CLEC1B (C-Type Lectin Domain Family 1, Member B)

2013-11-01   Katsue Suzuki-Inoue 

Department of Clinical, Laboratory Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, 409-3898 Chuo, Yamanashi, Japan

Identity

HGNC
LOCATION
12p13.2
LOCUSID
ALIAS
1810061I13Rik,CLEC2,CLEC2B,PRO1384,QDED721

DNA/RNA

Description

The gene is 982 bp in length and contains six exons.

Transcription

In human, mouse, rabbit, rat, and bovine species, transcription produces 2-4 different mRNAs, including alternatively spliced variants and 1 unspliced form.

Pseudogene

No known pseudogenes.

Proteins

Atlas Image
Schematic representation of the domain structure of CLEC-2 (Colonna et al., 2000; Watson et al., 2007; Wang et al., 2012). TM represents transmembrane region. Neck represents neck region. CTLD represents C-type lectin-like domain.

Description

CLEC-2 is a 32-kDa (229 amino acids) type II trans-membrane receptor that belongs to C-type lectin superfamily. CLEC-2 has 1 C-type lectin-like domain (CTLD) and belongs to the non-classical C-type lectins, which contain a CTLD homologous to a carbohydrate recognition domain but lack the consensus sequence for binding sugars and calcium (Colonna et al., 2000). CLEC-2 has a YxxL motif in its cytoplasmic tail, which is crucial for CLEC-2-mediated signal transduction. This sequence is called hemi-ITAM, since it resembles the immunoreceptor tyrosine-based activation motif (ITAM, YxxL-(X)10-12-YxxL), which includes 2 YxxL motifs. CLEC-2 was first identified through a bioinformatic screen for C-type lectin-like molecules with immune functions. The gene encoding human CLEC-2 is located in the natural killer complex on chromosome 12 along with other C-type lectin-like receptors, including NKG2D, LOX-1, and Dectin-1 (Sobanov et al., 2001).

Expression

Organ: Highly expressed in bone marrow and slightly expressed in liver.
Cell types: CLEC-2 protein is expressed at high levels in platelets/megakaryocytes and at low levels in sinusoidal endothelial cells (Chaipan et al., 2006) and Kupffer cells (Tang et al., 2010) in humans. In mice, CLEC-2 protein is highly expressed in platelets/megakaryocytes, and is slightly expressed in other blood cells, including neutrophils, monocytes, dendritic cells, NK cells, B cells (Chang et al., 2010; Mourao-Sa et al., 2011), and Kupffer cells (Tang et al., 2010).

Localisation

Plasma membrane.

