L-selectin
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| Aliases | SELL, CD62L, LAM1, LECAM1, LEU8, LNHR, LSEL, LYAM1, PLNHR, TQ1, selectin L | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 153240; MGI: 98279; HomoloGene: 539; GeneCards: SELL; OMA:SELL - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes and the preimplantation embryo. It belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant.[5] L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events.[6] These tethering interactions are essential for the trafficking of monocytes and neutrophils into inflamed tissue as well as the homing of lymphocytes to secondary lymphoid organs. L-selectin is also expressed by lymphoid primed hematopoietic stem cells and may participate in the migration of these stem cells to the primary lymphoid organs.[6] In addition to its function in the immune response, L-selectin is expressed on embryonic cells and facilitates the attachment of the blastocyst to the endometrial endothelium during human embryo implantation.[7]
L-selectin is composed of multiple structural regions: an N-terminus C-type lectin domain, an adjacent epidermal growth factor-like domain, two to the consensus repeat units homologous to those found in C3/C4-binding proteins, an extracellular cleavage site, a short transmembrane domain, and a cytoplasmic tail. It is cleaved by ADAM17.[6][8]
Ligands
- GlyCAM-1, found in the high endothelial venules of the lymph nodes.
- CD34, found on endothelial cells.
- MadCAM-1, found on endothelial cells of gut-associated lymphoid tissue.
- PSGL-1, binds with low affinity.
Expression
L-selectin is expressed constitutively on most circulating leukocytes.[6] Over time, these molecules are released through the process of ectodomain shedding and are replaced by newly synthesized L-selectin proteins. Ectodomain shedding is largely accomplished through cleavage by ADAM17.
L-selectin is expressed on naive T cells and is rapidly shed following T cell priming.[6] L-selectin expression is re-activated in cytotoxic T cells once they exit the lymph node. Mature central memory T cells express L-selectin while effector memory cells do not. L-selectin is also expressed by naive B cells, with the loss of L-selectin distinguishing activated B cells destined to differentiate to antibody-secreting cells
L-selectin is expressed on circulating neutrophils and is shed following neutrophil priming.[6] Expression of L-selectin in neutrophils decreases with neutrophil aging. Classical monocytes express high levels of L-selectin while in circulation. Shedding of L-selectin from monocytes occurs during trans-endothelial migration.
L-selectin expression is also observed on oocytes and early-stage embryos. Blastocysts express L-selectin following, but not prior to emergence from the zona pellucida. An increase in L-selectin expression is observed when both the blastocyst and cytotrophoblast attach to the endometrium. L-selectin expression decreases by the 17th week of pregnancy, and remains low or non-existent until term (2017).[7]
Function
Lymphocytes
L-selectin acts as a "homing receptor" for lymphocytes to enter secondary lymphoid tissues via high endothelial venules. Ligands present on endothelial cells will bind to lymphocytes expressing L-selectin, slowing lymphocyte trafficking through the blood, and facilitating entry into a secondary lymphoid organ at that point.[9] The receptor is commonly found on the cell surfaces of T cells. Naive T-lymphocytes, which have not yet encountered their specific antigen, need to enter secondary lymph nodes to encounter their antigen. Central memory T-lymphocytes, which have encountered antigen, express L-selectin to localize in secondary lymphoid organs. Here they reside ready to proliferate upon re-encountering antigen. Effector memory T-lymphocytes do not express L-selectin, as they circulate in the periphery and have immediate effector functions upon encountering antigen. High expression of L-selectin on human bone marrow progenitor cells is an early sign of cells becoming committed to lymphoid differentiation.[10]
Neutrophils and Monocytes
Similar to its role in homing lymphocytes to secondary lymphoid tissues, L-selectin expressed on the surface of monocytes and neutrophils is essential for facilitating the first stage of adhesion to venule epithelial cells (known as the “rolling stage”).[6][5] Adhesion to activated epithelial cells is a critical step in the immune response as it allows these immune cells to emigrate from the bloodstream into inflamed tissue. Prolonged rolling and transmigration of neutrophils can trigger shedding of L-selectin from the neutrophil plasma membrane.[5] The membrane-bound fragment left behind following cleavage of L-selectin has also been suggested to play a critical role in the interstitial chemotaxis of neutrophils along a cytokine gradient.[6] L-selectin shedding also occurs in monocytes; however, in these cells shedding is triggered only during trans-endothelial and not by earlier stages of the adhesion process.[6] The specific shedding of L-selectin from the leading migratory fronts of transmigrating monocytes suggests that this process plays a role in facilitating the directional migration of these cells (2019).[6]
Embryo
L-selectin is also present on the surface of human embryo trophoblasts prior to implantation into the uterus. Similar to its function in lymphocytes, L-selectin acts as a receptor to facilitate adhesion of the embryo to the site of invasion on the surface epithelium of the uterine endometrium. The embryo secretes human chorionic gonadotropin (hCG), which downregulates anti-adhesion factor, MUC-1, located on the uterine epithelium at the site of invasion. Removal of MUC-1 exposes the oligosaccharide ligands of the uterine epithelium, thus allowing binding by the L-selectin receptor of the trophoblast cell, followed by embryo adhesion and invasion.[11]
Clinical Significance
Human Immunodeficiency Virus (HIV)
L-selectin expressed on CD4 T lymphocytes has been implicated in mediating adhesion and entry of HIV. L-selectin binds gp120, one of the many glycans present on the HIV envelope. This binding allows for rolling adhesion to T cells and thus facilitates the binding of HIV to its target receptors.[12] Infection of the cell triggers shedding of L-selectin. The loss of L-selectin likely aids in the release of new virus from the cell.
