CD248 (CD248 molecule, endosialin)

2008-12-01   Renate Becker , Hellmut G Augustin 

Department Vascular Oncology, Metastasis Research, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

Identity

HGNC
LOCATION
11q13.2
LOCUSID
ALIAS
CD164L1,TEM1
FUSION GENES

DNA/RNA

Atlas Image
The endosialin gene is localized on the q arm of chromosome 11. The single-exon gene is transcribed from the minus strand (modified from Entrez Gene).

Description

Endosialin was identified to be transcribed from a 2557 bp single-exon gene localized on chromosome 11q13 (Rettig et al., 1992; Christian et al., 2001), a region containing genes for a number of cell surface antigens (Rettig et al., 1992; Rettig and Old, 1989).

Transcription

The 2580 bp mRNA of Endosialin consist of a 17 bp 5 UTR, an ORF of 2274 bp (AF279142), and a 289 bp 3 UTR (Christian et al., 2001).

Pseudogene

No.

Proteins

Note

Although Endosialin was originally described as tumor endothelial marker (Rettig et al., 1992; Seaman et al., 2007; St Croix et al., 2000), it turned out that Endosialin is a marker for activated mesenchymal cells, including myofibroblasts, pericytes and smooth muscle cells (SMC) (MacFadyen et al., 2005; Christian et al., 2008).
Atlas Image
Structure of Endosialin and its homologues Thrombomodulin and C1qRp.
A: The extracellular domain of Endosialin consists of a signal sequence (orange triangle), a C-lectin like domain (dark green octagon), a Sushi/CCP/scr domain (grey circle), 3 EGF-like domains (red circles), and a negatively charged, O-glycosylated mucin-like domain (light green rectangle). The single transmembrane domain (blue cylinder) is followed by a short cytoplasmic tail (yellow cylinder).
B: The globular domains of Endosialin are homologue to thrombomodulin, containing 6 EGF repeats and the complement receptor C1qRp, demonstrating 5 EGF repeats.

Description

Endosialin is a 757 amino acid (aa) type I C-type lectin-like transmembrane protein (Christian et al., 2001). The core protein has a molecular weight of 95 kDa (Rettig et al., 1992; Christian et al., 2001). The distinct extracellular domain (aa 1-685) consists of a signal leader peptide (aa 1-20) and 5 globular domains followed by a mucin-like region (Figure A) (Christian et al., 2001). The single hydrophobic transmembrane domain spans the aa 686-706, followed by a short intracellular domain of 50 aa (aa 707-757). The 5 globular domains are well defined as C-type lectin-like domain (aa 20-157), a Sushi/CCP/scr like domain (aa 176-230) and 3 EGF repeats (aa 235-271, aa 274-311, aa 316-350). The EGF repeats 2 and 3 are predicted to have a Ca2+ binding function. In contrast, in the C-terminal part (aa 360-757) specific binding sites or catalytic domains were not identified (Christian et al., 2001; Carson-Walter et al., 2001). The glycosylation and sialic acid modification of more than 30 possible O-glycosylation sites, but only N-glycosylation Asn-Xaa-(Ser/Thr) consensus sequence on Asn-628 results in a shift of the molecular weight from 95 kDa to 165 kDa (Rettig et al., 1992; Christian et al., 2001). Additionally, a 120 kDa asialo form of Endosialin was identified (Rettig et al., 1992; Christian et al., 2001). A ~150 kDa form of Endosialin was detectable in the LA1-5s neuroblastoma cell supernatant (Rettig et al., 1992; Christian et al., 2001).

