MUC13 (mucin 13, cell surface associated)

2010-01-01   Diane Maher , Brij Gupta , Mara Ebeling , Satoshi Nagata , Meena Jaggi , Subhash C Chauhan 

Identity

HGNC
LOCATION
3q21.2
LOCUSID
ALIAS
DRCC1,MUC-13
FUSION GENES

DNA/RNA

Atlas Image
Schematic diagram of the genomic MUC13 DNA (including neighboring genes) and the transcript of MUC13. MUC13 is located on chromosome 3 between ITGB5 and HEG-1. These 3 genes are transcribed from the reverse strand. The MUC13 transcript contains 12 exons and the final mRNA consists of 2,876 base pairs (figure modified from Ensembl).

Description

Human MUC13 was originally identified as a ortholog of the previously identified murine MUC13 (Williams et al., 2001). Based on fluorescence in situ hybridization, MUC13 was originally identified at location 3q13.3 (Williams et al., 2001); however, MUC13 is now reported to be located on chromosome 3; location 3q21.2, MUC13 is flanked by ITGB5 (beta 5 integrin) and HEG-1 (Heart of Glass), each transcribed from the reverse strand. Interestingly, HEG and MUC13 share some molecular features, suggesting they may be evolutionarily related (Lang et al., 2006).

Transcription

The predominate MUC13 transcript (exact match between Ensembl and Havana) contains 12 exons and encodes 511 amino acids. Splice variants have been detected and may alter the length of the tandem repeat domain (Lang et al., 2006); however they have not been well studied for MUC13.

Proteins

Note

Members of the mucin family are characterized by a hallmark feature: the presence of a tandem repeat domain, consisting of a protein backbone which acts as a scaffold for a large number of complex O-linked carbohydrate side chains (Williams et al., 2001). In general, mucins have important biological roles in the lubrication and protection of normal epithelial tissues. In normal tissue, mucins are expressed in a tissue type dependent manner; however, for many types of cancer, mucin expression becomes altered (down-regulated, up-regulated or newly expressed). The mucins ectodomain may protrude more than 200-2000 nm above the cell surface and can effectively block cell-cell adhesion. Therefore, the over-expression of mucins may be implicated in the exfoliation, dissemination and invasion of the cancer cells (Hollingsworth and Swanson, 2004).
Atlas Image
Schematic diagram and annotated amino acid sequence of MUC13. Left: a schematic diagram shows the structural features of MUC13, highlighting the signal peptide, mucin repeat domain, SEA module, EGF-like domains, transmembrane region and the cytoplasmic domain. Right: The annotated amino acid sequence shows the extensive post-translation modifications that MUC13 undergoes (O-glycosylation, N-glycosylation and predicted disulfide bonds). The signal peptide, SEA module and Transmembrane sequences are indicated by pink, red and green font, respectively.

Description

MUC13 is a recently identified membrane bound mucin (Williams et al., 2001). At the N-terminus, a signal peptide shuttles the protein into the secretary pathway. The signal peptide is followed by a large serine-threonine rich tandem repeat domain (TD). Composed of 10 degenerate tandem repeats, the tandem repeat domain provides a scaffold on which cells build oligosaccharide structures. O-glycosylation with complex oligosaccharides is crucial to mucin structure and function. The central region of MUC13 contains three epidermal growth factor (EGF)-like domains (EGF1, EGF2 and EGF3), suggesting that MUC13 may play an important role in a signaling cascade. A sea urchin sperm protein enterokinase arginine (SEA) module is present between EGF1 and EGF2 like domains, providing a cleavage site which separates MUC13 into an extracellular a subunit and a transmembrane beta subunit. It is expected that the SEA domain is cleaved while in transport to the cell surface and that after cleavage, the alpha and beta subunits are covalently bound together. Adjacent to the EGF3-like domain is a short transmembrane domain (TM), followed by a 69 amino acid long cytoplasmic domain (CD) (Williams et al., 2001; Shimamura et al., 2005). Within the cytoplasmic domain of MUC13, there are several potential phosphorylation sites (8 serine and 2 tyrosine residues) and a protein kinase C consensus phosphorylation motif, further supporting the hypothesis that MUC13 may be involved in cell signaling pathways.

Expression

Among normal tissues, MUC13 mRNA and/or protein has been detected in the large intestine, trachea, kidney, small intestine, gastric epithelium and esophagus (Williams et al., 2001). MUC13 is normally localized to the apical surface of epithelial cells lining the mucosal surface. In ovarian, gastric and colon cancers, MUC13 expression (determined by immunohistochemical analysis) is increased compared to expression levels of non-neoplastic tissues (Shimamura et al., 2005; Walsh et al., 2007; Chauhan et al., 2009).

