P-Selectin

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The three selectins (P-selectin, L-selectin, and E-selectin) have related and sometimes overlapping functions in cell adhesion and mediate some of the best characterized glycan-dependent cell adhesion events. Of the ligands for these three C-type lectins, the target ligand of P-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), is the best understood. Thus, P-selectin is used here to represent all three selectins.

Contents

CFG Participating Investigators contributing to the understanding of this paradigm

Selectin research was already at a relatively mature stage when the CFG began. Early PI work included structural studies, extensive analysis of leukocyte adhesion to endothelia in vivo, and characterization of knockout mice to demonstrate physiological function. In addition to submitting samples for glycan array analysis, PIs have been involved in analyzing selectin expression under different conditions, including in knockout mice lacking enzymes for making target ligands.

  • PIs working on P-selectin include: Hans-Peter Altevogt, Bruce Bochner, Pi-Wan Cheng, Richard Cummings, Robert Fuhlbrigge, Minoru Fukuda, Geoff Kansas, Klaus Ley, John Lowe, Rodger McEver, Steve Rosen, Ron Schnaar, Karen Snapp, Lloyd Stoolman, Martin Wild, Hermann Ziltener
  • Non-PIs who have used CFG resources to study P-selectin include: Roland Contreras, Leonard Seymour

Progress toward understanding this GBP paradigm

This section documents what is currently known about P-selectin, its carbohydrate ligands, and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Pages for human and mouse P-selectin in the CFG database.

Carbohydrate ligands

P-selectin binds cooperatively to tyrosine sulfates, other amino acids, and a core 2 O-glycan capped with sialyl Lewis x, all positioned near the N terminus of PSGL-1[1]

Cellular expression of GBP and ligands

P-selectin is expressed on platelets, endothelial cells, and some macrophages [2][3]. PSGL-1 is expressed on leukocytes and some endothelial cells[2][4].

Biosynthesis of ligands

SLeX (sialyl Lewis-X) like structures located on O-glycans at the N-terminus of PSGL-1 constitute the physiological ligands for all three members of the selectin family, L-, E- and P-selectin. Studies in which glycosyltransferases were reconstituted in heterologous cell types together with knockout mouse experiments suggest a role for polypeptide α-GalNAcT ppGalNAcT-1, core-1 β1,3GalactosylT T-synthase, core-2 β1,6GlcNAcT C2GnT-I, β1,4GalactosylT β4GalT-I, α(2,3)sialylT ST3GalT-IV and α(1,3) fucosylTs (FTs), FTIV and FTVII, in the synthesis of such structures. Sulfation of the peptide backbone by tyrosine sulfoT is also important for functional selectin ligand biosynthesis on PSGL-1.

Structure

image:P-selectin.jpg
The structures of a fragment of P-selectin containing the CRD and EGF domains in complex with a sialyl Lewisx-containing oligosaccharide as well as a glycopeptide from PSGL-1 that contains sulfated tyrosine residues have been determined.[5] The fucose residue of the sialyl Lewisx tetrasaccharide fits in the primary binding site and interacts with a Ca2+ bound to the protein, with secondary contacts to the galactose residue and electrostatic interactions with the carboxyl group of sialic acid. The EGF domain is located on the opposite side of the CRD from the glycan-binding site.

Biological roles of GBP-ligand interaction

Interactions between P-selectin and PSGL-1 initiate rolling of leukocytes on activated platelets and endothelial cells as one of the earliest responses to tissue injury and infection[6][2][7]. Engagement of PSGL-1 on neutrophils transduces signals that activate integrin LFA-1 to slow rolling on ICAM-1, thus augmenting neutrophil recruitment to inflammatory sites.[8][9][10][11][12]

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for P-selectin.

Glycan profiling

The glycans on the main target for P-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), were analyzed.[13]

Glycogene microarray

Probes for all three human and mouse selectins have been included in all versions of the CFG glycogene chip. Regulation of P-selectin expression was analyzed under multiple conditions; see all results here.

Knockout mouse lines

The phenotype of PSGL-1 knockout mice was analyzed by the CFG. The CFG did not generate mice deficient in the P-selectin gene, as these mice were published in 1993[14] and have since been extensively studied. P-selectin knockout mice exhibit defects in leukocyte behavior, including elevated numbers of circulating neutrophils, loss of leukocyte rolling in mesenteric venules, and delayed neutrophil recruitment to the peritoneal cavity after induction of inflammation[14]. They also show attentuated polymorphonuclear leukocyte accumulation and myocardial injury following brief ischaemia-reperfusion of the myocardium (i.e., P-selectin deficiency is cardioprotective; reviewed in [15].)

Glycan array

The comparative binding specificities of human and mouse P-selectins have been analyzed. See all glycan array results for P-selectin here.

Related GBPs

L-selectin (CFG data)and E-selectin (CFG data).

