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SELP
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1FSB, 1G1Q, 1G1R, 1G1S, 1HES
Identifiers
Aliases	SELP, CD62, CD62P, GMP140, GRMP, LECAM3, PADGEM, PSEL, selectin P
External IDs	OMIM: 173610; MGI: 98280; HomoloGene: 2260; GeneCards: SELP; OMA:SELP - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1q24.2 Start 169,588,849 bp End 169,630,193 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1 H2.2|1 71.42 cM Start 163,942,833 bp End 163,977,595 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right coronary artery monocyte left uterine tube olfactory zone of nasal mucosa upper lobe of left lung gastric mucosa gallbladder left coronary artery canal of the cervix appendix Top expressed in endothelial cell of lymphatic vessel zygote secondary oocyte granulocyte primary oocyte blood embryo ankle joint tibiofemoral joint ankle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function heparin binding oligosaccharide binding lipopolysaccharide binding calcium-dependent protein binding glycosphingolipid binding fucose binding carbohydrate binding sialic acid binding protein binding calcium ion binding metal ion binding Cellular component integral component of membrane membrane platelet alpha granule membrane platelet dense granule membrane external side of plasma membrane extracellular space integral component of plasma membrane plasma membrane Biological process leukocyte cell-cell adhesion heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules positive regulation of leukocyte migration platelet degranulation regulation of integrin activation cell adhesion defense response to Gram-negative bacterium positive regulation of phosphatidylinositol 3-kinase signaling inflammatory response calcium-mediated signaling using intracellular calcium source positive regulation of platelet activation leukocyte migration response to lipopolysaccharide calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules leukocyte tethering or rolling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6403 20344 Ensembl ENSG00000174175 ENSMUSG00000026580 UniProt P16109 Q01102 RefSeq (mRNA) NM_003005 NM_011347 RefSeq (protein) NP_002996 NP_002996.2 NP_035477 Location (UCSC) Chr 1: 169.59 – 169.63 Mb Chr 1: 163.94 – 163.98 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.

P-selectin functions as a cell adhesion molecule (CAM) on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activated platelets. In unactivated endothelial cells, it is stored in granules called Weibel-Palade bodies. In unactivated platelets P-selectin is stored in α-granules.

Other names for P-selectin include CD62P, Granule Membrane Protein 140 (GMP-140), and Platelet Activation-Dependent Granule to External Membrane Protein (PADGEM). It was first identified in endothelial cells in 1989.

Gene and regulation

P-selectin is located on chromosome 1q21-q24, spans > 50 kb and contains 17 exons in humans. P-selectin is constitutively expressed in megakaryocytes (the precursor of platelets) and endothelial cells. P-selectin expression is induced by two distinct mechanisms. First, P-selectin is synthesized by megakaryocytes and endothelial cells, where it is sorted into the membranes of secretory granules. When megakaryocytes and endothelial cells are activated by agonists such as thrombin, P-selectin is rapidly translocated to the plasma membrane from granules. Secondly, increased levels of P-selectin mRNA and protein are induced by inflammatory mediators such as tumor necrosis factor-a (TNF-a), LPS, and interleukin-4 (IL-4). Although TNF-a and LPS increase levels of both mRNA and protein in murine models, they do not appear to affect mRNA in human endothelial cells, while IL-4 increases P-selectin transcription in both species. The elevated synthesis of P-selectin may play an important role in the delivery of protein to the cell surface. In ischemic stroke patients, plasma P-selectin concentration was reported to be highly correlated to plasminogen activator inhibitor-1 activity and tissue plasminogen activator activity.

Structure

P-selectin is found in endothelial cells and platelets where it is stored in Weibel-Palade bodies and α-granules, respectively. In response to inflammatory cytokines such as IL-4 and IL-13, P-selectin is translocated to the plasma membrane in endothelial cells. The extracellular region of P-selectin is composed of three different domains like other selectin types; a C-type lectin-like domain in the N-terminus, an EGF-like domain and a complement-binding protein-like domains (same as complement regulatory proteins: CRP) having short consensus repeats (~60 amino acids). The number of CRP repeats is the major feature differentiating the type of selectin in extracellular region. In human, P-selectin has nine repeats while E-selectin contains six and L-selectin has only two. P-selectin is anchored in transmembrane region that is followed by a short cytoplasmic tail region.

Ligand

The primary ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1) which is expressed on almost all leukocytes, although P-selectin also binds to heparan sulfate and fucoidans. PSGL-1 is situated on various hematopoietic cells such as neutrophils, eosinophils, lymphocytes, and monocytes, in which it mediates tethering and adhesion of these cells. However, PSGL-1 is not specific for P-selectin, as it can also function as a ligand for both E- and L-selectin.