Function

Separation of blood and lymphatic vessels during development
Podoplanin is also expressed on the surface of lymphatic endothelial cells, but not vascular endothelial cells. During organ development, a cluster of endothelial cells in the cardinal vein is committed to the lymphatic phenotype, and sprouts to form the primary lymphatic sacs from which a portion of the peripheral lymphatic vasculature is generated by further centrifugal growth (Tammela and Alitalo, 2010). At this stage, platelets are activated by an association between CLEC-2 in the platelets and podoplanin in the lymphatic endothelial cells, which inhibits the growth and migration of lymphatic endothelial cells and facilitates the separation of blood and lymphatic vessels.
CLEC-2-deficient mice show blood-filled lymphatic vessels and severe edema due to lymphatic dysfunction (Bertozzi et al., 2010; Suzuki-Inoue et al., 2010; Finney et al., 2011). One controversial theory proposes that granule contents released from activated platelets inhibit the function of lymphatic endothelial cells (Osada et al., 2012).
Thrombus formation
Thrombus formation under flow conditions has been reported to be impaired in CLEC-2-deficient blood. In vivo thrombus formation is also inhibited in antibody-induced CLEC-2-deficient mice (May et al., 2009) or bone marrow chimeric mice deficient in CLEC-2 (Suzuki-Inoue et al., 2010). These findings suggest that CLEC-2 is involved in the stabilization of thrombus formation under flow conditions, although the precise mechanism by which this occurs has not yet been elucidated. Combined in vivo depletion of CLEC-2 and glycoprotein VI (GPVI), a collagen receptor in platelets, severely compromises haemostasis and abrogates arterial thrombosis in mice (Bender et al., 2013). CLEC-2 and GPVI, both of which generate activation signals depending on ITAMs and tyrosine kinases, play a complementary role in thrombosis and haemostasis.
Maintenance of vascular integrity
CLEC-2 is involved in maintaining vascular integrity in inflammation (Boulaftali et al., 2013) and high endothelial venules (HEVs) in lymph nodes upon lymphocyte transmigration (Herzog et al., 2013). Podoplanin is expressed on fibroblastic reticular cells, which surround HEVs. Upon lymphocyte transmigration, platelets extravasate to the perivenular space of HEVs and interact with podoplanin. Local release of sphingosine-1-phosphate after CLEC-2-podoplanin-mediated platelet activation is critical for HEV integrity during immune responses.
Antigen presentation
CLEC-2 is also expressed in dendritic cells (DCs) in mice. Associations between CLEC-2 in DCs and podoplanin in lymphatic endothelial and fibroblastic reticular cells in the lymph nodes facilitates DC entry into the lymphatics as well as movement to and within the lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of podoplanin was found to be necessary for DCs to spread and migrate along stromal surfaces, and was sufficient to induce membrane protrusions through Vav and Rac1 activation (Acton et al., 2012).
HIV transmission
Previous reports indicate that platelets capture and transfer infectious HIV-1 via DC-SIGN and CLEC-2, possibly facilitated HIV-1 dissemination in infected patients (Suzuki-Inoue et al., 2011). CLEC-2 does not directly bind to the viral envelope proteins, but to podoplanin incorporated into the HIV particles released from HEK-293T cells (Chaipan et al., 2010). This mechanism does not seem to be important for viral dispersion in vivo since podoplanin is not expressed on T cells, which are the major HIV target.
Phagocytosis and cytokine production
CLEC-2 is expressed in dendritic cells, NK cells, B cells, neutrophils, and monocytes, in addition to platelets (Kerrigan et al., 2009; Chang et al., 2010; Mourao-Sa et al., 2011). Murine CLEC-2 in neutrophils mediates the phagocytosis of anti-CLEC-2 antibody-coated beads. Moreover, neutrophils stimulated by rhodocytin produce proinflammatory cytokines such as TNF-α depending on CLEC-2, but not respiratory burst (Kerrigan et al., 2009). CLEC-2 ligation in macrophages and DCs selectively up-regulates production of IL-10, an anti-inflammatory cytokine, by Toll-like receptor stimulation. Although the physiological relevance of these phenomena has not been determined, CLEC-2 is expressed in myeloid cells and may be able to modulate the inflammatory response in vivo.

Homology

Among 226-229 amino acids of 5 species (human, mouse, rat, rabbit, and bovine) CLEC-2, there are 129 positions with 100% sequence conservation, 36 positions with 80% sequence conservation, and 44 positions with 60% sequence conservation. Human CLEC-2 is 62% identical to mouse CLEC-2, and 70% to rabbit CLEC-2.

Mutations

Note

No known mutations.

Implicated in

Entity name
Haematogenous tumour metastasis
Note
CLEC-2 has been identified as a receptor for a platelet activating snake venom, rhodocytin (Suzuki-Inoue et al., 2006). Podoplanin is a type I transmembrane sialomucin-like glycoprotein, and is identified as the endogenous ligand for CLEC-2 (Suzuki-Inoue et al., 2007; Christou et al., 2008). It is expressed on the surface of certain types of tumour cells, where it causes aggregation of platelets in the blood stream, facilitating haematogenous tumour metastasis. Platelet aggregation surrounding tumour cells is considered to protect the tumour cells from shear stress and NK cells (Nieswandt et al., 1999) in the blood stream and provide scaffolding for tumour cell nests. Growth factors released from activated platelets stimulate angiogenesis and/or tumour growth. In an experimental model of metastasis in mice, an anti-podoplanin blocking antibody significantly inhibited the number of tumour-cell containing metastatic lung nodules that expressed podoplanin, implying that CLEC-2/podoplanin may be a promising target protein for anti-metastatic drugs (Kato et al., 2008).
Entity name
Various diseases
Note
No implication in any specific diseases in human has been reported.