Abnormal Pregnancy and infertility
The binding of L-selectin to its ligands plays an important role in embryo implantation during human pregnancy. Deficiency epithelial expression of L-selectin ligands has been associated with infertility, while increased expression has been implicated in ectopic pregnancies[7]
Cancer
The adhesive properties of L-selectin have been shown to contribute to cancer progression. L-selectin interactions participate in trafficking of chronic lymphocytic leukemia cells to the lymph nodes where they are able to proliferate and evolve. Additionally, L-selectin interactions may play a role in metastasis.[13]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000188404 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026581 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c Ivetic A (March 2018). "A head-to-tail view of L-selectin and its impact on neutrophil behaviour". Cell and Tissue Research. 371 (3): 437–453. doi:10.1007/s00441-017-2774-x. PMC 5820395. PMID 29353325.
- ^ a b c d e f g h i j Ivetic A, Hoskins Green HL, Hart SJ (2019-05-14). "L-selectin: A Major Regulator of Leukocyte Adhesion, Migration and Signaling". Frontiers in Immunology. 10: 1068. doi:10.3389/fimmu.2019.01068. PMC 6527602. PMID 31139190.
- ^ a b c Feng Y, Ma X, Deng L, Yao B, Xiong Y, Wu Y, et al. (May 2017). "Role of selectins and their ligands in human implantation stage". Glycobiology. 27 (5): 385–391. doi:10.1093/glycob/cwx009. PMID 28115423.
- ^ Tvaroška I, Selvaraj C, Koča J (June 2020). "Selectins-The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules-A Review". Molecules. 25 (12): 2835. doi:10.3390/molecules25122835. PMC 7355470. PMID 32575485.
- ^ Robbins SL, Cotran RS, Kumar V, Collins T (1998). Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. ISBN 0-7216-7335-X.
- ^ Kohn LA, Hao QL, Sasidharan R, Parekh C, Ge S, Zhu Y, et al. (October 2012). "Lymphoid priming in human bone marrow begins before expression of CD10 with upregulation of L-selectin". Nature Immunology. 13 (10): 963–971. doi:10.1038/ni.2405. PMC 3448017. PMID 22941246.
- ^ James JL, Carter AM, Chamley LW (May 2012). "Human placentation from nidation to 5 weeks of gestation. Part I: What do we know about formative placental development following implantation?". Placenta. 33 (5): 327–334. doi:10.1016/j.placenta.2012.01.020. PMID 22374510.
- ^ Segura J, He B, Ireland J, Zou Z, Shen T, Roth G, Sun PD (2021-09-29). "The Role of L-Selectin in HIV Infection". Frontiers in Microbiology. 12: 725741. doi:10.3389/fmicb.2021.725741. PMC 8511817. PMID 34659153.
- ^ Natoni A, Macauley MS, O'Dwyer ME (2016). "Targeting Selectins and Their Ligands in Cancer". Frontiers in Oncology. 6: 93. doi:10.3389/fonc.2016.00093. PMC 4834419. PMID 27148485.
External links
- L-Selectin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Immunology at MCG 1/physresp
- Overview of all the structural information available in the PDB for UniProt: P14151 (L-selectin) at the PDBe-KB.
Further reading
- Ryan US, Worthington RE (February 1992). "Cell-cell contact mechanisms". Current Opinion in Immunology. 4 (1): 33–37. doi:10.1016/0952-7915(92)90120-4. PMID 1375831.
- Nicholson IC (2003). "CD62L (L-selectin)". Journal of Biological Regulators and Homeostatic Agents. 16 (2): 144–146. PMID 12144128.
- Ivetic A, Ridley AJ (December 2004). "The telling tail of L-selectin". Biochemical Society Transactions. 32 (Pt 6): 1118–1121. doi:10.1042/BST0321118. PMID 15506984.
- Lasky LA, Singer MS, Dowbenko D, Imai Y, Henzel WJ, Grimley C, et al. (June 1992). "An endothelial ligand for L-selectin is a novel mucin-like molecule". Cell. 69 (6): 927–938. doi:10.1016/0092-8674(92)90612-G. PMID 1376638. S2CID 9517058.
