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MUC2 (mucin 2, oligomeric mucus/gel-forming)

Written2009-11Suguru Yonezawa, Norishige Yamada, Seiya Yokoyama, Sho Kitamoto, Michiyo Higashi, Masamichi Goto
Department of Human Pathology, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University School of Medical, Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan (SY, SY, SK, MH); Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, 650-0047, Japan (NY); National Sanatorium Hoshizuka-Keiaien, Kanoya, Kagoshima 893-8502, Japan (MG)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesmucin 2
Other aliasMLP
MUC-2
SMUC
HGNC (Hugo) MUC2
LocusID (NCBI) 4583
Atlas_Id 41457
Location 11p15.5  [Link to chromosome band 11p15]
Location_base_pair Starts at 1074875 and ends at 1110508 bp from pter ( according to hg19-Feb_2009)  [Mapping MUC2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
MUC2 (11p15.5) / CKM (19q13.32)MUC2 (11p15.5) / LSR (19q13.12)TPM2 (9p13.3) / MUC2 (11p15.5)

DNA/RNA

Note MUC2 gene is the first human secretory mucin gene to be cloned and fully sequenced (Gum et al., 1994).
 
  MUC2 is located at the telomeric end of about 400kb gene cluster on chromosome 11p15.5 and oriented from centromere to telomere and clustered with another secretory mucin genes such as MUC6 and MUC5AC/B. These genes show sequence homology in their non-tandem repeat domains and are thought to have arisen by duplication from a common ancestor. MUC2 is composed of 49 exons, exon 30 being the largest one and coding for the tandem repeats region. The array indicate the direction of transcription (not to scale).
Description MUC2 is located within a 29-kb DNA fragment between MUC6, MUC5AC and MUCB on chromosome 11 in the region p15.5 (Griffiths et al., 1990; Desseyn et al., 1998; Rousseau et al., 2004), and cDNA is approximately 15.5 kb long. Genes that share some sequence homology are believed to have arisen by duplication from a common ancestor.
Transcription The MUC2 promoter contains a TATA box, and includes binding sequence motifs for transcription factors such as AP2, SP1 and CDX2 (Griffiths et al., 1990; Toribara et al., 1991; Gum et al., 1994). MUC2 expression has been reported to be regulated by the Sp family (Nogami et al., 1997; Aslam et al., 2001). SP1 activates transcription synergistically both close to and far from the transcription start site in an enhancer-like manner. In several human cancer cell lines, p53 has also been indicated to regulate MUC2 transactivation by binding to two of its sites (-1131/-1100 and -676/-650) (Ookawa et al., 2002). Moreover, NF-kB and CDX2 have been reported to up-regulate MUC2 transcription (Yamamoto et al., 2003; Ikeda et al., 2007). Methylation of cytosine residues at CpG dinucleotides is an important epigenetic change that has been linked to transcriptional repression and regulation of chromatin structure (Holliday et al., 1975; Meehan et al., 2001; Recillas-Targa et al., 2002). Increased methylation of promoter region causes suppression of MUC2 gene (Hanski et al., 1997b; Riede et al., 1998). Hamada et al. have determined the detailed methylation status of a wide area of the MUC2 promoter region in pancreatic cancer cell lines, and suggested that methylation of certain CpG sites may play a particularly important role in the regulation of MUC2 transcription (Hamada et al., 2005). A CDX2 binding site is present downstream of the MUC2 promoter, and Yamamoto et al. have reported that the homeodomain protein CDX2 interacts with the MUC2-WT cis element (bases -201 to -162) in the MUC2 promoter and that ectopic expression of the CDX2 protein activates transcription of MUC2 (Yamamoto et al., 2003). In bisulfite genomic sequencing study, CDX2-binding CpG site showed 95% methylation in PANC1 (MUC2-negative) and 50% methylation in BxPC3 (MUC2-positive) (Hamada et al., 2005). Thus, MUC2 expression might be regulated by epigenetic changes in the promoter region containing the CDX2 binding site. In addition to DNA methylation, H3-K9 methylation is closely related to DNA methylation and acts as an epigenetic marker for silencing of the MUC2 gene (Yamada et al., 2006; Vincent et al., 2007).

