Disease relevance of SELPLG

• SELPLG and SELP single-nucleotide polymorphisms in multiple sclerosis [1].
• Intracellular parasitism by the human granulocytic ehrlichiosis bacterium through the P-selectin ligand, PSGL-1 [2].
• CONCLUSION: We describe increased platelet-monocyte aggregates with reduced leucocyte PSGL-1 expression in patients with end-stage renal disease irrespective of dialysis modality, associated with an increased risk of cardiovascular disease [3].
• Polymorphisms in the P-selectin (CD62P) and P-selectin glycoprotein ligand-1 (PSGL-1) genes and coronary heart disease [4].
• Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation [5].

High impact information on SELPLG

• Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1 [6].
• The selectins bind weakly to sialyl Lewisx (SLe(X))-like glycans, but with high-affinity to specific glycoprotein counterreceptors, including PSGL-1 [6].
• We also present the crystal structure of P-selectin LE co-complexed with the N-terminal domain of human PSGL-1 modified by both tyrosine sulfation and SLe(X) [6].
• P-selectin binding to neutrophils requires a specific protein, P-selectin glycoprotein ligand 1 (PSGL-1), as well as sialyl-Lewis X (sLex) glycan determinants [7].
• P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like glycoprotein expressed on the surface of myeloid cells and serves as the high affinity counterreceptor for P-selectin [8].

Chemical compound and disease context of SELPLG

• P-Selectin (SELP) and P-selectin glycoprotein ligand-1 (SELPLG) constitute a receptor/ligand complex involved in the recruitment of activated lymphocytes, a critical event in the pathogenesis of multiple sclerosis (MS) [1].
• Here we postulated that blockade of the earliest steps in leukocyte adhesion (ie, leukocyte rolling) via administration of a recombinant soluble form of P-selectin glycoprotein ligand-1 (PSGL-1; the recombinant soluble form is rsPSGL.Ig) would attenuate selectin-mediated events observed in the rat during traumatic shock [9].

Biological context of SELPLG

• PSGL-1 engagement induces tyrosine phosphorylation of Syk and SRE-dependent transcriptional activity [10].
• Treatment of cells with the Syk inhibitor piceatannol and overexpression of either a Syk dead kinase mutant or an ITAM-mutated moesin abrogated PSGL-1-induced transcriptional activation [10].
• P-selectin glycoprotein ligand 1 (PSGL-1, CD162) and integrin alphaMbeta2 (Mac-1, CD11bCD18) are leukocyte adhesion molecules essential for innate immunity and inflammation [11].
• The gene for P-selectin glycoprotein ligand (PSGL-1) has been cloned from a human placenta genomic DNA library [12].
• Transfection experiments did not indicate a functional difference between these two variants of PSGL-1 [12].

Anatomical context of SELPLG

• ITAM-based interaction of ERM proteins with Syk mediates signaling by the leukocyte adhesion receptor PSGL-1 [10].
• P-selectin glycoprotein ligand 1 (PSGL-1) is a leukocyte adhesion molecule involved in cell tether and rolling on activated endothelium [10].
• We found that P-selectin immunoglobulin chimera and PSGL-1 monoclonal antibodies (mAbs) increased adhesion of human neutrophils to immobilized, but not soluble, fibrinogen [11].
• Human mast cell progenitors use alpha4-integrin, VCAM-1, and PSGL-1 E-selectin for adhesive interactions with human vascular endothelium under flow conditions [13].
• The genomic clone differs from the cDNA clone isolated from HL-60 cells in that it encodes an extra copy of the decameric repeat located in the extracellular domain of PSGL-1 [12].

Associations of SELPLG with chemical compounds

• The interaction of PSGL-1 with P-selectin (CD62P) mediates tethering, rolling, and weak adhesion of leukocytes, during which they become sufficiently activated in situ by locally released or displayed cytokines and chemoattractants for integrin-mediated firm adhesion [11].
• The organization of the PSGL-1 gene closely resembles those of CD43 and human platelet glycoprotein GPIb alpha, both of which have an intron in the 5'-noncoding region, a long second exon containing the complete coding region, and TATA-less promoters [12].
• The loss of CD162 and CD62L expression was inhibited by EDTA, which suggests that neutrophil activation and sheddase cleavage occurred [14].
• CONCLUSION: G-CSF, but not dexamethasone, down regulates PSGL-1 expression on the surface of neutrophils in humans [15].
• The remaining eosinophils in the allergen challenged asthmatics were not activated as defined by cell density or change of expression of VLA-4, Mac-1 and PSGL-1 [16].

