Angiogenesis, or the remodeling of preexisting quiescent blood vessel, is critical for embryonic development, wound healing, and various pathological conditions including tumor progression and atherosclerosis. We propose to study in molecular terms, the function of phosphatidic acid phosphatase 2b (PAP2b), a plasma- membrane protein that we discovered in a functional assay of angiogenesis. The PAP2b protein is expressed by endothelial cells, exhibits a cell adhesion sequence, and dephosphorylates phosphatidic acid phosphate (PAP) into diacylglycerol and phosphate, that has been implicated in signal transduction and lipid metabolism. The Pap2b gene inactivation is early embryonic lethal (die around E7.5 day) due to lack of functional vasculature. PAP2b is the first lipid phosphate phosphatase protein that is linked to the Wnt signaling pathway. We found that PAP2b is expressed by a subset of primary tumors, and over-expression of PAP2b supports tumor growth and angiogenesis. We observe that PAP2b interacts with p120catenin and promotes cell-cell-interactions, in turn, induces protein complex formation between beta-catenin and lymphoid enhancer-binding factor-1 (LEF-1), this event leads to fibronectin and IL-8 synthesis and secretion. Based upon our preliminary data, we hypothesize that during angiogenesis PAP2b plays a key role in the formation and organization of adhesion structures connecting endothelial cells. The mechanisms include the ability of PAP2b to form and organize large molecular complex, interact with a subset of integrins, and mediate synthesis of fibronectin through LEF-1 transcriptional machinery. The overall aim of this proposal is to determine the mechanism by which the PAP2b interacts with p120catenin, and mediates synthesis of fibronectin. We propose to test our hypothesis through two major specific aims: (1) Characterize the mechanism by which PAP2b interacts with p120catenin, alter LEF-transcription, and induce expression of fibronectin and IL-8, and (2) Examine the functional consequences of conditional deletion of Pap2b gene in the mice using Tie-2/Cre system. Examine the consequences of SiRNA mediated down-regulation of PAP2b using endothelial cells. We anticipate that our studies will further our understanding of the role of endothelial PAP2b in physiological and pathological angiogenesis. Together, these studies are expected to reveal a new target for anti-angiogenic molecular therapy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL079356-01A2
Application #
7100448
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Srinivas, Pothur R
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
1
Fiscal Year
2006
Total Cost
$310,000
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Zhang, Chongxu; Adamos, Crystal; Oh, Myung-Jin et al. (2017) oxLDL induces endothelial cell proliferation via Rho/ROCK/Akt/p27kip1 signaling: opposite effects of oxLDL and cholesterol loading. Am J Physiol Cell Physiol 313:C340-C351
Baruah, Jugajyoti; Hitzman, Ryan; Zhang, Jane et al. (2017) The allosteric glycogen synthase kinase-3 inhibitor NP12 limits myocardial remodeling and promotes angiogenesis in an acute myocardial infarction model. J Biol Chem 292:20785-20798
Wary, Anita; Wary, Neil; Baruah, Jugajyoti et al. (2017) Chromatin-modifying agents convert fibroblasts to OCT4+ and VEGFR-2+ capillary tube-forming cells. PLoS One 12:e0176496
Chatterjee, Ishita; Li, Fei; Kohler, Erin E et al. (2016) Induced Pluripotent Stem (iPS) Cell Culture Methods and Induction of Differentiation into Endothelial Cells. Methods Mol Biol 1357:311-27
Oh, Myung-Jin; Zhang, Chongxu; LeMaster, Elizabeth et al. (2016) Oxidized LDL signals through Rho-GTPase to induce endothelial cell stiffening and promote capillary formation. J Lipid Res 57:791-808
Chatterjee, Ishita; Baruah, Jugajyoti; Lurie, Erin E et al. (2016) Endothelial lipid phosphate phosphatase-3 deficiency that disrupts the endothelial barrier function is a modifier of cardiovascular development. Cardiovasc Res 111:105-18
Wu, Liangtang; Wary, Kishore K; Revskoy, Sergei et al. (2015) Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells. Stem Cell Reports 5:10-21
Gong, Haixia; Rehman, Jalees; Tang, Haiyang et al. (2015) Corrigendum. HIF2? signaling inhibits adherens junctional disruption in acute lung injury. J Clin Invest 125:1364
Toya, Sophie P; Wary, Kishore K; Mittal, Manish et al. (2015) Integrin ?6?1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells. Stem Cells 33:1719-29
Gong, Haixia; Rehman, Jalees; Tang, Haiyang et al. (2015) HIF2? signaling inhibits adherens junctional disruption in acute lung injury. J Clin Invest 125:652-64

Showing the most recent 10 out of 22 publications