Protein

Note MUC2 is one of the human gel-forming secreted mucins, and has a unique core peptide composed of 23 amino acids. The N-terminal and C-terminal regions of the MUC2 apomucin are very similar to von Willebrand factor (vWF). The N-terminal region is composed of disulfide-rich D-domains (D1, D2, D' and D3) which is seen in vWF. The C-terminal region has also domains seen in vWF (D4, B, C and CK). In the central part, there are the first Ser/Thr/Pro rich 21 repetitive region showing an irregular amino acid motif, and the second regular tandemly repeated motifs of 23 amino acids (PTTTPITTTTTVTPTPTPTGTQT) which show variable number of tandem repeat from 51 to 115. CYS domain are present between the N-terminal region and the first Ser/Thr/Pro rich 21 repetitive region, and also present between the first Ser/Thr/Pro rich repetitive region and the second 23 amino acids repetitive region.
 
  A: Schematic diagram of vWF (upper) and MUC2 mucin core protein (lower). N-terminal and C-terminal regions of MUC2 are highly similar to those of vWF, in its D, B, C and CK domains.
B: Illustration of the structure of MUC2 mucin monomer. The 1st tandem repeat (TR) region is Ser, Thr and Pro rich, and made of 21 repetitions of an irregular amino acid motif. The 2nd TR region show variable number of tandem repeat (VNTR) from 51 to 115 of TR composed of 23 amino acids.
C: The central repetitive domain is rigid owing to the heavy glycosylation. On the other hand, the unique sequences contain numerous cysteine residues that link monomers to oligomers via disulfide bonds.
Description The central repetitive domains are rigid owing to heavy glycosylation, whereas the unique sequences of N-terminal and C-terminal regions sparsely glycosylated and protease-sensitive. In addition, the unique sequences have numerous Cys residues that link monomers to oligomers by disulfide bonds.
Expression In normal physiological situation, MUC2 shows unique expression profiles in the limited organs and tissues such as intestine, bronchus and salivary gland.
In the normal human adult intestinal system, MUC2 expression is observed in the perinuclear areas of the goblet cells in the villi and crypts of the small intestine, and in the crypts of the colon and rectum, but not in the surface absorptive cells. MUC2 mRNA expression is also demonstrated at the perinuclear areas of those goblet cells (Chang et al., 1994; Buisine et al., 1998). Precise in situ hybridization (ISH) and immunohistochemistry (IHC) studies in electron microscopic level study demonstrated that MUC2 mRNA and MUC2 apomucin are located predominantly in the supranuclear and the perinuclear rough endoplasmic reticulum (RER), but not in the Golgi apparatus, in the goblet cells (Wang et al., 2001).
In ISH study in human embryonic and fetal tissues, in small intestine, MUC2 mRNA was detected between the primordial villi at 9 weeks after gestation, and was located mainly in immature crypts of Lieberkuhn after 10 weeks until 23 weeks. After that, MUC2 mRNA was expressed at the perinuclear regions of the goblet cells in villi and crypts. In the colon and rectum, MUC2 mRNA was detected at the perinulear regions of the goblet cells in crypts from 13 weeks of gestation (Buisine et al., 1998).
In the bronchial tissue, MUC2 was expressed below and around mucous secretory granules (RER and Golgi apparatus) in the bronchial surface epithelium and bronchial mucous glands (Jany et al., 1991).
Second-generation MAb to MUC2 (CCP58) detects weak expression in salivary glands in addition to the intense expression in the small and large intestine as described above glands (Xing et al., 1992).
Localisation After the multimerization forming oligomers and O-glycosylation, MUC2 mucin is stored in secretory granules. MUC2 is localized in the supra- and peri-nuclear areas, which are RER (Wang et al., 2001), of the columnar epithelium with goblets in small and large intestine. MUC2 is also seen in the peribronchial glands.
Function MUC2 mucin form gel layer which covers the intestinal mucosa, protect the mucosal surface, and plays a role of lubricant particularly at the large intestine. MUC2 also has a function as a tumor suppressor. MUC2 knockout mice frequently develop tumors in the small intestine, colon and rectum where MUC2 is predominantly expressed in the normal condition (Velcich et al., 2002). Alteration in protection and lubrication of the intestinal mucosal surface by the lack of MUC2 might induce an increase of bacterial flora carrying pro-carcinogenic effect, or might result in release of intestinal mucosa-derived factors which are normally depressed by MUC2 stimulating pro-carcinogenic factors, or might lead to destruction of a physical barrier of MUC2 to dietary carcinogens. Loss of MUC2 might compromise the signaling which contributes to the epithelial differentiation and proliferation through the contacts with membrane-bound mucins, or might alterate in the differentiation program of the intestinal mucosa resulting in the increased probability of tumor formation. High levels of MUC2 expression in indolent human pancreatobiliary neoplasms with a favorable prognosis (Osako et al., 1993; Yamashita et al., 1993; Yonezawa et al., 1997b; Yonezawa et al., 1997a; Yonezawa et al., 2008a) might be related with tumor suppressor activity by MUC2.
Homology The human gel-forming mucins, MUC5AC, MUC5B and MUC6, whose genes are located on chromosome 11p15.5 like MUC2, show homology with MUC2. MUC19, whose gene is located on chromosome 12q12, also has homology with MUC2. N-terminal and C-terminal regions of MUC5AC and MUC5B are same as those of MUC2, and are highly similar to those of vWF, in their D, B, C and CK domains which are observed in vWF. N-terminal regions of MUC6 and MUC19 are also same as that of MUC2, but the C-terminal region of MUC6 has only CK domain, and that of MUC19 has C and CK domains.