- Ord DC, Ernst TJ, Zhou LJ, Rambaldi A, Spertini O, Griffin J, Tedder TF (May 1990). "Structure of the gene encoding the human leukocyte adhesion molecule-1 (TQ1, Leu-8) of lymphocytes and neutrophils". The Journal of Biological Chemistry. 265 (14): 7760–7767. doi:10.1016/S0021-9258(19)38994-X. PMID 1692315.
- Bevilacqua M, Butcher E, Furie B, Furie B, Gallatin M, Gimbrone M, et al. (October 1991). "Selectins: a family of adhesion receptors". Cell. 67 (2): 233. doi:10.1016/0092-8674(91)90174-W. hdl:2027.42/29086. PMID 1717161. S2CID 35258400.
- Tedder TF, Isaacs CM, Ernst TJ, Demetri GD, Adler DA, Disteche CM (July 1989). "Isolation and chromosomal localization of cDNAs encoding a novel human lymphocyte cell surface molecule, LAM-1. Homology with the mouse lymphocyte homing receptor and other human adhesion proteins". The Journal of Experimental Medicine. 170 (1): 123–133. doi:10.1084/jem.170.1.123. PMC 2189363. PMID 2473156.
- Camerini D, James SP, Stamenkovic I, Seed B (November 1989). "Leu-8/TQ1 is the human equivalent of the Mel-14 lymph node homing receptor". Nature. 342 (6245): 78–82. doi:10.1038/342078a0. PMID 2509939. S2CID 4342053.
- Bowen BR, Nguyen T, Lasky LA (July 1989). "Characterization of a human homologue of the murine peripheral lymph node homing receptor". The Journal of Cell Biology. 109 (1): 421–427. doi:10.1083/jcb.109.1.421. PMC 2115458. PMID 2663882.
- Siegelman MH, Weissman IL (July 1989). "Human homologue of mouse lymph node homing receptor: evolutionary conservation at tandem cell interaction domains". Proceedings of the National Academy of Sciences of the United States of America. 86 (14): 5562–5566. doi:10.1073/pnas.86.14.5562. PMC 336895. PMID 2664786.
- Bajorath J, Aruffo A (November 1995). "A template for generation and comparison of three-dimensional selectin models". Biochemical and Biophysical Research Communications. 216 (3): 1018–1023. doi:10.1006/bbrc.1995.2722. PMID 7488174.
- Dianzani U, Bragardo M, Buonfiglio D, Redoglia V, Funaro A, Portoles P, et al. (May 1995). "Modulation of CD4 lateral interaction with lymphocyte surface molecules induced by HIV-1 gp120". European Journal of Immunology. 25 (5): 1306–1311. doi:10.1002/eji.1830250526. PMID 7539755. S2CID 37717142.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Brenner B, Gulbins E, Schlottmann K, Koppenhoefer U, Busch GL, Walzog B, et al. (December 1996). "L-selectin activates the Ras pathway via the tyrosine kinase p56lck". Proceedings of the National Academy of Sciences of the United States of America. 93 (26): 15376–15381. doi:10.1073/pnas.93.26.15376. PMC 26412. PMID 8986819.
- Zöllner O, Lenter MC, Blanks JE, Borges E, Steegmaier M, Zerwes HG, Vestweber D (February 1997). "L-selectin from human, but not from mouse neutrophils binds directly to E-selectin". The Journal of Cell Biology. 136 (3): 707–716. doi:10.1083/jcb.136.3.707. PMC 2134294. PMID 9024699.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Prakobphol A, Thomsson KA, Hansson GC, Rosen SD, Singer MS, Phillips NJ, et al. (April 1998). "Human low-molecular-weight salivary mucin expresses the sialyl lewisx determinant and has L-selectin ligand activity". Biochemistry. 37 (14): 4916–4927. doi:10.1021/bi972612a. PMID 9538010.
- Sassetti C, Tangemann K, Singer MS, Kershaw DB, Rosen SD (June 1998). "Identification of podocalyxin-like protein as a high endothelial venule ligand for L-selectin: parallels to CD34". The Journal of Experimental Medicine. 187 (12): 1965–1975. doi:10.1084/jem.187.12.1965. PMC 2212365. PMID 9625756.
- Malhotra R, Ward M, Sim RB, Bird MI (July 1999). "Identification of human complement Factor H as a ligand for L-selectin". The Biochemical Journal. 341 (1): 61–69. doi:10.1042/0264-6021:3410061. PMC 1220330. PMID 10377245.
- Bradley LM, Duncan DD, Tonkonogy S, Swain SL (September 1991). "Characterization of antigen-specific CD4+ effector T cells in vivo: immunization results in a transient population of MEL-14-, CD45RB- helper cells that secretes interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma". The Journal of Experimental Medicine. 174 (3): 547–559. doi:10.1084/jem.174.3.547. PMC 2118927. PMID 1678774.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.