DMBT1 (Deleted in malignant brain tumors 1)

2007-08-01   Jan Mollenhauer , Annemarie Poustka 

Division of Molecular Genome Analysis, German Cancer Research Center, Im Neuenheimer, Feld 280, 69120 Heidelberg, Germany

Identity

HGNC
LOCATION
10q26.13
LOCUSID
ALIAS
GP340,SAG,SALSA,muclin
FUSION GENES

DNA/RNA

Atlas Image
Genomic organization of DMBT1. Top line: scale in kb. Second line: exon-intron structure of DMBT1 drawn to scale. Exons have the color code of the domains they are coding for. Exon 55 marked in black represents an exon with homology to the mouse and rat homologues, in which it codes for a transmembrane domain. Exon 55 has not yet been identified in a human transcript. Arrows depict regions, in which exon and intron sequences share high homologies. Bottom line: domain organization of the DMBT1 protein predicted from assembly of the first 54 exons. Entries to color codes and abbreviations are depicted in the section describing the protein.

Description

The gene consists of 55 exons distributed over about 80 kb. Scavenger receptor cysteine-rich (SRCR) domains are coded by single exons. Two small exons coding for serine-threonine-proline-rich stretches of 20-24 amino acids in length follow each SRCR exon. To these stretches it has been referred to as SRCR-interspersed domains (SIDs). The only exception is that there is only one of the two SID exons between SRCR4 and SRCR5.

Transcription

Longest transcript identified so far: 7656 bp including 5-utr, exons 1-16 and exons 18-54. Various alternative transcripts with variable numbers of SRCR and SID exons exist. Exon 55 has not yet been verified to be present in human transcripts.

Pseudogene

No pseudogene known so far.

Proteins

Atlas Image
Domain organization of DMBT1. Prototype: protein assembled from the first 54 exons (corresponding transcripts not yet identified). DMBT1/8kb.2: secreted DMBT1 variant encoded by the largest known transcript. DMBT1/6kb.1: secreted DMBT1 variant encoded by the smallest known transcript. Pink triangle: signal peptide putatively required for secretion; blue box repetitive motif of unknown function; red circles: scavenger receptor cysteine-rich (SRCR) domains; orange circles: SRCR-interspersed domains (SIDs); orange circles with TTT and STP: threonine- and serine-threonine-proline-rich domains with limited similarity to SIDs; CUB: C1r/C1s-Uegf-Bmp1 domains; ZP: zona pellucida domain.

Description

The largest known protein variant (DMBT1/8kb.2) comprises 2413 amino acids and has a calculated molecular weight of 265 kDa. Probably due to glycosylation the molecular weight of the purified protein is approximately 340 kDa. The smallest known variant (DMBT1/6kb.1), which lacks several SRCR domains and SIDs, comprises 1785 amino acids with a calculated molecular weight of 196 kDa. Various other protein variants lacking one or more SRCR domains may exist. The protein variants may arise due to genetic polymorphisms and/or alternative splicing.
The SRCR domains are involved in ligand interactions. An 11 amino acid motif (GRVEVLYRGSW) present in each of the repeated SRCR domains has been shown to be responsible for the binding of a broad spectrum of Gram-positive and Gram-negative bacteria. The N-terminal SRCR1/SD1 domain has been shown to interact with HIV gp120 and to suppress HIV infection. The functions of the CUB domains and of SRCR14, which shows only limited similarity to the other SRCR domains within DMBT1, have not yet been determined. In other proteins, ZP domains have been shown to function in oligomerization. DMBT1 is also secreted as high molecular weight oligomers.
SRCR, CUB, and ZP domains exclusively occur in multicellular animal organisms.

Expression

Main sites of DMBT1 expression are surface epithelial cells and associated glands, in particular in the respiratory and gastrointestinal tract. In most tissues low to moderate DMBT1 levels are expressed under normal conditions. An upregulation has been observed in response to various pathophysiological conditions, such as bacterial infection, inflammation, tumor-flanking tissues, carcinogen exposure, etc. Expression has also been noted in other tissues such as the brain and in immune cells.

Localisation

Extracellular. DMBT1 is either secreted to the mucus and other body fluids or to the extracellular matrix.

Function

DMBT1 exerts at least two distinct functions. As extracellular matrix protein, DMBT1 triggers polarity and terminal differentiation of epithelial cells as well as differentiation of embryonic stem cells to monolayered epithelia, which has been demonstrated by in vitro studies with rodent orthologs of DMBT1. DMBT1 secreted to the luminal side of epithelial surfaces plays a role in defense against bacterial and viral pathogens. This mechanism includes pathogen recognition through a peptide motif present in the SRCR domains and mediation of pathogen aggregation. DMBT1 further has been shown to exert anti-inflammatory effects. In response to activation of the intracellular pattern recognition molecule NOD2 and consecutive NFkB-activation, upregulation of DMBT1 takes place, which in turn hinders bacterial invasion and LPS-induced TLR4-activation. Hindrance of bacterial invasion may abolish NOD2 activation. Thus DMBT1 may act anti-inflammatory via inhibiting both NOD2- and TLR4-mediated NF-kB-activation. As DMBT1 is NF-kB responsive, this presumably builds up an autoregulatory homeostatic loop, by which DMBT1 is able to regulate its own expression as extracellular sensory element. These data point to a function in anti-inflammatory immune exclusion similar to mucosal antibodies (sIgA).