Implicated in

Note
  
Entity Pancreatic neoplasms
Disease MUC2 shows unique expression profiles related with MUC1 as follows, in our serial IHC studies. Pancreatic ductal adenocarcinoma (PDAC) with aggressive biological behavior and poor outcome usually showed expression of MUC1 (pan-epithelial type membrane-associated mucin) but no expression of MUC2 (Osako et al., 1993). In contrast, intraductal papillary mucinous neoplasm (IPMN) with indolent biological behavior showed no expression of MUC1, and are divided into subtypes by MUC2 expression as well as the morphological appearances, i.e., IPMN-intestinal type with MUC2 expression and IPMN-gastric type without MUC2 expression (Yonezawa et al., 1999; Nakamura et al., 2002; Horinouchi et al., 2003). The IPMN-intestinal type shows sometimes malignant transformation with MUC1 expression in the cancerous tissue, resulting in poor outcome (Yonezawa et al., 1998; Nakamura et al., 2002). In contrast, the IPMN-gastric type shows rare malignant transformation (Nakamura et al., 2002; Horinouchi et al., 2003). MUC2 expression is very useful to differentiate the IPMN-intestinal type from precursor lesions of PDACs, pancreatic intraepithelial neoplasms (PanINs) which never express MUC2 (Nagata K et al., 2007; Yonezawa et al., 2008b; Yonezawa et al., 2009).
  
  
Entity Biliary neoplasms
Disease Also in bile duct neoplasms, similar phenomena are observed in our series of IHC studies for mucin expression in various bile duct neoplasms have demonstrated that the expression of MUC1 is related to invasive proliferation of tumors and/or a poor outcome for patients. On the other hand, the expression of MUC2 is related to non-invasive proliferation of tumors and/or a favorable outcome for patients (Yamashita et al., 1993; Kitamura et al., 1996; Higashi et al., 1999; Tamada et al., 2002; Yonezawa et al., 2002; Shibahara et al., 2004; Yonezawa et al., 2008a; Yonezawa et al., 2008b; Yonezawa et al., 2009).
  
  
Entity Gastric carcinoma
Disease Combined evaluation of MUC1 and MUC2 expression in gastric cancer demonstrated that the patients with gastric adenocarcinomas carrying MUC1+/MUC2- pattern showed the worst outcome, whereas those carrying MUC1-/MUC2+ pattern showed the best outcome (Utsunomiya et al., 1998).
  
  
Entity Colorectal neoplasm
Disease In colorectal neoplasms, increased MUC1 expression and reduced MUC2 expression are related to adenomas with high grade atypia or malignant transformation (Ajioka et al., 1997; Li et al., 2001).
In gastrointestinal tract, MUC2 expression shows interesting contrasts with MUC5AC (gastric type secreted mucin). In the gastric mucosa with intestinal metaplasia, the area of intestinal metaplasia is MUC2 positive but MUC5AC negative, whereas the normal gastric mucosa is MUC2 negative but MUC5AC positive. Gastric and colorectal neoplasms are also classified as intestinal type (MUC2+/MUC5AC-), gastric type (MUC2-/MUC5AC+) and their mixed type, according to the mucin expression patterns (Yao et al., 2001; Tsukashita et al., 2001).
  