Function

P-selectin plays an essential role in the initial recruitment of leukocytes (white blood cells) to the site of injury during inflammation. When endothelial cells are activated by molecules such as histamine or thrombin during inflammation, P-selectin moves from an internal cell location to the endothelial cell surface.

Thrombin is one trigger which can stimulate endothelial-cell release of P-selectin and recent studies suggest an additional Ca-independent pathway involved in the release of P-selectin.

Ligands for P-selectin on eosinophils and neutrophils are similar sialylated, protease-sensitive, endo-beta-galactosidase-resistant structures, clearly different from those reported for E-selectin, and suggest disparate roles for P-selectin and E-selectin during recruitment during inflammatory responses.

P-selectin is also very important in the recruitment and aggregation of platelets at areas of vascular injury. In a quiescent platelet, P-selectin is located on the inner wall of α-granules. Platelet activation (through agonists such as thrombin, Type II collagen and ADP) results in "membrane flipping" where the platelet releases α- and dense granules and the inner walls of the granules are exposed on the outside of the cell. The P-selectin then promotes platelet aggregation through platelet-fibrin and platelet-platelet binding.

P-selectin attaches to the actin cytoskeleton through anchor proteins that are still poorly characterized.

Role in cancer

P-selectin has a functional role in tumour metastasis similar to E-selectin. P-selectin is expressed on the surface of both stimulated endothelial cells and activated platelets, and helps cancer cells invade into the bloodstream for metastasis and provides local multiple growth factors, respectively. Moreover, platelets facilitate tumor metastasis by forming complexes with tumour cells and leukocytes in the vasculature, thus preventing recognition by macrophages. This is thought to contribute to the seeding of tumour microemboli in distant organs. In vivo mice experiments have shown that a reduction in circulating platelets could reduce cancer metastasis.

The oligosaccharide sialylated Lewis x (sLe(x)) is expressed on the surface of tumor cells and can be recognized by E-selectin and P-selectin, playing on a key role in metastasis of the tumor. However, in the 4T1 breast cancer cell line, E-selectin reactivity is sLe(x) dependent while P-selectin reactivity is sLe(x)-independent, suggesting P-selectin binding is Ca-independent and sulfation-dependent. One of the sulfated ligands is chondroitin sulfate, a type of glycosaminoglycan (GAG). Its activity in tumor metastasis has been probed by the addition of heparin that functions to blocks tumor metastasis. In addition to GAGs, mucin is of interest in P-selectin mediated tumor metastasis. Selective removal of mucin results in reduced interaction between P-selectin and platelets in vivo and in vitro.

Heparin has long been known to represent antiheparanase activity that is to keep an endoglycosidase from degrading heparan sulfate, one of the glycosaminoglycans, and to effectively inhibit P-selectin. Despite a striking effect of heparin on tumor progression shown in a number of clinical trials, the use of heparin as anti-cancer agent is limited because of its risk, which might induce adverse bleeding complications. Given those reasons, development of new compounds that target P-selectin is now emerging for cancer therapy. Among them, the inhibitory activity of semisynthetic sulfated tri mannose C-C-linked dimers (STMCs) to P-selectin was shown by the attenuation of tumor metastasis in vivo animal model, indicating the inhibition of interaction between tumor cell and endothelial cell is significant for blocking tumor dissemination.

As a drug target

Crizanlizumab is a monoclonal antibody against P-selectin. which has now been approved by Novartis on November 15, 2019 for the indication of vaso-occlusive crisis in sickle cell patients.

