Biology:CLEC1B

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

C-type lectin domain family 1 member B (also termed CLEC-1b, C-type lectin-like receptor 2, CLEC-2, CLEC2, CLEC2B, PRO1384, QDED721, C-type lectin domain family 1 member B, CLEC1B, activation-induced C-type lectin, AICL, and 1810061I13Rik) is a cell surface receptor protein. It binds certain biomolecules that act as ligands that when bound to the CLEC-1b expressed by cells stimulates certain functions in these cells. The human CLEC-1b receptor is encoded by the CLEC1B gene which is located on the short (i.e., "p")-arm of chromosome 12 at region 1, band 3, sub-band 1 to sub-band 2 (position notated as 12p13.31-p13.2).<https://www.ncbi.nlm.nih.gov/gene/387836> Most of the recent literature terms the C-type lectin domain family 1 member B as CLEC-2.[1][2][3][4][5][6] Since current reports commonly use CLEC-2 rather than CLEC-1b, CLEC-2 will be used here in place of CLEC1b in further describing this protein.

CLEC-2 is a member of the broad family of pattern recognition receptors (i.e., PRRs). Vertebrate PRRs can be classified into five types based on their structural similarities: a) toll-like receptors, b) NOD-like receptors, c) RIG-I-like receptors, d) AIM2 (also termed absent in melanoma 2 or interferon-inducible protein AIM2), and e) C-type lectin receptors (i.e., CLR).[7][8] CLRs are a superfamily of more than 1,000 proteins. They are subdivided into 17 subgroups. All members of this family possess one or more C-type lectin-like domains, i.e., protein domains that have a characteristic loop-in-a-loop structure formed by their amino acid sequences which form a large loop that encloses a smaller, internal loop or some other type of secondary structure. These internal loops or other structures are formed by two disulfide bridges located at the bases of these loops.[9]. CLEC-2 is a C-type lectin receptor.[10]

Agents activating CLEC-2

While podoplanin is the most studied activator of CLEC-2, CLEC-2 is also activated by: rhodocytin (a platelet-activating snake venom also termed aggretin); hemin (an iron-containing porphyrin containing chlorine); galectin-9; the human immunodeficiency virus (which causes the acquired immunodeficiency syndrome, i.e. AIDs); dextran sulfate; sulfated polysaccharides; fucoidan (a long chain sulfated polysaccharide found in various species of brown algae); katacine (an extract of the Polygonaceae family of flowering plants); S100A13 (i.e., S100 calcium-binding protein A13); humsn CLEC7A (also termed C-type lectin domain family 7 member A or dectin-1); and the soot, carbon, and other particles in the exhaust gas of diesel engines.[8][11][12][13]

Cells expressing CLEC-2

CLEC-2 is highly expressed on mouse and human platelets as well as megakaryocytes, i.e., platelet-forming cells.[14][15] It is also expressed on the surface membranes of myeloid cells (i.e., a broad category of blood cells that originate from hematopoietic stem cells in the bone marrow and differentiate into NK cells, B cells[4][16]; platelets, dendritic cells,[17] follicular dendritic cells, mesothelial cells (i.e., simple squamous epithelial cells of mesodermal origin in the mesothelium), epithelial cells in lymphatic vessels, and cancer-associated fibroblasts (i.e., non-malignant fibroblasts that are located in cancer tissues).[18]

Functions of activated CLEC-2

Podoplanin activation of CLEC-2

Based primarily on preclinical studies done in rodents, podoplanin-induced activation of CLEC-2 (see the podoplanin page for details): a) on megakaryocytes promotes their production of platelets;[12][19][20] b) ischemia/reperfusion tissue damage,[21][22][23] cancer-associated venous thromboembolisms, atherosclerosis,[12][24][22] and regeneration of the liver after 70% of it is removed experimentally;[8][25] and c) on the platelets of fetuses in order for them to develop normal normal blood vessels, lymphatic vessels, the heart[20], and lung.[26]

S100A13 activation of CLEC-2

Studies in isolated human and mouse aortas and mice strongly suggest that the S100A13 expressed on the surface of smooth muscle cells is responsible for activating platelets and causing thrombus formation during the early stages of thrombus formation before podoplanin is expressed.[7][12][27]