  
Entity Mucinous carcinomas of the colon, pancreas, breast and ovary
Disease In ovarian tumors, colon adenocarcinomas metastatic to ovary show MUC2+/MUC5AC- pattern, whereas many of primary ovarian mucinous cystadenocarcinomas show MUC2+/MUC5AC+ pattern. From these findings, combined evaluation of MUC2 and MUC5AC may be useful in the distinction between them (Albarracin et al., 2000).
On the other view points, overexpression or ectopic expression of MUC2 is the common phenomenon to mucinous carcinomas of the colon, pancreas, breast and ovary, indicating a common genetic lesion associated with the mucinous tumor phenotype (Tashiro et al., 1994; Yonezawa et al., 1995; Hanski et al., 1997a; Matsukita et al., 2003).
  
  
Entity Cystic fibrosis
Disease In cystic fibrosis (CF), which is a genetic disorder associated with defects of cystic fibrosis transmembrane conductance regulator (CFTR) gene, and the plugging of the ducts of exocrine glands by viscid mucin is a major manifestation, MUC2 gene is expressed at 3 to 4 higher levels in CF nasal mucosa than in non-CF nasal tissue (Li et al., 1997).
Prognosis Generally, expression of MUC2 is related to non-invasive proliferation of tumors and/or a favorable prognosis for the patients, whereas expression of MUC1 is related to invasive proliferation of tumors and/or a poor outcome for the patients (Osako et al., 1993; Yamashita et al., 1993; Kitamura et al., 1996; Yonezawa et al., 1997b; Yonezawa et al., 1997a; Utsunomiya et al., 1998; Higashi et al., 1999; Tamada et al., 2002; Yonezawa et al., 2008a). But, in indolent pancreatobiliary neoplasms such as IPMN-intestinal type or mucin-producing bile duct tumor (MPBT)-columnar type with MUC2 expression show sometimes invasive proliferation with aberrant MUC1 expression and show poorer prognosis compared with the other indolent panceratobiliary neoplasms such as IPMN-gastric type or MPBT-cuboidal type with no or low MUC2 expression (Nakamura et al., 2002; Horinouchi et al., 2003; Shibahara et al., 2004).
  

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Citation

This paper should be referenced as such :
Yonezawa, S ; Yamada, N ; Yokoyama, S ; Kitamoto, S ; Higashi, M ; Goto, M
MUC2 (mucin 2, oligomeric mucus/gel-forming)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):827-833.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MUC2ID41457ch11p15.html