Expression

Endosialin is expressed in the majority of human carcinomas, sarcomas and neuroectodermal tumors (Rettig et al., 1992; St Croix et al., 2000; Brady et al., 2004; Huber et al., 2006; Madden et al., 2004; Davies et al., 2004; Rmali et al., 2005; Christian et al., 2008) as well as during physiological processes, such as corpus luteum formation and wound healing (Carson-Walter et al., 2001; St Croix et al., 2000). In contrast, Endosialin is not or weakly expressed in the mesenchymal compartment of corresponding normal human tissues (MacFadyen et al., 2007; MacFadyen et al., 2005; Carson-Walter et al., 2001). Endosialin-positive cells in the tumors were identified as myofibroblasts, tumor vessel-associated pericytes and smooth muscle cells (MacFadyen et al., 2005; Huber et al., 2006; Christian et al., 2008; MacFadyen et al., 2007; Bagley et al., 2008a; Virgintino et al., 2007; Simonavicius et al., 2008), although Endosialin was described as tumor endothelial marker (Rettig et al., 1992; St Croix et al., 2000). In addition, recent publications identified Endosialin expressing CD45+ VE-cadherin+ CD146+ CD34+ CD31+ TEM1+ Tem7+ vascular leukocytes (VLC) (Conejo-Garcia et al., 2005), as well as Endosialin-positive VEGFR 2+ CD31+ CD45- VE-cadherin+ endothelial precursor cells (EPC) (Bagley et al., 2008b). During neovascularization of the human fetal telencephalon, Endosialin is expressed by vessel-associated pericytes (Virgintino et al., 2007).
In vitro, Endosialin is expressed by fibroblasts, pericytes, smooth muscle cells and preadipocytes (Christian et al., 2008). Some neuroblastoma cell lines including LA1-5s, IMR-32 and SMS-SAN express Endosialin (Rettig et al., 1992).
The mouse homologue of Endosialin is strongly and heterogeneously expressed in almost all tissues during embryonic development (Opavsky et al., 2001; Rupp et al., 2006; MacFadyen et al., 2007). The expression is decreased in new-born mice and almost undetectable in tissues of adult mice (Carson-Walter et al., 2001; MacFadyen et al., 2007; Lax et al., 2007; Rupp et al., 2006).

Localisation

Endosialin is localized on the cell surface (Christian et al., 2001; Christian et al., 2008; MacFadyen et al., 2005). Some staining of the Golgi can also be observed, since Endosialin is a Typ-I transmembrane protein (MacFadyen et al., 2005).

Function

A role of Endosialin in tumor progression and metastasis was demonstrated by experiments with Endosialin knock-out mice. In abdominal xenograft transplantations, tumor volume and the incidence of distant metastases were significantly reduced in knock-out mice compared to wild type mice, resulting in an increased survival rate of Endosialin-deficient mice (Nanda et al., 2006). Nevertheless, the molecular function of Endosialin is far from being understood. Recent publications demonstrated a role of Endosialin in the proliferation and migration of myofibroblasts (Christian et al., 2008). The tube-formation and migration of Endosialin expressing pericytes could be blocked by anti-Endosialin antibodies (Bagley et al., 2008a). Additionally, Endosialin overexpressing CHO cells demonstrated increased adhesion to fibronectin, migration though Matrigel and MMP-9 activity (Tomkowicz et al., 2007).
It is not clarified yet, how these functions of Endosialin result in tumor progression and metastasis. However, these findings indicate a role of Endosialin in early angiogenic stages (Bagley et al., 2008b) and vessel maturation, as well as a function of Endosialin in tumor stroma formation and reorganization of the tumor stroma including tumor blood vessels in tissues where areas of stable blood supply are in close proximity to regions of necrosis, hypoxia and excessive growth (Christian et al., 2001). Interestingly, recent findings described the induction of Endosialin expression by hypoxia, mediated by HIF-2a (Ohradanova et al., 2008).
Additionally, Endosialin functions as receptor for extracellular matrix components (Tomkowicz et al., 2007) and tumor cell expressed ligands like Mac-2 Binding Protein. The Endosialin-Mac-2 Binding Protein interaction results in a decreased adhesion between tumor cells and the surrounding myofibroblasts (Becker et al., 2008). However, this mechanism is not analyzed in detail.

