CD151 (CD151 molecule (Raph blood group))

2009-07-01 Judith Weidenhofer , Leonie K Ashman Affiliation

Medical Biochemistry, School of Biomedical Sciences, Pharmacy, University of Newcastle, NSW, Australia

Identity

HGNC

CD151

LOCATION

11p15.5

LOCUSID

977

ALIAS

GP27,MER2,PETA-3,RAPH,SFA1,TSPAN24

FUSION GENES

Show Gene Fusions

DNA/RNA

Note

Information sourced from UCSC Genome Database Mar 2006 Assembly (hg18) RefSeq genes and from analysis of mouse gene organisation (Fitter et al., 1998) and human gene structure (Whittock et al., 2001).

The red bars indicate utr and green bars indicate coding exons. The size of each intron is indicated at the top and each exon below. An alternate transcript may be generated from splicing out exon 2 in the 5utr as indicated with the blue lines.

Description

5884 bp, 9 exons (7 coding).

Transcription

mRNA 1574bp (length may vary for utr alternate splicing).

Pseudogene

None in humans.

Proteins

The red bars indicate transmembrane regions as predicted by TMHMM (Krogh et al., 2001), with the green circles palmitoylation sites (Berditchevski et al., 2002). The blue Y indicates an N-linked glycosylation site (Fitter et al., 1995) and the light blue lines indicate approximate sites of potential di-sulphide bridges (Seigneuret et al., 2001).

Description

Size: 253 aa, 28247 Da with a mature protein size of 32 kDa; pI: pH 7.44.
Post-translational modifications include disulphide bridges and an N-linked glycosylation site in the large extracellular loop and 6 palmitoylation sites.

Expression

Widely expressed, particularly on epithelial cells, endothelial cells, Schwann cells, muscle cells, megakaryocytes and platelets. Tissues typically display expression restricted to these cell types with lung, kidney, spleen, tonsil and cardiac muscle all having high levels. Low expression detected on fibroblasts, erythrocytes and leukocytes (Sincock et al., 1997).
Highly expressed (mRNA) in: heart, uterus, lung, prostate, liver (adult), spleen, placenta, pancreas.
Low/no expression (mRNA) in: foetal liver, brain, testes, ovaries.

Localisation

Plasma membrane, endosomes, endothelial cell junctions and hemidesmosomes in basal epithelial cells (Sincock et al., 1999; Sterk et al., 2000).

Function

CD151 is a major component of tetraspanin enriched microdomains, which are platforms for assembly of membrane signalling complexes (Hemler et al., 2005; Charrin et al., 2009). CD151 functions in signal transduction through forming direct complexes with integrins particularly alpha3beta1, alpha6beta1, alpha6beta4 and alphaIIbbeta3, thereby influencing a variety of cell functions including motility and adhesion which are outlined further below. CD151 also affects matrix metalloproteinase activity, with overexpression of CD151 in human melanoma cells resulting in increased expression of MMP9 (Hong et al., 2006). CD151 has been shown to interact with pro-matrix metalloptroteinase 7 in osteoarthritic cartilage and regulate its activity (Fujita et al., 2006). In endothelial cells CD151 associates with the matrix metalloproteinase MT1-MMP and regulates its collagenolytic activity (Yañez-Mó et al., 2008).

Homology

Tetraspanin protein family. This protein family has 33 members in humans and is well conserved throughout vertebrates and also present in invertebrates. Key characteristics include the presence of 4 transmembrane domains with both N- and C-terminals in the cytoplasm, conserved cysteine-containing motifs and disulphide bonds in the large extra cellular loop and charged residues in the transmembrane domains.

Mutations

Note

Only 3 mutations have been identified in humans to date, two (G533A and C511T), are predicted not to significantly alter CD151 function and are not associated with disease (Karamatic Crew et al., 2004; Karamatic Crew et al., 2008).

Germinal

Homozygous 1bp insertion, G383, resulting in a frameshift at Lys127 and a truncated protein at codon 140.
Homozygous G533A substitution resulting in an Arg178His mutation.
Homozygous C511T substitution resulting in an Arg171His mutation.