Homology

Homologies exist to other SRCR proteins such as CD5 and CD6, which function in immune defense. However, to date there is no SRCR protein known that additionally contains CUB and ZP domains. At the level of the SRCR domains, DMBT1 further shares some homologies with the sponge aggregation receptor (AR), which initiates the first steps in regeneration of a complete sponge body after dissociation.

Mutations

Germinal

Initial evidence has been gained that the SRCR- and SID-coding exons are subjected to copy number variations.

Somatic

Few point mutations have been identified in cancer so far. There is no hard evidence for an inactivation by biallelic mutation in cancer. Copy number variations of the SRCR- and SID-coding exons have been noted in different cancer types, including brain, lung, breast, gastrointestinal tumors and melanoma. It has not yet been determined to which extent these represent de novo rearrangements or germline mutations/polymorphisms. Underexpression has been observed for lung, colon, gastric, esophageal, breast, and skin cancer. By contrast overexpression was observed for pancreatic and prostate cancer.

Implicated in

Entity name
Cancer
Disease
Based on underexpression and on its role in triggering differentiation, a role in tumor suppression of different cancer types, mainly of epithelial origin, has been proposed. A genetic scan in mice identified DMBT1 as candidate genetic modifier, which may determine the penetrance of breast cancer in the presence of p53 mutations. Lower DMBT1 protein levels have been observed in the normal mammary gland epithelium of women, which developed breast cancer versus tissues obtained from healthy donors.
Entity name
Crohns Disease
Disease
Activation of DMBT1 was found to be impaired in the intestinal epithelium of Crohns disease with predisposing NOD2 mutations.
Entity name
Infection
Disease
Based on its broad bacterial binding specificity and inhibitory effects on bacterial and viral (HIV, influenza A viruses) infection in vitro, a role in infectious diseases has been proposed.
Entity name
Caries
Disease
DMBT1 alias SAG (salivary agglutinin) has been studied for about two decades as the major caries bacteria agglutinating non-immunoglobulin in the saliva/oral cavity. Based on its capacity to aggregate caries bacteria (e. g. Streptococcus mutans), it was proposed to exert functions in preventing caries. Based on its capacity to mediate bacterial adhesion to enamel-like surfaces, it was proposed to exert functions in promoting caries by other groups.

Bibliography

Pubmed IDLast YearTitleAuthors
145159852003Terminal differentiation of epithelia.Al-Awqati Q et al
153559852004Bacteria binding by DMBT1/SAG/gp-340 is confined to the VEVLXXXXW motif in its scavenger receptor cysteine-rich domains.Bikker FJ et al
123681922002Heterogeneity of ductular reactions in adult rat and human liver revealed by novel expression of deleted in malignant brain tumor 1.Bisgaard HC et al
175252702007Genetic mapping in mice identifies DMBT1 as a candidate modifier of mammary tumors and breast cancer risk.Blackburn AC et al
111522812000Processing of pro-Muclin and divergent trafficking of its products to zymogen granules and the apical plasma membrane of pancreatic acinar cells.De Lisle RC et al
128718542003Lung and salivary scavenger receptor glycoprotein-340 contribute to the host defense against influenza A viruses.Hartshorn KL et al
103642061999Only multimeric hensin located in the extracellular matrix can induce apical endocytosis and reverse the polarity of intercalated cells.Hikita C et al
111214382000Induction of terminal differentiation in epithelial cells requires polymerization of hensin by galectin 3.Hikita C et al
104859051999Cloning of gp-340, a putative opsonin receptor for lung surfactant protein D.Holmskov U et al
154777572004Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression.Hustinx SR et al
175620172007Innate immunity glycoprotein gp-340 variants may modulate human susceptibility to dental caries.Jonasson A et al
157609202005Induction of DMBT1 expression by reduced ERK activity during a gastric mucosa differentiation-like process and its association with human gastric cancer.Kang W et al
126814772003DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration?Kang W et al
164016392006Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene.Li Z et al
115639892001Human salivary agglutinin binds to lung surfactant protein-D and is identical with scavenger receptor protein gp-340.Ligtenberg TJ et al
97969771998Allelic deletion analyses of MMAC/PTEN and DMBT1 loci in gliomas: relationship to prognostic significance.Lin H et al
128843082003CRP-ductin, the mouse homologue of gp-340/deleted in malignant brain tumors 1 (DMBT1), binds gram-positive and gram-negative bacteria and interacts with lung surfactant protein D.Madsen J et al
147329202004Carcinogen inducibility in vivo and down-regulation of DMBT1 during breast carcinogenesis.Mollenhauer J et al
98884591999Lack of DMBT1 expression in oesophageal, gastric and colon cancers.Mori M et al
121855982002Rare mutations of the DMBT1 gene in human astrocytic gliomas.Mueller W et al
147391452004Inflammation of the cystic fibrosis mouse small intestine.Norkina O et al
126720332003Mutation analysis of DMBT1 in glioblastoma, medulloblastoma and oligodendroglial tumors.Pang JC et al
110077862000Salivary agglutinin, which binds Streptococcus mutans and Helicobacter pylori, is the lung scavenger receptor cysteine-rich protein gp-340.Prakobphol A et al
175486592007Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion.Rosenstiel P et al
149959122004The Scavenger Receptor Cysteine-Rich (SRCR) domain: an ancient and highly conserved protein module of the innate immune system.Sarrias MR et al
119121562002DMBT1 polymorphisms: relationship to malignant glioma tumorigenesis.Sasaki H et al
122087372002Peptidomics-based approach reveals the secretion of the 29-residue COOH-terminal fragment of the putative tumor suppressor protein DMBT1 from pancreatic adenocarcinoma cell lines.Sasaki K et al
145112522003Decrease of deleted in malignant brain tumour-1 (DMBT-1) expression is a crucial late event in intrahepatic cholangiocarcinoma.Sasaki M et al
97967061998Molecular analysis of two putative tumour suppressor genes, PTEN and DMBT, which have been implicated in glioblastoma multiforme disease progression.Somerville RP et al
105513161999Expression of the DMBT1 gene is frequently suppressed in human lung cancer.Takeshita H et al
154521492004Conversion of ES cells to columnar epithelia by hensin and to squamous epithelia by laminin.Takito J et al
104445831999Hensin, the polarity reversal protein, is encoded by DMBT1, a gene frequently deleted in malignant gliomas.Takito J et al
100853011999Hensin remodels the apical cytoskeleton and induces columnarization of intercalated epithelial cells: processes that resemble terminal differentiation.Vijayakumar S et al
159513322005Respiratory innate immune proteins differentially modulate the neutrophil respiratory burst response to influenza A virus.White MR et al
102134901999Expression of DMBT1, a candidate tumor suppressor gene, is frequently lost in lung cancer.Wu W et al
152425362004gp340 (SAG) binds to the V3 sequence of gp120 important for chemokine receptor interaction.Wu Z et al
167965262006The N-terminal SRCR-SID domain of gp-340 interacts with HIV type 1 gp120 sequences and inhibits viral infection.Wu Z et al
126894122003Salivary agglutinin inhibits HIV type 1 infectivity through interaction with viral glycoprotein 120.Wu Z et al