Localisation

MUC13 is a transmembrane glycoprotein present at the apical surface in normal cells. In cancer cells, MUC13 is over-expressed and aberrantly located in the cytoplasm and occasionally in the nucleus (Williams et al., 2001; Chauhan et al., unpublished data).

Function

Under normal physiological conditions, mucins, including MUC13, protect the epithelial surface of mucosal surfaces (gastrointestinal tract, respiratory tract and reproductive tract). Mucins create a physical barrier from the extracellular environment and protect epithelial tissues from noxious and toxic substances. When aberrantly expressed, MUC13 has oncogenic functions which are described below.

Homology

MUC13 is known to have orthologs in mice, rats, chickens, dogs, cows, chimpanzees and even fish (Williams et al., 2001; Lang et al., 2006; NCBI: homologene). Additional putative orthologs are likely in a variety of different species and can be viewed via Ensembl.

Mutations

Note

While a variety of Single Nucleotide Polymorphisms (SNPs) have been identified, the clinical significance has not yet been determined (NCBI: SNPs).

Implicated in

Entity name
Ovarian cancer
Disease
Ovarian cancer is the most lethal gynecological cancer and the fifth most common cause of cancer mortality in women in the United States (Jemal et al., 2009). In 2009, it is estimated that 21550 women will be diagnosed with ovarian cancer and 14600 women will die due to this disease (Jemal et al., 2009). A high percent of women with ovarian cancer are diagnosed at an advanced stage (67%) and have a 5 year survival rate of only 46% (Jemal et al., 2009).
Oncogenesis
In a recently published report, we analyzed the expression profile and functions of MUC13 to elucidate its potential role in ovarian cancer diagnosis and pathogenesis. We determined the expression profile of MUC13 by immunohistochemistry, using ovarian cancer tissue microarrays and 56 additional epithelial ovarian cancer (EOC) samples. The expression of MUC13 was significantly (p
Entity name
Colon cancer
Disease
Colon cancer is the third leading cause of cancer related deaths among men and women worldwide, with an estimated 639000 deaths in 2004 (WHO, 2009). In the United States in 2009, approximately 106000 people were diagnosed with colon cancer and 49900 people died, making colon cancer the second leading cause of deaths among all cancers (Jemal et al., 2009). Colon cancer has an overall survival rate of 49%, which is drastically dependent on the stage of diagnosis (Jemal, et al., 2009). For example, if colon cancer is detected in an early stage, prior to metastasis, survival is 90%; however, if colon cancer is not treated until an advanced stage (with metastasis to distant organs), survival decreases to approximately 10% (Jemal et al., 2009).
Oncogenesis
Walsh et al studied the expression of MUC13 in various stages of colon cancer (99 samples) (Walsh et al., 2007). Using immunohistochemical analysis, MUC13 was detected predominantly on the apical surface, with some cytoplasmic staining, of glands in normal colon. Scoring of the normal tissue was not done for this study, so it is difficult to state a comparison of MUC13 staining between normal and cancer cells. However, MUC13 was highly expressed in most of the colon tumors, with 81% of well differentiated adenocarcinomas exhibiting strong MUC13 staining. Interestingly, although the significance is not yet known, this study also found that tumors originating from the left side of the patients body had a higher proportion of MUC13-positive cancer cells. Mucinous tumors expressed MUC13, but at a lower staining intensity (50% indicating strong staining) compared to adenocarcinomas. While MUC13 was most intense on the apical surface, it was also detected in the cytoplasm. Basolateral staining was detected in 24% of the cases, most frequently in poorly differentiated tumors (55% of poorly differentiated tumors showed basolateral staining). Although not statistically significant, there was a trend toward poorer survival in patients with tumors showing basolateral MUC13 expression. Taken together, these observations suggest aberrant expression of MUC13 may affect colon cancer pathogenesis. In contrast to these results, Packer et al reported that the RNA level of MUC13 was decreased in colon cancer; however this was a small study with only 23 samples of colon cancer and 6 normal colon tissues (Packer et al., 2004). In our own studies, we have observed the over-expression of MUC13 in colon and pancreatic cancer compared to normal colon and pancreas (unpublished data). Taken together, these data suggest that MUC13 may be a potential diagnostic/prognostic biomarker for colon, pancreatic and ovarian cancers. Additionally, due to its cell surface expression, MUC13 may be a suitable target for antibody guided therapy for cancer treatment.
Entity name
Gastric cancer
Disease
Gastric cancer is the second most common cause of cancer related deaths worldwide, accounting for approximately 803000 deaths each year (WHO, 2009). In the United States, 21130 people were diagnosed with gastric cancer and 10620 died due to gastric cancer (Jemal et al., 2009). When diagnosed with localized gastric cancer, the survival rate is approximately 60%; however, if gastric cancer has metastasized to distant sites, the survival rate is very low (4%) (Jemal et al., 2009).
Oncogenesis
Shimamura et al detected an increased expression of MUC13 at both mRNA and protein levels (Shimamura et al., 2005). In normal tissue, MUC13 protein was detected at the luminal surface of crypts in both the small and large intestines, but not in normal gastric tissues. However, MUC13 staining in gastric cancer tissue was positive in 64.9% of cases and the cellular localization of MUC13 was dependent upon the histological type of gastric cancer. MUC13 was also detected in 9 out of 10 cases of intestinal metaplasia (precancerous lesions of intestinal type gastric cancer). When correlated with clinicopathological factors, MUC13 expression only correlated significantly with intestinal types of gastric cancer. MUC13 expression did not correlate with the expression of other mucins (MUC2, MUC5AC, MUC6 and CD10), suggesting that MUC13 may be regulated in a different manner then other mucins markers for gastric cancer (Shimamura et al., 2005).