Physical interactions of SELPLG

• Interaction of PSGL-1 with moesin was shown in HL-60 cell lysates by isolating a complex with glutathione S-transferase fusions of the cytoplasmic domain of PSGL-1 [17].
• Exogenous eosinophil activation converts PSGL-1-dependent binding to CD18-dependent stable adhesion to platelets in shear flow [18].
• Crystals of the radixin FERM domain bound to PSGL-1 belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 80.74, b = 85.73, c = 117.75 A, and contain two complexes in the crystallographic asymmetric unit [19].
• These data show that P-selectin requires only the lectin and EGF domains to bind to PSGL-1 [20].
• Simultaneous expression of core-2 beta1,6-N-acetylglucosaminyltransferase and fucosyltransferase VII was required for optimal L-selectin binding to PSGL-1 [21].

Enzymatic interactions of SELPLG

• Consistent with this, cathepsin G cleaved a synthetic peptide based on the PSGL-1 N-terminus between Tyr-7/Leu-8 [22].

Regulatory relationships of SELPLG

• In contrast, G-CSF rapidly down regulated PSGL-1 expression on neutrophils within 90 minutes, whereas neither dexamethasone nor placebo had an effect [15].
• Similar to G-CSF, GM-CSF down regulated PSGL-1 in vitro [15].
• Anti-P-selectin glycoprotein ligand-1 (PSGL-1) antibodies dramatically block the recruitment of CD8+ cells in brain vessels of patients with MS, suggesting that PSGL-1 represents a novel pharmaceutical target that may be exploited to block the selective entrance of CD8+ cells during early inflammation [23].
• This study shows that binding of P-selectin to PSGL-1 triggers tyrosine kinase-dependent mechanisms that lead to CD11b/CD18 activation in PMN [24].
• Pharmacologic disruption of interactions between moesin and F-actin in cells expressing PSGL-1 resulted in a dose-dependent inhibition of rolling on P-selectin [25].

Other interactions of SELPLG

• Thus, PrMCs derived in vitro predominantly use alpha4-integrin, VCAM-1, PSGL-1, and other ligands that bind E-selectin for adhesion to cytokine-activated HUVEC monolayers [13].
• Cathepsin G- or neutrophil elastase-mediated PSGL-1 proteolysis may constitute a potential autocrine mechanism for down-regulation of neutrophil adhesion to P-selectin [22].
• Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule [24].
• Importantly, leukocyte rolling on P-selectin induced the recruitment of spleen tyrosine kinase (Syk), a tyrosine kinase associated to lipid raft PSGL-1 [26].
• P-selectin glycoprotein ligand-1 (PSGL-1) is a disulfide-bonded, homodimeric mucin ( approximately 250 kDa) on leukocytes that binds to P-selectin on platelets and endothelial cells during the initial steps in inflammation [27].
• These data suggest a novel function that ADAM28s promotes PSGL-1/P-selectin-mediated leukocyte rolling adhesion to endothelial cells and subsequent infiltration into tissue spaces through interaction with PSGL-1 on leukocytes under inflammatory conditions [28].

Analytical, diagnostic and therapeutic context of SELPLG

• The gene for human PSGL-1, which has been designated SELPLG by the Human Gene Nomenclature Committee, was mapped to chromosome 12q24 using Southern blot analysis of DNA from a set of human-mouse cell hybrids, and fluorescent in situ hybridization on metaphase chromosome spreads [12].
• Flow cytometry revealed that neutrophils and eosinophils from allergic-asthmatic subjects had increased expression of PSGL-1, whereas expression of another adhesion molecule, L-selectin, was unchanged [29].
• In a parallel plate chamber with well defined flow conditions, live time video microscopy analyses revealed that microspheres coated with PSGL-1 attached and rolled on 4-h tumor necrosis factor-alpha-activated endothelial cell monolayers, which express high levels of E-selectin, and CHO monolayers stably expressing E- or P-selectin [30].
• This inactivation corresponded to loss of the N-terminal domain of PSGL-1, as assessed by Western blot analysis [22].
• We have previously reported that neutrophils rolling on E-selectin are sufficient for signaling cell arrest through beta(2)-integrin binding of ICAM-1 in a process dependent upon ligation of L-selectin and P-selectin glycoprotein ligand 1 (PSGL-1) [31].

References