L-selectin mediates the initial adhesion of lymphocytes to high endothelial venules (HEV) in lymph nodes during the process of lymphocyte homing. It also functions in leukocyte-endothelial interactions underlying the trafficking of leukocytes into chronic inflammatory sites. L-selectin functions as a lectin-like receptor by recognizing a discrete set of HEV-expressed ligands including GlyCAM-1, CD34, and podocalyxin. These ligands bear O-linked carbohydrate chains that are sulfated, fucosylated and sialylated. All three of these modifications are required for optimal recognition by L-selectin. A detailed analysis of GlyCAM-1 and CD34 has revealed that tile recognition determinant for L-selectin binding is a sulfated structure known as 6-sulfo sLex, a tetrasaccharide that possesses a sulfate ester on the C-6 position of N-acetylglucosamine. In the search for the sulfotransferase that elaborates this critical modification within HEV, the Rosen laboratory has cloned a family of GlcNAc-6-O-sulfotransferases. Two of these, known as GST-2 and GST-3, are present in HEV. GST-3 has been given the name HEC-GlcNAc6ST because of its highly restricted expression in high endothelial cells (HEC) of HEV. The direct involvement of HEC-GlcNAc6ST in elaborating L-selectin ligands has been established by disrupting this gene in mice. HEC-GIcNAc6ST knockout mice exhibit a significant but incomplete loss of HEV-expressed ligands for L-selectin and an impairment of lymphocyte homing to lymph nodes. The present grant will continue the study of HEC-GlcNAc6ST and the related enzyme, GST-2, with respect to their functions in lymphocyte homing and inflammatory leukocyte trafficking.
The specific aims are: 1) To determine the contribution of HEC-GIcNAc6ST to the activity of L-selectin ligands generated in situ; 2) To determine the expression of HEC-GlcNAc6ST in activated endothelium at sites of inflammation; 3) To determine the contribution of HEC-GlcNAc6ST to leukocyte recruitment and disease in mouse models of chronic inflammation; and 4) To determine the contribution of GST-2 to the generation of L-selectin ligands. Gaining further understanding of these sulfotransferases has considerable biomedical relevance, because these enzymes are potential therapeutic targets for blocking inflammatory diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Pathobiochemistry Study Section (PBC)
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Marino, Pamela
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University of California San Francisco
Anatomy/Cell Biology
Schools of Medicine
San Francisco
United States
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Patnode, Michael L; Bando, Jennifer K; Krummel, Matthew F et al. (2014) Leukotriene B4 amplifies eosinophil accumulation in response to nematodes. J Exp Med 211:1281-8
Patnode, Michael L; Yu, Shin-Yi; Cheng, Chu-Wen et al. (2013) KSGal6ST generates galactose-6-O-sulfate in high endothelial venules but does not contribute to L-selectin-dependent lymphocyte homing. Glycobiology 23:381-94
Patnode, Michael L; Cheng, Chu-Wen; Chou, Chi-Chi et al. (2013) Galactose 6-O-sulfotransferases are not required for the generation of Siglec-F ligands in leukocytes or lung tissue. J Biol Chem 288:26533-45
Zhang, Yafeng; Chen, Yi-Chun Maria; Krummel, Matthew F et al. (2012) Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells. J Immunol 189:3914-24
Arata-Kawai, Hanayo; Singer, Mark S; Bistrup, Annette et al. (2011) Functional contributions of N- and O-glycans to L-selectin ligands in murine and human lymphoid organs. Am J Pathol 178:423-33
Kerr, Sheena C; Fieger, Claudia B; Snapp, Karen R et al. (2008) Endoglycan, a member of the CD34 family of sialomucins, is a ligand for the vascular selectins. J Immunol 181:1480-90
Kanda, Hidenobu; Newton, Rebecca; Klein, Russell et al. (2008) Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs. Nat Immunol 9:415-23
Nawroth, Roman; van Zante, Annemieke; Cervantes, Sara et al. (2007) Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One 2:e392
Veerman, Krystle M; Williams, Michael J; Uchimura, Kenji et al. (2007) Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs. Nat Immunol 8:532-9
Lum, David H; Tan, Jenille; Rosen, Steven D et al. (2007) Gene trap disruption of the mouse heparan sulfate 6-O-endosulfatase gene, Sulf2. Mol Cell Biol 27:678-88

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