Implicated in

Note

In vitro studies
In vitro assays on Cd151-null keratinocytes, showed lack of migration compared to wild-type keratinocytes (Geary et al., 2008). Over-expression and knock-down studies of CD151 in various cell lines generally show that CD151 promotes migration and adhesion, however these finding are influenced by cell type and extracellular matrix components and primarily appear to be modified by the expression of the integrin alpha3beta1 (Berditchevski et al., 2002; Winterwood et al., 2006; Liu et al., 2007; Yang et al., 2008). CD151 is down-regulated by HIF-1alpha in colon cancer cells and is re-expressed upon normal oxygenation. This is proposed to allow detachment from the primary tumour and re-attachment at sites of metastasis (Chien et al., 2008).

Oncogenesis

Increased CD151 expression may lead to enhanced tumour progression and metastatic capacity based on enhanced motility, migration and adhesion of CD151 expressing cells. Antibodies to CD151 blocked in vivo metastasis in model systems (Testa et al., 1999; Zijlstra et al., 2008). Xenograft breast cancer models involving silencing of CD151 showed a delay in tumour formation (Yang et al., 2008). CD151 expression is increased in metastasis compared to primary tumour site in colon cancer (Chien et al. 2008).

Entity name

Prostate cancer

Note

Immunohistochemical detection of CD151 in a prostate cancer tissue specimens had greater prognostic value than Gleason grading (Ang et al., 2004).

Prognosis

High CD151 expression was indicative of poor outcome.

Oncogenesis

High CD151 expression indicated poor survival outcome, suggesting a role for CD151 in enhancing tumourigenesis or resistance to treatment. Also refer to In vitro studies.

Entity name

Gingival squamous cell carcinoma

Note

Real-time PCR analysis of CD151 gene expression compared to GAPDH was analysed (Hirano et al., 2009). Assessment of protein expression by immunohistochemistry correlated with gene expression however no statistical analyses were performed on protein expression.

Prognosis

High CD151 expression was indicative of poor outcome.

Oncogenesis

High CD151 expression indicated poor survival outcome, suggesting a role for CD151 in enhancing tumourigenesis or resistance to treatment. Also refer to In vitro studies.

Entity name

Colon cancer

Note

Real-time PCR analysis of CD151 gene expression compared to beta-actin was analysed (Hashida et al., 2003). Assessment of protein expression by immunohistochemistry correlated with gene expression however no statistical analyses were performed on protein expression.

Prognosis

High CD151 expression was indicative of poor outcome.

Oncogenesis

High CD151 expression indicated poor survival outcome, suggesting a role for CD151 in enhancing tumourigenesis or resistance to treatment. Also refer to In vitro studies.

Entity name

Hepatocellular carcinoma

Note

Real-time PCR analysis of CD151 gene expression compared to GAPDH was analysed. Assessment of protein expression by immunohistochemistry and immunoblotting generally correlated with gene expression. CD151 expression was increased in hepatocellular carcinomas compared to normal liver tissues (Ke et al., 2009).
Immunohistochemical analysis of tissue microarrays identified a positive correlation between CD151 expression and aggressive histopathological factors such as vascular invasion and poor tumour differentiation. CD151 expression was also indicative of poor outcome (Ke et al., 2009).

Prognosis

High CD151 expression was indicative of poor outcome.

Oncogenesis

High CD151 expression indicated poor survival outcome, suggesting a role for CD151 in enhancing tumourigenesis or resistance to treatment. Also refer to In vitro studies.

Entity name

Non-small cell lung carcinoma

Note

Real-time PCR analysis of CD151 gene expression compared to beta-actin was analysed (Tokuhara et al., 2001). Assessment of protein expression by immunohistochemistry correlated with gene expression however no statistical analyses were performed on protein expression.

Prognosis

High CD151 expression was indicative of poor outcome.

Oncogenesis

High CD151 expression indicated poor survival outcome, suggesting a role for CD151 in enhancing tumourigenesis or resistance to treatment. Also refer to In vitro studies.

