphatase, is required for septate junction-mediated barrier function

KIF13B regulates angiogenesis through golgi-plasma membrane trafficking of VEGFR2

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