References

  1. Leppanen A, White SP, Helin J, McEver RP, Cummings RD (2000) Binding of glycosulfopeptides to P-selectin requires stereospecific contributions of individual tyrosine sulfate and sugar residues. J Biol Chem 275, 39569-39578.
  2. 2.0 2.1 2.2 McEver RP (2002) Selectins: lectins that initiate cell adhesion under flow. Curr Opin Cell Biol 14, 581-588.
  3. Tchernychev B, Furie B, Furie BC (2003) Peritoneal macrophages express both P-selectin and PSGL-1. J Cell Biol 163, 1145-1155
  4. Rivera-Nieves J, Burcin TL, Olson TS, Morris MA, McDuffie M, Cominelli F, Ley K (2006) Critical role of endothelial P-selectin glycoprotein ligand 1 in chronic murine ileitis. J Clin Invest 203, 907-919
  5. Somers W. S., Tang J., Shaw G. D,. Camphausen R. T. (2000) Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLex and PSGL-1. Cell 103, 467-479
  6. McEver, R. P. (2001) Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost 86, 746-756.
  7. McEver, R. P. and Zhu, C. (2010) Rolling cell adhesion. Annu Rev Cell Dev Biol 26, in press.
  8. Zarbock, A., Lowell, C. A., Ley, K. (2007) Spleen tyrosine kinase Syk is necessary for E-selectin-induced αLβ2 integrin-mediated rolling on intercellular adhesion molecule-1. Immunity 26, 773-783.
  9. Zarbock, A., Abram, C. L., Hundt, M., Altman, A., Lowell, C. A., Ley, K. (2008) PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling. J Exp Med 205, 2339-2347.
  10. Miner, J. J., Xia, L., Yago, T., Kappelmayer, J., Liu, Z., Klopocki, A. G., Shao, B., McDaniel, J. M., Setiadi, H., Schmidtke, D. W., McEver, R. P. (2008) Separable requirements for cytoplasmic domain of PSGL-1 in leukocyte rolling and signaling under flow. Blood 112, 2035-2045.
  11. Yago, T., Shao, B., Miner, J. J., Yao, L., Klopocki, A. G., Maeda, K., Coggeshall, K. M., McEver, R. P. (2010) E-selectin engages PSGL-1 and CD44 through a common signaling pathway to induce integrin αLβ2-mediated slow leukocyte rolling. Blood March 18 [Epub ahead of print].
  12. Mueller, H., Stadtmann, A., Van Aken, H., Hirsch, E., Wang, D., Ley, K., Zarbock, A. (2010) Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways. Blood 115, 3118-27.
  13. Kawar ZS, Johnson TK, Natunen S, Lowe JB, Cummings RD (2008) PSGL-1 from the murine leukocytic cell line WEHI-3 is enriched for core 2-based O-glycans with sialyl Lewis x antigen. Glycobiology 18, 441-446
  14. 14.0 14.1 Mayadas TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell. 1993 Aug 13;74(3):541-54. PubMed PMID: 7688665.
  15. Kakkar AK, Lefer DJ. Leukocyte and endothelial adhesion molecule studies in knockout mice. Curr Opin Pharmacol. 2004 Apr;4(2):154-8. Review. PubMed PMID:15063359.
  • Mitoma J, Miyazaki T, Sutton-Smith M, Suzuki M, Saito H, Yeh JC, Kawano T, Hindsgaul O, Seeberger PH, Panico M, Haslam SM, Morris HR, Cummings RD, Dell A, Fukuda M (2009) The N-glycolyl form of mouse sialyl Lewis X is recognized by selectins but not by HECA-452 and FH6 antibodies that were raised against human cells. Glycoconj J 26, 511-523.
  • Kawar ZS, Johnson TK, Natunen S, Lowe JB, Cummings RD (2008) PSGL-1 from the murine leukocytic cell line WEHI-3 is enriched for core 2-based O-glycans with sialyl Lewis x antigen. Glycobiology 18, 441-446.
  • Mitoma J, Bao X, Petryanik B, Schaerli P, Gauguet JM, Yu SY, Kawashima H, Saito H, Ohtsubo K, Marth JD, Khoo KH, von Andrian UH, Lowe JB, Fukuda M (2007) Critical functions of N-glycans in L-selectin-mediated lymphocyte homing and recruitment. Nat Immunol 8, 409-418.
  • Veerman KM, Williams MJ, Uchimura K, Singer MS, Merzaban JS, Naus S, Carlow DA, Owen P, Rivera-Nieves J, Rosen SD, Ziltener HJ (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, 532-539.
  • Chen S, Kawashima H, Lowe JB, Lanier LL, Fukuda M (2005) Suppression of tumor formation in lymph nodes by L-selectin-mediated natural killer cell recruitment. J Exp Med 202, 1679-1689.
  • Kawashima H, Petryniak B, Hiraoka N, Mitoma J, Huckaby V, Nakayama J, Uchimura K, Kadomatsu K, Muramatsu T, Lowe JB, Fukuda M (2005) N-acetylglucosamine-6-O-sulfotransferases 1 and 2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nat Immunol 6, 1096-1104.
  • Piccio L, Rossi B, Colantonio L, Grenningloh R, Gho A, Ottoboni L, Homeister JW, Scarpini E, Martinello M, Laudanna C, DAmbrosio D, Lowe JB, (2005) Constantin G Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII. J Immunol 174, 5805-5813.
  • Homeister JW, Daugherty A, Lowe JB (2004) α(1,3)Fucosyltransferases FucT-IV and FucT-VII control susceptibility to atherosclerosis in apolipoprotein E -/- mice. Arterioscler Thromb Vasc Biol 24, 1897-1903.
  • Lowe JB (2003) Glycan-dependent leukocyte adhesion and recruitment in inflammation Curr Opin Cell Biol 15, 531-538.
  • Smith PL, Myers JT, Rogers CE, Zhou L, Petryniak B, Becher DJ, Homeister JW, Lowe JB (2002) Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus. J Cell Biol 158, 801-815.

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Rodger McEver, Yvette van Kooyk

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