Bibliography

Pubmed IDLast YearTitleAuthors
191763982009Expression and functions of transmembrane mucin MUC13 in ovarian cancer.Chauhan SC et al
146816892004Mucins in cancer: protection and control of the cell surface.Hollingsworth MA et al
194743852009Cancer statistics, 2009.Jemal A et al
168870382006An inventory of mucin genes in the chicken genome shows that the mucin domain of Muc13 is encoded by multiple exons and that ovomucin is part of a locus of related gel-forming mucins.Lang T et al
153755642004Expression of the cell surface mucin gene family in adenocarcinomas.Packer LM et al
159044672005Overexpression of MUC13 is associated with intestinal-type gastric cancer.Shimamura T et al
173600252007The MUC13 cell surface mucin is highly expressed by human colorectal carcinomas.Walsh MD et al
112784392001Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells.Williams SJ et al

Other Information

Locus ID:

NCBI: 56667
MIM: 612181
HGNC: 7511
Ensembl: ENSG00000173702

Variants:

dbSNP: 56667
ClinVar: 56667
TCGA: ENSG00000173702
COSMIC: MUC13

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000173702ENST00000478191C9IZG1
ENSG00000173702ENST00000616727Q9H3R2

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
O-linked glycosylationREACTOMER-HSA-5173105
O-linked glycosylation of mucinsREACTOMER-HSA-913709
Termination of O-glycan biosynthesisREACTOMER-HSA-977068
DiseaseREACTOMER-HSA-1643685
Diseases of glycosylationREACTOMER-HSA-3781865
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
C-type lectin receptors (CLRs)REACTOMER-HSA-5621481
Dectin-2 familyREACTOMER-HSA-5621480
Diseases associated with O-glycosylation of proteinsREACTOMER-HSA-3906995
Defective C1GALT1C1 causes Tn polyagglutination syndrome (TNPS)REACTOMER-HSA-5083632
Defective GALNT3 causes familial hyperphosphatemic tumoral calcinosis (HFTC)REACTOMER-HSA-5083625
Defective GALNT12 causes colorectal cancer 1 (CRCS1)REACTOMER-HSA-5083636

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
170580672006Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease.46
191763982009Expression and functions of transmembrane mucin MUC13 in ovarian cancer.44
252771922014MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer.44
220276892012MUC13 mucin augments pancreatic tumorigenesis.38
214509062011Mucin 13: structure, function, and potential roles in cancer pathogenesis.27
159044672005Overexpression of MUC13 is associated with intestinal-type gastric cancer.24
229146482012Increased expression and aberrant localization of mucin 13 in metastatic colon cancer.17
237080572013The mucin-type glycosylating enzyme polypeptide N-acetylgalactosaminyltransferase 14 promotes the migration of ovarian cancer by modifying mucin 13.16
241140562013Overexpression of membrane proteins in primary and metastatic gastrointestinal neuroendocrine tumors.11
252613232015Nasopharyngeal gene expression, a novel approach to study the course of respiratory syncytial virus infection.11

Citation

Diane Maher ; Brij Gupta ; Mara Ebeling ; Satoshi Nagata ; Meena Jaggi ; Subhash C Chauhan

MUC13 (mucin 13, cell surface associated)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/41454/muc13