See also

• Selectin

References

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2. ^ GRCm38: Ensembl release 89: ENSMUSG00000026580 – Ensembl, May 2017
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7. Herrmann SM, Ricard S, Nicaud V, Mallet C, Evans A, Ruidavets JB, et al. (August 1998). "The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction". Human Molecular Genetics. 7 (8): 1277–1284. doi:10.1093/hmg/7.8.1277. PMID 9668170.
8. Pan J, Xia L, McEver RP (April 1998). "Comparison of promoters for the murine and human P-selectin genes suggests species-specific and conserved mechanisms for transcriptional regulation in endothelial cells". The Journal of Biological Chemistry. 273 (16): 10058–10067. doi:10.1074/jbc.273.16.10058. PMID 9545353.
9. Disdier M, Morrissey JH, Fugate RD, Bainton DF, McEver RP (March 1992). "Cytoplasmic domain of P-selectin (CD62) contains the signal for sorting into the regulated secretory pathway". Molecular Biology of the Cell. 3 (3): 309–321. doi:10.1091/mbc.3.3.309. PMC 275532. PMID 1378326.
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13. Panés J, Perry M, Granger DN (February 1999). "Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention". British Journal of Pharmacology. 126 (3): 537–550. doi:10.1038/sj.bjp.0702328. PMC 1565837. PMID 10188959.
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15. Woltmann G, McNulty CA, Dewson G, Symon FA, Wardlaw AJ (May 2000). "Interleukin-13 induces PSGL-1/P-selectin-dependent adhesion of eosinophils, but not neutrophils, to human umbilical vein endothelial cells under flow". Blood. 95 (10): 3146–3152. doi:10.1182/blood.V95.10.3146. PMID 10807781.
16. Vestweber D, Blanks JE (January 1999). "Mechanisms that regulate the function of the selectins and their ligands". Physiological Reviews. 79 (1): 181–213. doi:10.1152/physrev.1999.79.1.181. PMID 9922371.
17. Lorenzon P, Vecile E, Nardon E, Ferrero E, Harlan JM, Tedesco F, et al. (September 1998). "Endothelial cell E- and P-selectin and vascular cell adhesion molecule-1 function as signaling receptors". The Journal of Cell Biology. 142 (5): 1381–1391. doi:10.1083/jcb.142.5.1381. PMC 2149355. PMID 9732297.
18. Cleator JH, Zhu WQ, Vaughan DE, Hamm HE (April 2006). "Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP". Blood. 107 (7): 2736–2744. doi:10.1182/blood-2004-07-2698. PMC 1895372. PMID 16332977.
19. Wein M, Sterbinsky SA, Bickel CA, Schleimer RP, Bochner BS (March 1995). "Comparison of human eosinophil and neutrophil ligands for P-selectin: ligands for P-selectin differ from those for E-selectin". American Journal of Respiratory Cell and Molecular Biology. 12 (3): 315–319. doi:10.1165/ajrcmb.12.3.7532979. PMID 7532979.
20. Martinelli S, Chen EJ, Clarke F, Lyck R, Affentranger S, Burkhardt JK, et al. (2013). "Ezrin/Radixin/Moesin proteins and flotillins cooperate to promote uropod formation in T cells". Frontiers in Immunology. 4: 84. doi:10.3389/fimmu.2013.00084. PMC 3619129. PMID 23579783.
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26. Garcia J, Callewaert N, Borsig L (February 2007). "P-selectin mediates metastatic progression through binding to sulfatides on tumor cells". Glycobiology. 17 (2): 185–196. doi:10.1093/glycob/cwl059. PMID 17043066.
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29. Borsig L, Vlodavsky I, Ishai-Michaeli R, Torri G, Vismara E (May 2011). "Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase". Neoplasia. 13 (5): 445–452. doi:10.1593/neo.101734. PMC 3084621. PMID 21532885.
30. Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. (February 2017). "Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease". The New England Journal of Medicine. 376 (5): 429–439. doi:10.1056/NEJMoa1611770. PMC 5481200. PMID 27959701.

Further reading

• Bajorath J, Stenkamp R, Aruffo A (November 1993). "Knowledge-based model building of proteins: concepts and examples". Protein Science. 2 (11): 1798–1810. doi:10.1002/pro.5560021103. PMC 2142283. PMID 7505680.
• Varki NM, Varki A (February 2002). "Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans". Seminars in Thrombosis and Hemostasis. 28 (1): 53–66. doi:10.1055/s-2002-20564. PMID 11885026. S2CID 3222756.
• Furie B, Furie BC (April 2004). "Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation". Trends in Molecular Medicine. 10 (4): 171–178. doi:10.1016/j.molmed.2004.02.008. PMID 15059608.
• Cambien B, Wagner DD (April 2004). "A new role in hemostasis for the adhesion receptor P-selectin". Trends in Molecular Medicine. 10 (4): 179–186. doi:10.1016/j.molmed.2004.02.007. PMID 15059609.
• Chen M, Geng JG (2006). "P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis". Archivum Immunologiae et Therapiae Experimentalis. 54 (2): 75–84. doi:10.1007/s00005-006-0010-6. PMID 16648968. S2CID 33274938.

External links

• P-Selectin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P16109 (Human P-selectin) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q01102 (Mouse P-selectin) at the PDBe-KB.

• Genes on human chromosome 1
• Cell adhesion proteins
• Selectins