Homology

Whereas the C terminal part of human Endosialin (aa 361-757) showed no sequence homology to other proteins (Christian et al., 2001), the globular N-terminal extracellular part (aa 30-360) demonstrated 39% homology to thrombomodulin precursor protein and 33% homology to the complement receptor C1qRp (Figure B) (Christian et al., 2001). Although there is only moderate sequence identity, cysteine residues predicted to form disulfide bridges and a WIGL consensus motive found in endocytosis regulating proteins (Dean et al., 2000; Nepomuceno et al., 1997) localized in the C-type lectin-like domain are conserved in all three proteins.
Mouse Endosialin (mEn) shows 77.5% homology to human Endosialin (Opavsky et al., 2001; Carson-Walter et al., 2001). Like its human counterpart, mEn is a 765 aa type I transmembrane protein with a 17 aa signal peptide, a C-type lectin-like domain (aa 22-157), a Sushi domain (aa 164-230) and 3 EGF-like repeats (aa 234-272, aa 274-311 and aa 315-351), followed by a sialomucin-like region, a single membrane spanning domain (22 aa), and a 51 aa long cytoplasmatic tail. mEn is also transcribed from a single copy, intron-less gene, located on mouse chromosome 19, a region homologue to human chromosome region 11q. The 82 kDa core protein has multiple O- glycosylation sites in the extracellular domain but only one predicted N-glycosylation site on position aa 636, resulting in a glycosylated protein of 92 kDa. Whereas the mucine-like domain of mEn (aa 478-610) and human Endosialin are hardly conserved, the transmembrane domains are identical and only 4 aa are substituted in the cytoplasmatic tails (Carson-Walter et al., 2001; Opavsky et al., 2001). Additionally, possible phosphorylation and N-myristoylation sites as well as a PDZ binding sequence (Carson-Walter et al., 2001) were identified in the intracellular domain, indicating an evolutionary conserved function between mouse and human Endosialin.

Mutations

Note

In one publication, a single base pare substitution at bp 717 (aa 239) was detected (Brady et al., 2004). A resulting change in the function of Endosialin caused by this mutation has not been referred yet.

Implicated in

Entity name
Tumors
Disease
Endosialin is poorly detectable in normal tissues. In contrast, it is highly expressed in human carcinomas, sarcomas and neuroectodermal tumors (Rettig et al., 1992; Christian et al., 2008).
Entity name
Brain tumors
Disease
Endosialin expression was detected in 40% of analyzed benign meningioma (grade I) and less invasive grade II astrocytoma specimens, whereas Endosialin is undetectable in normal brain. In higher grade brain tumors Endosialin expression was detectable in 67% and 100% of grade III anaplastic astrocytoma and highly invasive glioblastoma multiforme specimens, respectively (Brady et al., 2004).
Prognosis
Endosialin expression correlates with high tumor grade and aggressive histological behavior in human brain tumors (Brady et al., 2004; Simonavicius et al., 2008).
Entity name
Breast carcinomas
Disease
Endosialin is significantly upregulated in breast carcinoma samples of patients with nodal involvement, as well as in specimens of patients with recurrent disease or death caused by breast cancer (Davies et al., 2004).
Entity name
Malignant melanoma
Disease
Endosialin expression was detectable in benign melanocytic nevi, cutaneous melanoma metastases, lymph node metastases, basal cell carcinomas and squamous cell carcinomas. Whereas Endosialin expression is restricted to scattered fibroblasts in the normal human skin, the Endosialin expression pattern is heterogeneous (reactive fibroblasts and vessel-like structures) in the different stages of malignant melanoma progression (Huber et al., 2006; Christian et al., 2008).

