MRC1 (mannose receptor, C type 1)

2010-01-01 Silvia Rasi , Alessio Bruscaggin , Gianluca Gaidano Affiliation

Division of Hematology, Department of Clinical, Experimental Medicine & Center of Biotechnologies for Applied Medical Research, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy

Identity

HGNC

MRC1

LOCATION

10p12.33

IMAGE

LEGEND

A. Chromosomal location of MRC1 gene.

LEGEND

B. Mapping of MRC1 gene and local order on genomic context of the chromosome 10.

LOCUSID

4360

ALIAS

CD206,CLEC13D,MMR

DNA/RNA

Exon-intron structure of MRC1 gene. The blue boxes correspond to protein coding sequences, while the white boxes correspond to non coding regions.

Description

MRC1 is a functional gene of 101.74 kb comprising 30 exons and 29 introns. The 5 part of exon 1 and the 3 part of exon 30 are non coding.

Transcription

Length of the transcript is 5171 bp.
Coding sequence: CDS 104-4474.
mRNA is mainly expressed in thyroid, spleen and blood.

Proteins

Representation of the MRC1 protein with localization of recognized domains. The ricin b-type lectin domain (RICIN) is shown in green, the fibronectin type-II domain (FN2) in yellow, the C-type lectin-like domains (CTLDs) in blue, while the transmembrane domain (TM) in red (UniProtKB/Swiss-Prot entry P22897).

Description

Protein length of the unprocessed precursor: 1456 amino acids.
Molecular weight of the unprocessed precursor: 166 KDa.
The protein encoded by the MRC1 gene is classified as a type I transmembrane receptor since the protein COOH terminus is located on the cytoplasmic side of the membrane.
MRC1 is a membrane receptor containing:
- a ricin b-type lectin domain (RICIN), that is a cystein-rich (CysR) domain located at the extreme N-terminus and that can bind specific sulphated glycoproteins,
- a fibronectin type-II domain (FN2), that is the most conserved of the extracellular domains of the MR family and can bind several forms of collagen,
- 8 C-type lectin-like domains (CTLDs), that are Ca(2+)-dependent structural motifs. The fourth of these domains, CTLD4, is the only functional domain. In cooperation with CTLD5, CTLD4 is central to ligand binding by the receptor,
- a single transmembrane domain (TM),
- a short cytosolic domain that contains motifs capable of recognizing components of the endocytic pathway.
The first 3 exons of MRC1 gene encode the signal sequence, the RICIN domain and the FN2 domain, while exon 30 encodes the TM anchor and the cytoplasmic tail. The other 26 exons encode the 8 CTLD domains and intervening spacer elements.
Probably the MRC1 receptor acts with an alternation between bent and extended conformations, that might serve as a "conformational switch" to regulate ligand binding and receptor activity.
MRC1 interacts with CHEK2 (CHK2 checkpoint homolog - S. pombe) protein.

Expression

MRC1 is commonly expressed on macrophages and endothelial cells.

Localisation

Plasma membrane.

Function

- MRC1 mediates the endocytosis of glyproteins by macrophages binding both sulfated and non-sulfated polysaccharide chains.
- MRC1 acts as a phagocytic receptor binding a range of pathogens, such as bacteria, viruses and fungi, through high-mannose structures that are in their surface.
- MRC1 is required for rapid clearance of a subset of mannose-bearing serum glycoproteins that are normally elevated during inflammation.
- MRC1 binds and internalises collagen and gelatin in a carbohydrate-independent mechanism.
- MRC1 can function as an antigen-acquisition system in a subset of dendritic cells.
- MRC1 is implicated in the regulation of macrophage migration during different stages of pathogenesis.
- MRC1 has an important role in binding and transmission of HIV-1 by macrophages.

Homology

Ortholog to murine Mrc1, rat Mrc1, cow LOC787578, chimpanzee MLR1L1, canine LOC487114.
Paralog to MRC1L1, CD302, PLA2R1, MRC2.

Mutations

Note

No mutations have been reported for MRC1 gene.

Implicated in

Entity name

Pediatric acute lymphoblastic leukemia (ALL)

Disease

ALL is a form of leukemia characterized by excess of lymphoblastic cells that is most common in childhood. The rate of cure in children is of nearly 80%, while only 30/40% of adults with ALL are cured.
It is a heterogeneous disease consisting of a number of genetically distinct leukemia subtypes that differ in the response to chemotherapy. These include B-lineage leukemias that contain t(9;22)[BCR-ABL], t(1;19)[E2A-PBX1], t(12;21)[TEL-AML1], rearrangements in the MLL gene on chromosome 11q23, or a hyperdiploid karyotype, and T-lineage leukemias (T-ALL).

Prognosis

ALL is a heterogeneous disease and patients are assigned to specific risk groups. In fact, ALL prognosis differs among individuals and depends on several factors: sex, age and white blood cell count at diagnosis, leukemia spread to the central nervous system, morphological, immunological, and genetic subtypes, patients response to initial treatment.
Various genetic alterations are correlated with prognosis in ALL. In particular ALLs with the presence of t(12;21)[TEL-AML1] and hyperdiploid karyotype have favorable prognosis, while ALLs with t(9;22)[BCR-ABL], t(1;19)[E2A-PBX1] or rearrangements in MLL (11q23) have a poor prognosis.

