Regulation of endothelial cell-cell adherens junction integrity and paracellular pathway function.
Our laboratory is interested in the intracellular effector mechanisms that couple specific receptor-ligand interactions with opening of the endothelial paracellular pathway. More specifically, we have focused on the tyrosine phosphorylation signaling events that regulate protein-protein interactions within the zonula adherens multiprotein complex, actin organization, and cell-cell homophilic adhesion. Our studies have included bacterial constituents (e.g. lipopolysaccharide or endotoxin) cytokines (e.g. TNF-alpha), and members of a family of novel counteradhesive proteins (e.g. thrombospondin-1 and SPARC i.e. Secreted Protein Acidic and Rich in Cysteine). More recently, we have begun to study a receptor protein tyrosine phosphatase (PTP), PTPmu, that associates with and restrains tyrosine phosphorylation of zonula adherens proteins. More recently, we have studied the ability of EGF motif-containing proteins like thrombospondins, to activate the epidermal growth factor receptor (EGFR) and the role this plays in epithelial repair.
In a collaborative project with the laboratory of Dr. Alan S. Cross, we are engaged in studies of endogenous sialidases and the role of desialylation of surface structures on neutrophils and the endothelial barrier and how these events regulate neutrophil adherence to and migration across the endothelium. In another collaboration, we are studying the signaling events that couple stimulation by either the prokaryotic protein, zonula occludin toxin (ZOT), or the eukaryotic homologue, zonulin (now identified as prehaptoglobin-2), with tight junction disassembly.
Cross AS, Sakarya S, Rifat S, Held TK, Drysdale B-E, Grange PA, Cassels FJ, Wang L-X, Stamatos NM, Farese A, Casey D, Powell J, Bhattacharjee AK, Kleinberg M, and GOLDBLUM SE. Recruitment of murine neutrophils in vivo through endogenous sialidase activity. J Biol Chem 2003, 278:4112-4120.
Sakarya S, Rifat S, Zhou J, Bannerman DD, Stamatos NM, Cross AS, and GOLDBLUM SE. Mobilization of neutrophil sialidase activity desialylates the pulmonary vascular endothelial surface and increases resting neutrophil adhesion to and migration across the endothelium. Glycobiology 2004;14:481-494.
Sui X, Kiser TD, Hyun SW, Angelini DJ, Del Vecchio RL, Young BA, Hasday JD, Romer LH, Passaniti A, Tonks NK, and GOLDBLUM SE. Receptor Protein Tyrosine Phosphatase m Regulates the Paracellular Pathway in Human Lung Microvascular Endothelia. Am J Pathol 2005;166:1247-1258.
Gong P, Angelini DJ, Yang S, Xia G, Cross AS, Mann D, Bannerman DD, Vogel SN, GOLDBLUM SE. Toll-like receptor 4 signaling is coupled to src family kinase activation, tyrosine phosphorylation of zonula adherens proteins, and opening of the paracellular pathway in human lung microvascular endothelia. J Biol Chem 2008; 283:13437-13449.
Liu A, Garg P, Yang S, Gong P, Pallero MA, Annis DS, Liu Y, Passaniti A, Mann D, Mosher DF, Murphy-Ullrich JE, GOLDBLUM SE. The EGF-like repeats of thrombospondins activate phospholipase Cγ and increase epithelial cell migration through indirect epidermal growth factor receptor activation. J Biol Chem 2009; 284:6389-6402.
Tripathi A, Lammers KM, GOLDBLUM SE, Shea-Donohue T, Netzel-Arnett S, Buzza MS, Antalis TM, Vogel SN, Zhao A, Yang S, Arrietta M-C, Meddings JB, and Fasano, A. Identification of Human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci (USA) 2009; 106:16799-16804.
GOLDBLUM SE, Rai U, Tripathi A, Thakar M, De Leo L, Di Toro N, Not T, Ramachandran R, Puche AC, Hollenberg MD, Fasano A. The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation. FASEB J 2011; 25:144-158.
Garg P, Yang S, Liu A, Pallero MA, Buchsbaum DJ, Mosher DF, Murphy-Ullrich JE, and GOLDBLUM SE. Thrombospondin-1 opens the paracellular pathway in pulmonary microvascular endothelia through EGFR/ErbB2 activation. Am J Physiol Lung Cell Mol Physiol 2011; 301:L79-L90.
Liu A, Gong P, Hyun SW, Wang KZ, Cates EA, Perkins D, Bannerman DD, Puché AC, Toshchakov VY, Fang S, Auron PE, Vogel SN, GOLDBLUM SE. TRAF6 couples TLR4 signaling to Src family kinase activation and opening of the paracellular pathway in human lung microvascular endothelia. J Biol Chem 2012; 287:16132-16145.
Lillehoj EP, Hyun SW, Feng C, Zhang L, Liu A, Guang W, Nguyen C, Luzina IG, Atamas SP, Passaniti A, Twaddell WS, Puche AC, Wang LX, Cross AS, GOLDBLUM SE. NEU1 Sialidase expressed in human airway epithelia regulates epidermal growth factor receptor (EGFR) and MUC1 signaling. J Biol Chem 2012; 287:8214-8231.
Cross AS, Hyun SW, Miranda-Ribera A, Feng C, Liu A, Nguyen C, Zhang L, Luzina IG, Atamas SP, Twaddell WS, Guang W, Lillehoj EP, Puché AC, Huang W, Wang LX, Passaniti A, GOLDBLUM SE. NEU1 and NEU3 Sialidase Activity Expressed in Human Lung Microvascular Endothelia. NEU1 restrains endothelial cell migration whereas NEU3 does not. J Biol Chem 2012, 287:15966-15980.
Lee C, Liu A, Miranda-Ribera A, Hyun SW, Lillehoj EP, Cross AS, Passaniti A, GOLDBLUM SE. NEU1 Sialidase Regulates the Sialylation State of CD31 and Disrupts CD31-Driven Capillary-Like Tube Formation in Human Lung Microvascular Endothelia. J Biol Chem 2014; 289:9121-9135.
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