AQP1 (aquaporin 1 (Colton blood group))

2019-02-01   Jean Loup Huret 

jean-loup.huret@atlasgeneticsoncology.org

Identity

HGNC
LOCATION
7p14.3
LOCUSID
ALIAS
AQP-CHIP,CHIP28,CO
FUSION GENES

Abstract

Review on aquaporin-1 (AQP1), with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Transcription

There are various splicing forms. Canonical form transcript (hg38), including UTRs: chr7:30,911,694 - 30,925,516, size: 13,823bp on forward (+) strand; coding region: chr7:30,911,910 - 30,923,629, size: 11,720bp, according to UCSC. Four exons: exon1 (nt 1 - 600) codes for amino acids (aa) 1-128, exon2 (nt 10373 - 10537) for aa 129-183; exon3 (nt 10871 - 10951) for aa 184-210, and exon4 (nt 11757 - 13823) for aa 211-269 (nextProt).

Proteins

Note

Aquaporins are a family of hydrophobic transmembrane channel proteins involved in transport of water and small molecules in response to osmotic gradients. They are distributed throughout many tissues, with various known roles of production, secretion, reabsorption and regulation of water, but also of cell migration (angiogenesis), signal transduction, and cell proliferation. There are 14 AQPs in humans (and 5 pseudogenes): MIP (previously called AQP0), AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, AQP10, AQP11, AQP12Aand AQP12B. They are classified into two families: orthodox aquaporins, that transport water only, and aquaglyceroporins (AQP3, AQP7 and AQP9), which also transport glycerol, urea and other small molecules. AQPs form homo-tetramers (Review in Papadopoulos and Saadoun, 2015). The monomeric units of AQPs are ~30 kDa proteins and consist of 6 transmembrane α-helices (M1, M2, M4 to M6 and M8), 2 intramembrane half helices (M3 and M7), and 5 connecting loops (loops A to E) (Review in Verkman et al., 2014). They bear conserved intramembrane Asn-Pro-Ala (NPA) sequence motifs in the intramembrane domains, and six tilted transmembrane helices per monomer, with linkers (loops A to E). The NPA motifs act as hydrogen-bond donors and acceptors that coordinate the transport of water through the pore (Verkman et al., 2014).
Atlas Image
Figure 1. Aquaporin-1 (AQP1) gene exons and protein domains.

Description

Aquaporin-1 canonical form: 269 aa; 28.526kDa; other isoforms; 218, 186, and 154 aa. AQP1 is a transmembrane protein, with a N-term and a C-term cytoplasmic domains: amino acids 2 - 7 (Cytoplasmic), 8 - 36 (Transmembrane), 37 - 48 (Extracellular ("Loop A")), 49 - 66 (Transmembrane), 67 - 70 (Cytoplasmic), 71 - 84 (Intramembrane), 85 - 94 (Cytoplasmic ("Loop B"), 95 - 115 (Transmembrane), 116 - 136 (Extracellular ("Loop C")), 137 - 155 (Transmembrane), 156 - 166 (Cytoplasmic ("Loop D")), 167 - 183 (Transmembrane), 184 - 186 (Extracellular ("Loop E")), 187 - 200 (Intramembrane), 201 - 207 (Extracellular), 208 - 228 (Transmembrane), 229 - 269 (Cytoplasmic) (Figure. 1).

Helical subunits in Loop B and E juxtapose to form a water pore in the monomere. The central pore of the homotetramer (Figure. 2) would be a path for ion and gas (Review in Tomita et al., 2017). Remarkable sites: (Figure. 1)
NPA: aa 76-78, 192-194
N-myristoylation sites (role in membrane targeting): aa 30-35, 40-45, 57-62, 82-87, 104-109, 114-119, 121-126, 132-137, 136-141, 173-178, 190-195, 219-224.
N-glycosylation sites: aa 42-45, 205-208.
Protein kinase C phosphorylation sites: aa 157 - 159, 239-241 (Thr 157 and 239); Casein kinase II phosphorylation site: aa 262 - 265 (Ser 262).
Poly Arg (for preventing proton conduction): aa 159-162.
Atlas Image
Figure 2. Aquaporins monomere and tetramere. Aquaporins are transmembrane proteins involved in transport of water and small molecules in response to osmotic gradients (water channels).
Atlas Image
Figure 3. ModBase predicted comparative 3D structure.

Expression

AQPs are widely expressed. AQP1 is the main water channel in human (especially erythrocytes), but its function in water permeation can be alternatively supported by urea transporters SLC14A1 and SLC14A2 and glucose transporter SLC2A1 (GLUT1). The CO2-transporting function of APQ1 is replaceable by RHAG gas channel. (Hsu 2018). AQP1 is expressed in all tissues, in particular in renal tubules, exocrine pancreas, neuropil (synaptically dense regions of brain), bile ducts, corneal endothelium, bone marrow, myoepithelial cells of breast and endothelial cells (The Human Protein Atlas). AQP1 is present in pleura and microvessels. AQP1 and AQP4 are expressed in the iris and ciliary epithelium and play important roles in regulating aqueous humor (review in Huber et al. 2012).
Choroid plexus epithelium: AQP1 is highly expressed in the apical side of choroid plexus epithelium, where it facilitates cerebrospinal fluid (CSF) secretion and intracranial pressure regulation (Longatti et al., 2006; review in Huber et al. 2012).
Renal proximal tubule and loop of Henle: mice deficient in AQP1 have a reduced ability to concentrate urine and there is also a moderate defective urinary concentrating ability in AQP1 deficient patients (King et al., 2001).
Erythrocyte: CO2 metabolite enters erythrocytes via diffusion and/or gas channels (e.g. AQP1 and RHAG).
AQP1 is a H2O/CO2 channel in the erythrocyte. There are 160,000-200,000 copies of AQP1 on one erythrocyte membrane (Hsu 2018). AQP1 forms complex with SLC4A1 (band 3) and CA2 (carbonic anhydrase II) for intraerythrocytic CO2/HCO3 conversion in relation to desoxy-hemoglobin (Hsu 2018). 60% of CO2 flux in or out of RBCs is via AQP1 gas channel. The rest of CO2 flux is likely through another gas channel, RHAG, and/or direct diffusion (Hsu 2018).