Other Information

Locus ID:

NCBI: 1755
MIM: 601969
HGNC: 2926
Ensembl: ENSG00000187908

Variants:

dbSNP: 1755
ClinVar: 1755
TCGA: ENSG00000187908
COSMIC: DMBT1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000187908ENST00000330163Q9UGM3
ENSG00000187908ENST00000338354Q9UGM3
ENSG00000187908ENST00000344338Q9UGM3
ENSG00000187908ENST00000368909Q9UGM3
ENSG00000187908ENST00000368955Q9UGM3
ENSG00000187908ENST00000368956Q9UGM3
ENSG00000187908ENST00000619379Q9UGM3
ENSG00000187908ENST00000652446Q9UGM3
ENSG00000187908ENST00000653442Q9UGM3
ENSG00000187908ENST00000656203A0A590UK99
ENSG00000187908ENST00000657942Q9UGM3
ENSG00000187908ENST00000664003A0A590UJF8
ENSG00000187908ENST00000664692Q9UGM3
ENSG00000187908ENST00000664974A0A590UJZ9
ENSG00000187908ENST00000666315A0A590UJ76
ENSG00000187908ENST00000668486A0A590UIX5

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90

Pathways

PathwaySourceExternal ID
Salivary secretionKEGGko04970
Salivary secretionKEGGhsa04970
Metabolism of proteinsREACTOMER-HSA-392499
Surfactant metabolismREACTOMER-HSA-5683826

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
163854512006A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.69
175486592007Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion.56
157310262005The StcE protease contributes to intimate adherence of enterohemorrhagic Escherichia coli O157:H7 to host cells.51
204182542010Review: Gp-340/DMBT1 in mucosal innate immunity.49
120501642002Identification of the bacteria-binding peptide domain on salivary agglutinin (gp-340/DMBT1), a member of the scavenger receptor cysteine-rich superfamily.45
220693082012A novel role for interleukin-27 (IL-27) as mediator of intestinal epithelial barrier protection mediated via differential signal transducer and activator of transcription (STAT) protein signaling and induction of antibacterial and anti-inflammatory proteins.44
177095272007gp340 expressed on human genital epithelia binds HIV-1 envelope protein and facilitates viral transmission.38
153559852004Bacteria binding by DMBT1/SAG/gp-340 is confined to the VEVLXXXXW motif in its scavenger receptor cysteine-rich domains.36
128718542003Lung and salivary scavenger receptor glycoprotein-340 contribute to the host defense against influenza A viruses.34
179838032007DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn's disease.31

Citation

Jan Mollenhauer ; Annemarie Poustka

DMBT1 (Deleted in malignant brain tumors 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-08-01

Online version: http://atlasgeneticsoncology.org/gene/309/dmbt1-(deleted-in-malignant-brain-tumors-1)