External links

Nomenclature
HGNC (Hugo)MUC2   7512
Cards
AtlasMUC2ID41457ch11p15
Entrez_Gene (NCBI)MUC2  4583  mucin 2, oligomeric mucus/gel-forming
AliasesMLP; MUC-2; SMUC
GeneCards (Weizmann)MUC2
Ensembl hg19 (Hinxton) [Gene_View]
Ensembl hg38 (Hinxton) [Gene_View]  chr11:1074875-1110508 [Contig_View]  MUC2 [Vega]
TCGA cBioPortalMUC2
AceView (NCBI)MUC2
Genatlas (Paris)MUC2
WikiGenes4583
SOURCE (Princeton)MUC2
Genetics Home Reference (NIH)MUC2
Genomic and cartography
GoldenPath hg38 (UCSC)MUC2  -     chr11:1074875-1110508 +  11p15.5   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MUC2  -     11p15.5   [Description]    (hg19-Feb_2009)
EnsemblMUC2 - 11p15.5 [CytoView hg19]  MUC2 - 11p15.5 [CytoView hg38]
Mapping of homologs : NCBIMUC2 [Mapview hg19]  MUC2 [Mapview hg38]
OMIM158370   
Gene and transcription
Genbank (Entrez)AA527400 AF257167 AW054915 BG982960 BQ340542
RefSeq transcript (Entrez)NM_002457
RefSeq genomic (Entrez)NC_000011 NC_018922 NG_051929 NT_187681 NW_015148966
Consensus coding sequences : CCDS (NCBI)MUC2
Cluster EST : UnigeneHs.315 [ NCBI ]
CGAP (NCI)Hs.315
Gene ExpressionMUC2 [ NCBI-GEO ]   MUC2 [ EBI - ARRAY_EXPRESS ]   MUC2 [ SEEK ]   MUC2 [ MEM ]
Gene Expression Viewer (FireBrowse)MUC2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4583
GTEX Portal (Tissue expression)MUC2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ02817   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ02817  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ02817
Splice isoforms : SwissVarQ02817
PhosPhoSitePlusQ02817
Domaine pattern : Prosite (Expaxy)CTCK_1 (PS01185)    CTCK_2 (PS01225)    VWFC_1 (PS01208)    VWFC_2 (PS50184)    VWFD (PS51233)   
Domains : Interpro (EBI)Cys_knot_C    MUC2    TIL_dom    Unchr_dom_Cys-rich    VWF_dom    VWF_type-D    WxxW_domain   
Domain families : Pfam (Sanger)C8 (PF08742)    Mucin2_WxxW (PF13330)    TIL (PF01826)    VWD (PF00094)   
Domain families : Pfam (NCBI)pfam08742    pfam13330    pfam01826    pfam00094   
Domain families : Smart (EMBL)C8 (SM00832)  CT (SM00041)  VWC (SM00214)  VWC_out (SM00215)  VWD (SM00216)  
Conserved Domain (NCBI)MUC2
DMDM Disease mutations4583
Blocks (Seattle)MUC2
SuperfamilyQ02817
Peptide AtlasQ02817
HPRD11828
IPIIPI00027201   IPI00383269   IPI00383420   IPI00513909   IPI00936133   IPI00921608   
Protein Interaction databases
DIP (DOE-UCLA)Q02817
IntAct (EBI)Q02817
BioGRIDMUC2
STRING (EMBL)MUC2
ZODIACMUC2
Ontologies - Pathways
QuickGOQ02817
Ontology : AmiGOstimulatory C-type lectin receptor signaling pathway  protein binding  Golgi lumen  plasma membrane  O-glycan processing  maintenance of gastrointestinal epithelium  inner mucus layer  outer mucus layer  
Ontology : EGO-EBIstimulatory C-type lectin receptor signaling pathway  protein binding  Golgi lumen  plasma membrane  O-glycan processing  maintenance of gastrointestinal epithelium  inner mucus layer  outer mucus layer  
Pathways : BIOCARTATrefoil Factors Initiate Mucosal Healing [Genes]   
Pathways : KEGGVibrio cholerae infection    Amoebiasis   
REACTOMEQ02817 [protein]
REACTOME PathwaysR-HSA-977068 [pathway]   
NDEx NetworkMUC2
Atlas of Cancer Signalling NetworkMUC2
Wikipedia pathwaysMUC2
Orthology - Evolution
OrthoDB4583
Phylogenetic Trees/Animal Genes : TreeFamMUC2
HOVERGENQ02817
HOGENOMQ02817
Homologs : HomoloGeneMUC2
Homology/Alignments : Family Browser (UCSC)MUC2
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMUC2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MUC2
dbVarMUC2
ClinVarMUC2
1000_GenomesMUC2 
Exome Variant ServerMUC2
ExAC (Exome Aggregation Consortium)
Genetic variants : HAPMAP4583
Genomic Variants (DGV)MUC2 [DGVbeta]
DECIPHERMUC2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMUC2 
Mutations
ICGC Data PortalMUC2 
TCGA Data PortalMUC2 
Broad Tumor PortalMUC2
OASIS PortalMUC2 [ Somatic mutations - Copy number]
Mutations and Diseases : HGMDMUC2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MUC2
DgiDB (Drug Gene Interaction Database)MUC2
DoCM (Curated mutations)MUC2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MUC2 (select a term)
intoGenMUC2
NCG5 (London)MUC2
Cancer3DMUC2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM158370   
Orphanet
MedgenMUC2
Genetic Testing Registry MUC2
NextProtQ02817 [Medical]
TSGene4583
GENETestsMUC2
Target ValidationMUC2
Huge Navigator MUC2 [HugePedia]
snp3D : Map Gene to Disease4583
BioCentury BCIQMUC2
ClinGenMUC2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4583
Chemical/Pharm GKB GenePA31316
Clinical trialMUC2
Miscellaneous
canSAR (ICR)MUC2 (select the gene name)
Probes
Litterature
PubMed155 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMUC2
EVEXMUC2
GoPubMedMUC2
iHOPMUC2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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