C-type lectin domain family 7 member A activation of CLEC-2

Studies in various cultured cell systems indicate that the CLEC7A (i.e., C-type lectin domain family 7 member protein, also termed dectin-1) from humans (sometimes notated as hdectin-1) as well as the dectin-1 proteins isolated from the cells of higher primates activate human as well as mouse CLEC-2. However, the CLEC7A protein isolated from mouse cells (sometimes notated as mdectin-1) does not activate human or mouse CLEC-2.[13] A structurally similar protein, CLEC6A (i.e., C-type lectin domain containing 6A, also termed dectin-2) has a very different set of actions and does not activate CLEC-2. CLEC7A (i.e., dectin-1) in humans is expressed on the surface membranes of vascular endothelial cells, tissue dendritic cells, tissue macrophages, and circulating white blood cells such as neutrophils, monocytes, and circulating dendritic cells.[7][13] CLEC7A identifies and interacts with various fungi (e.g., yeast, Candida albicans, Pneumocystis jirovecii and Aspergillus species to promote immune responses against these pathogens. CLEC7A also stimulates isolated human platelets and mouse platelets made to express human CLEC-2 but not mouse platelets expressing mouse CLEC-2. Further studies in mice made to express human CLEC-2 in place of mouse CLEC2 were found to stimulate platelets without triggering venous thromboses whereas podoplanin triggered both platelet activation and venous thromboses. These latter findings suggest that CLEC7A is a comparatively moderate antihemorrhagic agent (i.e., inhibitor of bleeding) which may control physiological processes through platelets thrombosis-independent mechanisms. Further studies may show that CLEC-2 is useful for inhibiting bleeding without causing thrombosis.[13][28]