Bibliography

Pubmed IDLast YearTitleAuthors
228843132012Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2.Acton SE et al
234489722013Combined in vivo depletion of glycoprotein VI and C-type lectin-like receptor 2 severely compromises hemostasis and abrogates arterial thrombosis in mice.Bender M et al
203637742010Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling.Bertozzi CC et al
233487382013Platelet ITAM signaling is critical for vascular integrity in inflammation.Boulaftali Y et al
204828802010Incorporation of podoplanin into HIV released from HEK-293T cells, but not PBMC, is required for efficient binding to the attachment factor CLEC-2.Chaipan C et al
207387642010A novel mechanism of cytokine release in phagocytes induced by aggretin, a snake venom C-type lectin protein, through CLEC-2 ligation.Chang CH et al
182151372008Renal cells activate the platelet receptor CLEC-2 through podoplanin.Christou CM et al
106712292000Molecular characterization of two novel C-type lectin-like receptors, one of which is selectively expressed in human dendritic cells.Colonna M et al
221869942012CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development.Finney BA et al
239956782013Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2.Herzog BH et al
179449732008Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2.Kato Y et al
192997122009CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils.Kerrigan AM et al
196411852009CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis.May F et al
217281732011CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses.Mourão-Sá D et al
100965621999Lysis of tumor cells by natural killer cells in mice is impeded by platelets.Nieswandt B et al
225564082012Platelet activation receptor CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation, migration, and tube formation of lymphatic endothelial cells.Osada M et al
117453692001A 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.Sobanov Y et al
217812412011Novel platelet activation receptor CLEC-2: from discovery to prospects.Suzuki-Inoue K et al
201787402010Lymphangiogenesis: Molecular mechanisms and future promise.Tammela T et al
205628622010A mouse knockout library for secreted and transmembrane proteins.Tang T et al
227402302012Structural and functional conservation of CLEC-2 with the species-specific regulation of transcript expression in evolution.Wang L et al
171326232007The crystal structure and mutational binding analysis of the extracellular domain of the platelet-activating receptor CLEC-2.Watson AA et al

Other Information

Locus ID:

NCBI: 51266
MIM: 606783
HGNC: 24356
Ensembl: ENSG00000165682

Variants:

dbSNP: 51266
ClinVar: 51266
TCGA: ENSG00000165682
COSMIC: CLEC1B

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000165682ENST00000298527Q9P126
ENSG00000165682ENST00000348658Q9P126
ENSG00000165682ENST00000398937H7BYT7
ENSG00000165682ENST00000428126Q9P126

Expression (GTEx)

0
1
2
3

Pathways

PathwaySourceExternal ID
HemostasisREACTOMER-HSA-109582
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604

References

Pubmed IDYearTitleCitations
176165322007Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells.143
169405072006DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets.63
201542192010CLEC-2 activates Syk through dimerization.52
225564082012Platelet activation receptor CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation, migration, and tube formation of lymphatic endothelial cells.46
182151372008Renal cells activate the platelet receptor CLEC-2 through podoplanin.42
226821302012Platelet CLEC-2 and podoplanin in cancer metastasis.33
205495152010Genome-wide searching of rare genetic variants in WTCCC data.29
201542142010Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization, secondary mediators, and Rac.28
202374962010New genetic associations detected in a host response study to hepatitis B vaccine.27
187075442008Characterization of anti-podoplanin monoclonal antibodies: critical epitopes for neutralizing the interaction between podoplanin and CLEC-2.22

Citation

Katsue Suzuki-Inoue

CLEC1B (C-Type Lectin Domain Family 1, Member B)

Atlas Genet Cytogenet Oncol Haematol. 2013-11-01

Online version: http://atlasgeneticsoncology.org/gene/49856/clec1b