During inflammation, flowing leukocytes roll on vascular surfaces through interactions of selectins with their glycosylated ligands. Activated endothelial cells express P-selectin and E-selectin. Their major ligands on leukocytes are P-selectin glycoprotein ligand-1 (PSGL-1), which binds to P- and E-selectin, and CD44, which binds to E-selectin. Data obtained during the previous funding period demonstrated that the organization of selectins and their ligands on cell surfaces has major impact on functions. We hypothesize that selectins and their ligands form homodimers through self-associations of their transmembrane domains. They localize in specialized membrane regions (e.g. microvilli, clathrin-coated pits, or lipid rafts) through interactions of their transmembrane or cytoplasmic domains with lipids, adaptor proteins, or cytoskeletal elements. Dimerization and membrane-domain targeting cooperate to enhance adhesive and signaling functions. We propose to test these hypotheses by making monomeric and dimeric forms of P-selectin, E-selectin, PSGL-1, and CD44 that do or do not target to lipid rafts or clathrin-coated pits. Other variants will test interactions with cytoskeletal and signaling proteins. Cells from knockout mice lacking signaling components will also be used. These tools will probe how cells organize selectins and their ligands to regulate leukocyte adhesion and signaling in vitro and in vivo. Because selectins and their ligands are major contributors to pathological inflammation and thrombosis, understanding how they function in their cellular environments may suggest new opportunities for therapeutic intervention.
White blood cells (leukocytes) combat infection and repair tissue injury. To do this, they must move from blood into the affected tissues, a process that begins when circulating leukocytes attach to blood vessel surfaces through """"""""adhesion receptors."""""""" This project addresses how leukocytes and cells lining blood vessels control the display and function of these receptors. Because excessive recruitment of leukocytes contributes to many diseases, including heart attacks and strokes, understanding how cells regulate adhesion receptors may suggest new therapeutic strategies.
|Yago, Tadayuki; Liu, Zhenghui; Ahamed, Jasimuddin et al. (2018) Cooperative PSGL-1 and CXCR2 signaling in neutrophils promotes deep vein thrombosis in mice. Blood 132:1426-1437|
|Mehta-D'souza, Padmaja; Klopocki, Arkadiusz G; Oganesyan, Vaheh et al. (2017) Glycan Bound to the Selectin Low Affinity State Engages Glu-88 to Stabilize the High Affinity State under Force. J Biol Chem 292:2510-2518|
|Panicker, Sumith R; Mehta-D'souza, Padmaja; Zhang, Nan et al. (2017) Circulating soluble P-selectin must dimerize to promote inflammation and coagulation in mice. Blood 130:181-191|
|Liu, Zhenghui; Yago, Tadayuki; Zhang, Nan et al. (2017) L-selectin mechanochemistry restricts neutrophil priming in vivo. Nat Commun 8:15196|
|Liu, Zhenghui; Zhang, Nan; Shao, Bojing et al. (2016) Replacing the Promoter of the Murine Gene Encoding P-selectin with the Human Promoter Confers Human-like Basal and Inducible Expression in Mice. J Biol Chem 291:1441-7|
|Zhang, Nan; Liu, Zhenghui; Yao, Longbiao et al. (2016) P-Selectin Expressed by a Human SELP Transgene Is Atherogenic in Apolipoprotein E-Deficient Mice. Arterioscler Thromb Vasc Biol 36:1114-21|
|Pruenster, Monika; Kurz, Angela R M; Chung, Kyoung-Jin et al. (2015) Extracellular MRP8/14 is a regulator of ?2 integrin-dependent neutrophil slow rolling and adhesion. Nat Commun 6:6915|
|Yago, Tadayuki; Petrich, Brian G; Zhang, Nan et al. (2015) Blocking neutrophil integrin activation prevents ischemia-reperfusion injury. J Exp Med 212:1267-81|
|Shao, Bojing; Yago, Tadayuki; Setiadi, Hendra et al. (2015) O-glycans direct selectin ligands to lipid rafts on leukocytes. Proc Natl Acad Sci U S A 112:8661-6|
|McEver, Rodger P (2015) Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res 107:331-9|
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