Entity name

Breast cancer

Note

Immunohistochemical analysis of CD151 expression in a cohort of invasive ductal carcinoma identified a significantly higher risk of death from breast cancer in CD151 positive tumours compared to CD151 negative tumours. CD151 expression was also positively associated with the involvement of regional lymph nodes. No associations between CD151 expression and other clinical factors including estrogen receptor status were found (Sadej et al.,2009).
Immunohistochemical analysis of CD151 in breast tissue Microarrays identified positive correlations between CD151 expression and high tumour grade as well as negativity for the estrogen receptor. No other associations were identified between CD151 expression and clinical factors (Yang et al., 2008). Associations between CD151 expression and outcome were not able to be made due to unavailability of data.

Prognosis

High CD151 expression was indicative of poor outcome.

Oncogenesis

High CD151 expression indicated poor survival outcome, suggesting a role for CD151 in enhancing tumourigenesis or resistance to treatment. Also refer to In vitro studies.

Entity name

Pancreatic cancer

Note

Immunohistochemical analysis of pancreatic cancer cell lines and pancreatic tumours identified high CD151 expression associated with tumours/cell lines compared to normal tissue. Tumour stroma also expressed CD151 (Geiserich et al., 2005).

Oncogenesis

Refer to In vitro studies.

Entity name

Neovascularisation/Pathologic Angiogenesis

Note

Determined from in vivo studies in Cd151-null mice and in vitro studies of Cd151-null mouse lung endothelial cells (Takeda et al., 2007). Analysis of a rat myocardial ischaemia model also showed that viral delivery of CD151 can promote neovascularisation (Zheng and Liu, 2006).

Disease

Cancer, ischaemia

Oncogenesis

Lack of Cd151 expression resulted in impaired tumour angiogenesis, suggesting that Cd151 may be involved in promoting tumour angiogenesis.

Entity name

Nephropathy

Note

CD151 is expressed normally in the kidney particularly in the glomerular basement membrane (Sincock et al., 1997).

Disease

Nephropathy in humans (Karamatic Crew et al., 2004).
Cd151-null mice develop progressive renal failure on the FVB/N strain but not the C57BL/6 strain (Sachs et al., 2006; Baleato et al., 2008).

Prognosis

Loss of CD151 activity leads to chronic renal failure.

Cytogenetics

Homozygous frameshift mutation causing a premature stop codon (codon 140) due to the insertion of 1bp in exon 5 of CD151 (G383).

Hybrid gene

Resultant protein lacks the integrin binding domain and causes null expression of the CD151/MER2 antigen (Karamatic Crew et al., 2004).

Entity name

Pretibial epidermolysis bullosa

Note

The Nephropathy described above is attributed to the same mutation in CD151 and occurs in conjunction with pretibial epidermolysis bullosa and deafness (Karamatic Crew et al., 2004).
Wound repair in wild-type mice is associated with an up-regulation of Cd151 in the migrating epidermis at the wound edge (Cowin et al. 2006).

Disease

Pretibial epidermolysis bullosa in humans.
Defective wound repair in Cd151-null mice (Cowin et al. 2006; Geary et al 2008).

Cytogenetics

Homozygous frameshift mutation causing a premature stop codon (codon 140) due to the insertion of 1bp in exon 5 of CD151 (G383).

Hybrid gene

Resultant protein lacks the integrin binding domain and causes null expression of the CD151/MER2 antigen.

Entity name

Deafness

Note

This loss of function of CD151 is attributed to the same mutation in CD151 as that described above for nephropathy and pretibial epidermolysis bullosa, with all 3 disorders occurring in the same patients (Karamatic Crew et al., 2004).

Prognosis

Progressive deafness occurring by early adulthood.

Cytogenetics

Homozygous frameshift mutation causing a premature stop codon (codon 140) due to the insertion of 1bp in exon 5 of CD151 (G383).

Hybrid gene

Resultant protein lacks the integrin binding domain and causes null expression of the CD151/MER2 antigen.