Bibliography

Pubmed IDLast YearTitleAuthors
187610222008Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization.Bagley RG et al
187234982008Human endothelial precursor cells express tumor endothelial marker 1/endosialin/CD248.Bagley RG et al
184903832008Tumor stroma marker endosialin (Tem1) is a binding partner of metastasis-related protein Mac-2 BP/90K.Becker R et al
156247642004Human endosialin (tumor endothelial marker 1) is abundantly expressed in highly malignant and invasive brain tumors.Brady J et al
115595282001Cell surface tumor endothelial markers are conserved in mice and humans.Carson-Walter EB et al
181875652008Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells.Christian S et al
153586282005Vascular leukocytes contribute to tumor vascularization.Conejo-Garcia JR et al
150656002004Levels of expression of endothelial markers specific to tumour-associated endothelial cells and their correlation with prognosis in patients with breast cancer.Davies G et al
109342102000Molecular and cellular properties of the rat AA4 antigen, a C-type lectin-like receptor with structural homology to thrombomodulin.Dean YD et al
164203102006Expression of stromal cell markers in distinct compartments of human skin cancers.Huber MA et al
176285492007CD248/Endosialin is dynamically expressed on a subset of stromal cells during lymphoid tissue development, splenic remodeling and repair.Lax S et al
169659412007Endosialin is expressed on stromal fibroblasts and CNS pericytes in mouse embryos and is downregulated during development.MacFadyen J et al
158622922005Endosialin (TEM1, CD248) is a marker of stromal fibroblasts and is not selectively expressed on tumour endothelium.MacFadyen JR et al
152772332004Vascular gene expression in nonneoplastic and malignant brain.Madden SL et al
164927582006Tumor endothelial marker 1 (Tem1) functions in the growth and progression of abdominal tumors.Nanda A et al
90472341997cDNA cloning and primary structure analysis of C1qR(P), the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro.Nepomuceno RR et al
188133102008Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2.Ohradanova A et al
114898952001Molecular characterization of the mouse Tem1/endosialin gene regulated by cell density in vitro and expressed in normal tissues in vivo.Opavsky R et al
14382851992Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer.Rettig WJ et al
26533741989Immunogenetics of human cell surface differentiation.Rettig WJ et al
157619642005Prognostic values of tumor endothelial markers in patients with colorectal cancer.Rmali KA et al
168754352006Mouse endosialin, a C-type lectin-like cell surface receptor: expression during embryonic development and induction in experimental cancer neoangiogenesis.Rupp C et al
175603352007Genes that distinguish physiological and pathological angiogenesis.Seaman S et al
181929702008Endosialin (CD248) is a marker of tumor-associated pericytes in high-grade glioma.Simonavicius N et al
109479882000Genes expressed in human tumor endothelium.St Croix B et al
179866152007Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration.Tomkowicz B et al
172259552007An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis.Virgintino D et al

Other Information

Locus ID:

NCBI: 57124
MIM: 606064
HGNC: 18219
Ensembl: ENSG00000174807

Variants:

dbSNP: 57124
ClinVar: 57124
TCGA: ENSG00000174807
COSMIC: CD248

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000174807ENST00000311330Q9HCU0

Expression (GTEx)

0
100
200
300
400
500
600

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
158622922005Endosialin (TEM1, CD248) is a marker of stromal fibroblasts and is not selectively expressed on tumour endothelium.56
181875652008Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells.56
179866152007Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration.50
181929702008Endosialin (CD248) is a marker of tumor-associated pericytes in high-grade glioma.36
204849762010Endosialin/TEM-1/CD248 regulates pericyte proliferation through PDGF receptor signaling.33
156247642004Human endosialin (tumor endothelial marker 1) is abundantly expressed in highly malignant and invasive brain tumors.30
187610222008Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization.25
184903832008Tumor stroma marker endosialin (Tem1) is a binding partner of metastasis-related protein Mac-2 BP/90K.22
188133102008Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2.21
214905892011CD248+ stromal cells are associated with progressive chronic kidney disease.20

Citation

Renate Becker ; Hellmut G Augustin

CD248 (CD248 molecule, endosialin)

Atlas Genet Cytogenet Oncol Haematol. 2008-12-01

Online version: http://atlasgeneticsoncology.org/gene/968/cd248