References

  1. ↑ "Molecular characterization of two novel C-type lectin-like receptors, one of which is selectively expressed in human dendritic cells". Eur J Immunol 30 (2): 697–704. Mar 2000. doi:10.1002/1521-4141(200002)30:2<697::AID-IMMU697>3.0.CO;2-M. PMID 10671229. 
  2. ↑ "A novel cluster of lectin-like receptor genes expressed in monocytic, dendritic and endothelial cells maps close to the NK receptor genes in the human NK gene complex". Eur J Immunol 31 (12): 3493–503. Dec 2001. doi:10.1002/1521-4141(200112)31:12<3493::AID-IMMU3493>3.0.CO;2-9. PMID 11745369. 
  3. ↑ "Entrez Gene: CLEC1B C-type lectin domain family 1, member B". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51266. 
  4. ↑ 4.0 4.1 "The Role of CLEC-2 and Its Ligands in Thromboinflammation". Frontiers in Immunology 12. 2021. doi:10.3389/fimmu.2021.688643. PMID 34177942. 
  5. ↑ "An integrative analysis to reveal that CLEC2B and ferroptosis may bridge the gap between psoriatic arthritis and cancer development". Scientific Reports 12 (1). August 2022. doi:10.1038/s41598-022-19135-2. PMID 36030279. Bibcode: 2022NatSR..1214653L. 
  6. ↑ "Comprehensive analysis identifies CLEC1B as a potential prognostic biomarker in hepatocellular carcinoma". Cancer Cell Interna-tional 23 (1). June 2023. doi:10.1186/s12935-023-02939-1. PMID 37308868. 
  7. ↑ 7.0 7.1 7.2 "Pattern recognition receptors in health and diseases". Signal Transduction and Targeted Therapy 6 (1). August 2021. doi:10.1038/s41392-021-00687-0. PMID 34344870. 
  8. ↑ 8.0 8.1 8.2 "C-type lectin-like receptor 2: roles and drug target". Thrombosis Journal 22 (1). March 2024. doi:10.1186/s12959-024-00594-8. PMID 38504248. 
  9. ↑ "The C-type lectin-like domain superfamily". The FEBS Journal 272 (24): 6179–217. December 2005. doi:10.1111/j.1742-4658.2005.05031.x. PMID 16336259. 
  10. ↑ "Myeloid C-type lectin receptors in innate immune recognition". Immunity 57 (4): 700–717. April 2024. doi:10.1016/j.immuni.2024.03.005. PMID 38599166. 
  11. ↑ "Katacine Is a New Ligand of CLEC-2 that Acts as a Platelet Agonist". Thrombosis and Haemostasis 122 (8): 1361–1368. August 2022. doi:10.1055/a-1772-1069. PMID 35170009. 
  12. ↑ 12.0 12.1 12.2 12.3 "Vascular Smooth Muscle Cells Stimulate Platelets and Facilitate Thrombus Formation through Platelet CLEC-2: Implications in Atherothrombosis". PLOS ONE 10 (9). 2015. doi:10.1371/journal.pone.0139357. PMID 26418160. Bibcode: 2015PLoSO..1039357I. 
  13. ↑ 13.0 13.1 13.2 13.3 "Human Dectin-1 is O-glycosylated and serves as a ligand for C-type lectin receptor CLEC-2". eLife 11. December 2022. doi:10.7554/eLife.83037. PMID 36479973. 
  14. ↑ "CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow". The Journal of Experimental Medicine 212 (12): 2133–46. November 2015. doi:10.1084/jem.20150057. PMID 26552707. 
  15. ↑ "CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses". European Journal of Immunology 41 (10): 3040–53. October 2011. doi:10.1002/eji.201141641. PMID 21728173. 
  16. ↑ "CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils". Journal of Immunology (Baltimore, Md. : 1950) 182 (7): 4150–7. April 2009. doi:10.4049/jimmunol.0802808. PMID 19299712. 
  17. ↑ "Podoplanin: An emerging cancer biomarker and therapeutic target". Cancer Science 109 (5): 1292–1299. May 2018. doi:10.1111/cas.13580. PMID 29575529. 
  18. ↑ "PDGF upregulates CLEC-2 to induce T regulatory cells". Oncotarget 6 (30): 28621–32. October 2015. doi:10.18632/oncotarget.5765. PMID 26416420. 
  19. ↑ "Podoplanin: Its roles and functions in neurological diseases and brain cancers". Frontiers in Pharmacology 13. 2022. doi:10.3389/fphar.2022.964973. PMID 36176432. 
  20. ↑ 20.0 20.1 "A role of platelet C-type lectin-like receptor-2 and its ligand podoplanin in vascular biology". Current Opinion in Hematology 31 (3): 130–139. May 2024. doi:10.1097/MOH.0000000000000805. PMID 38359177. 
  21. ↑ "Podoplanin and its multifaceted roles in mammalian developmental program". Cells & Development 180. December 2024. doi:10.1016/j.cdev.2024.203943. PMID 39111713. 
  22. ↑ 22.0 22.1 "Podoplanin: A potential therapeutic target for thrombotic diseases". Frontiers in Neurology 14. 2023. doi:10.3389/fneur.2023.1118843. PMID 36970507. 
  23. ↑ "A Role of the Podoplanin-CLEC-2 Axis in Promoting Inflammatory Response After Ischemic Stroke in Mice". Neurotoxicity Research 39 (2): 477–488. April 2021. doi:10.1007/s12640-020-00295-w. PMID 33165736. 
  24. ↑ "Podoplanin expression on endothelial cells promotes superficial erosive injury and thrombus formation in rat carotid artery: Implications for plaque erosion". Thrombosis Research 183: 76–79. November 2019. doi:10.1016/j.thromres.2019.10.015. PMID 31670230. 
  25. ↑ "The platelet-activating receptor C-type lectin receptor-2 plays an essential role in liver regeneration after partial hepatectomy in mice". Journal of Thrombosis and Haemostasis 15 (5): 998–1008. May 2017. doi:10.1111/jth.13672. PMID 28294559. 
  26. ↑ "Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction". Blood 132 (11): 1167–1179. September 2018. doi:10.1182/blood-2017-12-823369. PMID 29853539. 
  27. ↑ "New horizon in platelet function: with special reference to a recently-found molecule, CLEC-2". Thrombosis Journal 14 (Suppl 1). 2016. doi:10.1186/s12959-016-0099-8. PMID 27766053. 
  28. ↑ "Secondary Sites of the C-type Lectin-Like Fold". Chemistry (Weinheim an der Bergstrasse, Germany) 30 (30). May 2024. doi:10.1002/chem.202400660. PMID 38527187. 

See also

Podoplanin



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