Entity name

Hemostasis

Note

As assessed in Cd151-null mice, loss of Cd151 caused increased bleeding time and decreased clotting ability, suggesting endothelial and/or platelet cell functional defects. Cd151-null mice did not show any overt physiological differences unless challenged (Wright et al., 2004). Further in vitro analysis of Cd151-null platelets showed impaired functions relating to aggregation, spreading and clot retraction (Lau et al., 2004).

Bibliography

Pubmed ID	Last Year	Title	Authors
15533898	2004	CD151 protein expression predicts the clinical outcome of low-grade primary prostate cancer better than histologic grading: a new prognostic indicator?	Ang J et al
18787104	2008	Deletion of CD151 results in a strain-dependent glomerular disease due to severe alterations of the glomerular basement membrane.	Baleato RM et al
12110679	2002	Expression of the palmitoylation-deficient CD151 weakens the association of alpha 3 beta 1 integrin with the tetraspanin-enriched microdomains and affects integrin-dependent signaling.	Berditchevski F et al
19426143	2009	Lateral organization of membrane proteins: tetraspanins spin their web.	Charrin S et al
19073968	2008	Regulation of CD151 by hypoxia controls cell adhesion and metastasis in colorectal cancer.	Chien CW et al
16410781	2006	Wound healing is defective in mice lacking tetraspanin CD151.	Cowin AJ et al
9602068	1998	Characterisation of the mouse homologue of CD151 (PETA-3/SFA-1); genomic structure, chromosomal localisation and identification of 2 novel splice forms.	Fitter S et al
7632941	1995	Molecular cloning of cDNA encoding a novel platelet-endothelial cell tetra-span antigen, PETA-3.	Fitter S et al
17009258	2006	Tetraspanin CD151 is expressed in osteoarthritic cartilage and is involved in pericellular activation of pro-matrix metalloproteinase 7 in osteoarthritic chondrocytes.	Fujita Y et al
18534576	2008	The role of the tetraspanin CD151 in primary keratinocyte and fibroblast functions: implications for wound healing.	Geary SM et al
15837731	2005	Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility.	Gesierich S et al
12838318	2003	Clinical significance of transmembrane 4 superfamily in colon cancer.	Hashida H et al
16314869	2005	Tetraspanin functions and associated microdomains.	Hemler ME et al
19330835	2009	Tetraspanin gene expression levels as potential biomarkers for malignancy of gingival squamous cell carcinoma.	Hirano C et al
16798740	2006	Homophilic interactions of Tetraspanin CD151 up-regulate motility and matrix metalloproteinase-9 expression of human melanoma cells through adhesion-dependent c-Jun activation signaling pathways.	Hong IK et al
18522704	2008	Two MER2-negative individuals with the same novel CD151 mutation and evidence for clinical significance of anti-MER2.	Karamatic Crew V et al
19065669	2009	Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma.	Ke AW et al
11152613	2001	Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes.	Krogh A et al
15226180	2004	The tetraspanin superfamily member CD151 regulates outside-in integrin alphaIIbbeta3 signaling and platelet function.	Lau LM et al
17716972	2007	Tetraspanin CD151 promotes cell migration by regulating integrin trafficking.	Liu L et al
17015618	2006	Kidney failure in mice lacking the tetraspanin CD151.	Sachs N et al
19531562	2009	CD151 regulates tumorigenesis by modulating the communication between tumor cells and endothelium.	Sadej R et al
11483611	2001	Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion.	Seigneuret M et al
10036233	1999	PETA-3/CD151, a member of the transmembrane 4 superfamily, is localised to the plasma membrane and endocytic system of endothelial cells, associates with multiple integrins and modulates cell function.	Sincock PM et al
10811835	2000	The tetraspan molecule CD151, a novel constituent of hemidesmosomes, associates with the integrin alpha6beta4 and may regulate the spatial organization of hemidesmosomes.	Sterk LM et al
17023588	2007	Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro.	Takeda Y et al
10447000	1999	Eukaryotic expression cloning with an antimetastatic monoclonal antibody identifies a tetraspanin (PETA-3/CD151) as an effector of human tumor cell migration and metastasis.	Testa JE et al
11751509	2001	Clinical significance of CD151 gene expression in non-small cell lung cancer.	Tokuhara T et al
11181065	2001	Genomic organization, amplification, fine mapping, and intragenic polymorphisms of the human hemidesmosomal tetraspanin CD151 gene.	Whittock NV et al
16571677	2006	A critical role for tetraspanin CD151 in alpha3beta1 and alpha6beta4 integrin-dependent tumor cell functions on laminin-5.	Winterwood NE et al
15199151	2004	Characterization of mice lacking the tetraspanin superfamily member CD151.	Wright MD et al
18663148	2008	MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells.	Yañez-Mó M et al
18451146	2008	CD151 accelerates breast cancer by regulating alpha 6 integrin function, signaling, and molecular organization.	Yang XH et al
17225869	2006	CD151 gene delivery activates PI3K/Akt pathway and promotes neovascularization after myocardial infarction in rats.	Zheng Z et al
18328426	2008	The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151.	Zijlstra A et al