Oncogenesis

In cases having ALL with MLL rearrangements, expression of MRC1 is lower than in normal cells, suggesting a putative involvement of MRC1 in MLL-mediated growth of leukemic cells.

Entity name

Acute monocytic leukemia (M5-AML)

Note

In acute monocytic leukemia, a trimannose conjugate (TMC), with a high affinity for mannose-specific lectins, binds to MRC1 and this concatenation may play an important role in the activation of monocytic leukemia cells. TMC may be a good candidate to target MRC1 in leukemia cells.

Disease

Acute monocytic leukemia is a type of acute myeloid leukemias (AML), characterized by a dominance of monocytes in the bone marrow.

Entity name

Cancer

Note

MRC1 on lymphatic endothelial cells is involved in leukocyte trafficking and contributes to the metastatic behavior of cancer cells. Moreover, expression of the MRC1 gene is up-regulated in vascular endothelial cells during early development indicating that this gene is a potential regulator of vasculature formation.
Blocking of MRC1 may provide a new approach to controlling inflammation and cancer metastasis by targeting the lymphatic vasculature.

Entity name

Kaposis sarcoma (KS)

Note

KS cells express MRC1, since MRC1 is detected in more than 95% of KS cells in all of the major clinical forms of the disease. It is likely that KS lesions derive from tissue accumulation and local proliferation of a subset of macrophages with endotelial features.

Disease

KS is a multicentric proliferative disease, involving cutaneous and visceral tissues. The etiology is unknown and the pathogenesis is unclear. KS lesions derive from local proliferation of spindleshaped cells (KS cells), that represent the histological hallmark of this disease.

Bibliography

Pubmed ID	Last Year	Title	Authors
12223280	2002	The mannose receptor family.	East L et al
8001982	1994	Assignment of the human macrophage mannose receptor gene (MRC1) to 10p13 by in situ hybridization and PCR-based somatic cell hybrid mapping.	Eichbaum Q et al
11721968	2001	Novel synthesized trimannose conjugate induces endocytosis and expression of immunostimulatory molecules in monocytic leukemia cells.	Kanbe E et al
1294118	1992	Organization of the gene encoding the human macrophage mannose receptor (MRC1).	Kim SJ et al
11884756	2002	Mannose receptor-mediated regulation of serum glycoprotein homeostasis.	Lee SJ et al
18193159	2008	Extended and bent conformations of the mannose receptor family.	Llorca O et al
16619293	2006	Carbohydrate-independent recognition of collagens by the macrophage mannose receptor.	Martinez-Pomares L et al
18434610	2008	Macrophage mannose receptor on lymphatics controls cell trafficking.	Marttila-Ichihara F et al
17404279	2007	Mannose receptor expression and function define a new population of murine dendritic cells.	McKenzie EJ et al
12645947	2003	Involvement of macrophage mannose receptor in the binding and transmission of HIV by macrophages.	Nguyen DG et al
9718381	1998	Acute lymphoblastic leukemia.	Pui CH et al
17596337	2007	Mannose receptor regulation of macrophage cell migration.	Sturge J et al
2373685	1990	Primary structure of the mannose receptor contains multiple motifs resembling carbohydrate-recognition domains.	Taylor ME et al
9060831	1997	Kaposi's sarcoma cells express the macrophage-associated antigen mannose receptor and develop in peripheral blood cultures of Kaposi's sarcoma patients.	Uccini S et al
19504456	2009	Identification of vasculature-specific genes by microarray analysis of Etsrp/Etv2 overexpressing zebrafish embryos.	Wong KS et al
12086872	2002	Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.	Yeoh EJ et al

Other Information

Locus ID:

NCBI: 4360
MIM: 153618
HGNC: 7228
Ensembl: ENSG00000260314

Variants:

dbSNP: 4360
ClinVar: 4360
TCGA: ENSG00000260314
COSMIC: MRC1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000260314	ENST00000569591	P22897

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Phagosome	KEGG	ko04145
Phagosome	KEGG	hsa04145
Tuberculosis	KEGG	ko05152
Tuberculosis	KEGG	hsa05152
Immune System	REACTOME	R-HSA-168256
Adaptive Immune System	REACTOME	R-HSA-1280218
Class I MHC mediated antigen processing & presentation	REACTOME	R-HSA-983169
Antigen processing-Cross presentation	REACTOME	R-HSA-1236975
Cross-presentation of soluble exogenous antigens (endosomes)	REACTOME	R-HSA-1236978

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19772890	2009	Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages.	236
16203868	2005	The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis.	164
14568928	2003	Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program.	108
20554962	2010	Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses.	92
16385451	2006	A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.	69
20610655	2010	The mannose receptor mediates the uptake of diverse native allergens by dendritic cells and determines allergen-induced T cell polarization through modulation of IDO activity.	57
21331365	2010	Engagement of the mannose receptor by tumoral mucins activates an immune suppressive phenotype in human tumor-associated macrophages.	38
15155616	2004	Pneumocystis activates human alveolar macrophage NF-kappaB signaling through mannose receptors.	35
24498098	2014	Overexpression of CD163, CD204 and CD206 on alveolar macrophages in the lungs of patients with severe chronic obstructive pulmonary disease.	34
17020928	2007	Pneumocystis-mediated IL-8 release by macrophages requires coexpression of mannose receptors and TLR2.	33

Citation

Silvia Rasi ; Alessio Bruscaggin ; Gianluca Gaidano

MRC1 (mannose receptor, C type 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/44561/mrc1