Other Information

Locus ID:

NCBI: 977
MIM: 602243
HGNC: 1630
Ensembl: ENSG00000177697

Variants:

dbSNP: 977
ClinVar: 977
TCGA: ENSG00000177697
COSMIC: CD151

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000177697	ENST00000322008	P48509
ENSG00000177697	ENST00000322008	A0A024RCB3
ENSG00000177697	ENST00000397420	P48509
ENSG00000177697	ENST00000397420	A0A024RCB3
ENSG00000177697	ENST00000397421	P48509
ENSG00000177697	ENST00000397421	A0A024RCB3
ENSG00000177697	ENST00000524748	K4DIA7
ENSG00000177697	ENST00000525333	E9PK37
ENSG00000177697	ENST00000525718	E9PSA1
ENSG00000177697	ENST00000526439	E9PP93
ENSG00000177697	ENST00000526693	E9PLZ6
ENSG00000177697	ENST00000527341	K4DIB7
ENSG00000177697	ENST00000528011	E9PMR4
ENSG00000177697	ENST00000528867	E9PJE8
ENSG00000177697	ENST00000529810	E9PRJ3
ENSG00000177697	ENST00000530320	E9PJC8
ENSG00000177697	ENST00000530726	P48509
ENSG00000177697	ENST00000530726	A0A024RCB3

Expression (GTEx)

100

200

300

400

500

600

700

800

900

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
Cell-Cell communication	REACTOME	R-HSA-1500931
Cell junction organization	REACTOME	R-HSA-446728
Type I hemidesmosome assembly	REACTOME	R-HSA-446107
Extracellular matrix organization	REACTOME	R-HSA-1474244
Collagen formation	REACTOME	R-HSA-1474290
Assembly of collagen fibrils and other multimeric structures	REACTOME	R-HSA-2022090

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
18328426	2008	The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151.	105
11907260	2002	Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution, and integrin-dependent cell morphology.	77
18451146	2008	CD151 accelerates breast cancer by regulating alpha 6 integrin function, signaling, and molecular organization.	76
15591117	2005	Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation.	72
19065669	2009	Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma.	70
15265795	2004	CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin.	68
21320503	2011	CD151 amplifies signaling by integrin α6β1 to PI3K and induces the epithelial-mesenchymal transition in HCC cells.	63
23302890	2013	Tetraspanin CD151 mediates papillomavirus type 16 endocytosis.	62
16571677	2006	A critical role for tetraspanin CD151 in alpha3beta1 and alpha6beta4 integrin-dependent tumor cell functions on laminin-5.	61
11884516	2002	Association of the tetraspanin CD151 with the laminin-binding integrins alpha3beta1, alpha6beta1, alpha6beta4 and alpha7beta1 in cells in culture and in vivo.	54

Citation

Judith Weidenhofer ; Leonie K Ashman

CD151 (CD151 molecule (Raph blood group))

Atlas Genet Cytogenet Oncol Haematol. 2009-07-01

Online version: http://atlasgeneticsoncology.org/gene/967/cd151