Localisation

Localized to the plasma membrane.

Function

AQPs mains role is to maintain tissue water balance. AQPs also facilitate cell migration, cell proliferation and cell adhesion. Cell migration: AQPs concentrate at the leading end of migrating cells and facilitate the formation of the lamellipodium (Papadopoulos and Saadoun, 2015). Cell proliferation: AQPs may activates transduction pathways such as the mitogen-activated protein kinase pathways or the Wnt/ β-catenin signaling.
AQP1 may also be involved in down regulation of apoptosis. AQP1 up-regulation induces CTNNB1 (β-catenin) overexpression and serves as co-activator in the nucleus to activate Wnt responsive genes such as MYC, CCND1 (cyclin D1), JUN and FOSL1. AQP1 stabilises the cadherin/ CTNNB1/Lin7/F-actin complex to enhance the migratory and invasive capacity of tumor cells. AQP1 enhances the activity of MMP2 and MMP9 through PTK2 (FAK) and Wnt signalling pathways. Hypoxia induces AQP1 overexpression in tumour cells, in combination with important downstream effectors including CTNNB1, FAK and the Rho family of GTPases known for their role in tumorigenesis. (see review in Tomita et al., 2017).

Mutations

Germinal

Polymorphism: AQP1 is responsible for the Colton blood group system, with high incidence of Co(a) allele/antigen (Ala in aa 45), and low incidence of Co(b) allele/antigen (Val in aa 45). Colton-null phenotype Co(a-b-), is an aquaporin-1 deficiency. The patients, under stress, have a defect in urinary concentration capacity (King et al., 2002). AQP1-null mice have a significant decrease in urine osmolarity, but a normal survival.

Epigenetics

Increased expression of aquaporins 1 and 4 was found in Creutzfeldt-Jakob disease (Rodrèguez et al. 2006).

Implicated in

Top note
Aquaporin-1 is a well-established marker of proliferating tumor microvessels (Saadoun et al., 2002).
Aquaporin-1 is present in tumor vascular endothelium. AQP-expressing cancer cells show enhanced migration in vitro and greater local tumor invasion, tumor cell extravasation, and metastases in vivo than aquaporin-1-null transgenic mice. Aquaporin-1 facilitates endothelial cell migration and angiogenesis.
Entity name
Astrocytoma
Note
A t(1;7)(p13;p14) AQP1/ CHI3L2 has been found in low grade astrocytoma (Yoshihara et al., 2015).
The fusion gene ADCYAP1R1/AQP1 7p14-7p14 has been found in astrocytoma (Hu et al., 2018).
There was a significant increase in aquaporin-1 expression from low-grade to high-grade astrocytomas. AQP1 up-regulation was predominantly located perivascularly, and associated with angiogenesis, as well as with invasion of grade IV astrocytoma (El Hindy et al., 2013). Aquaporin-1 was expressed in microvessel endothelia and neoplastic astrocytes in metastatic carcinomas. Aquaporin-1 may participate in the formation of brain tumor edema (Saadoun et al., 2002).
Entity name
Bladder urothelial carcinoma
Note
Marked increase expression levels of aquaporin-1 was noted with bladder urothelial carcinoma histological grade and pathological stage. The expression of aquaporin-1 was markedly higher in cancerous tissues with lymph node metastasis (Liu et al., 2015).
Entity name
Breast adenocarcinoma
Note
A t(7;19)(p14;p13) AQP1/ TYK2 has been found in breast adenocarcinoma (Hu et al., 2018).
Aquaporin-1 is thought to be involved in estrogen mediated angiogenesis in the mammary gland (Mobasheri and Barrett-Jolley, 2014).
Entity name
Cholangiocarcinoma
Note
Strong aquaporin-1 expression predicts poor survival, regardless of pathological features in hilar cholangiocarcinoma (Li et al., 2017).
Entity name
Choroid plexus carcinoma
Note
Aquaporin-1 plays a role in tumor angiogenesis, cell migration, extravasation, and metastasis in choroid plexus carcinoma.
Entity name
Colorectal cancer
Note
Aquaporin-1 is an independent prognostic factor in advanced colon cancer (Yoshida et al., 2013). Expression of aquaporins 1, 3, and 5 was found in seven colon and colorectal cancer cell lines. The expression of aquaporins 1 and 5 was induced in early-stage disease (early dysplasia) and maintained through the late stages of colon cancer development (Moon et al., 2003).
Entity name
Head and neck cancer
Note
High expression is correlated with better prognosis in head and neck cancer, according to The Human Protein Atlas. On the other hand, aquaporin-1 was overexpressed in nasopharyngeal cancer tissues; migrated tumor tissue had even higher expression (Li and Zhang 2010).
Entity name
Hemangioblastoma
Note
Upregulation of aquaporin-1 expression was found in hemangioblastoma (Chen et al. 2006).
Entity name
Kidney adenocarcinomay
Note
A t(7;20)(p14;q13) AQP1/ ARFGEF2 has been found in adenocarcinoma of the kidney (Hu et al., 2018).
High expression is correlated with better prognosis in renal cell cancer according to The Human Protein Atlas.
Entity name
Lung cancer
Note
A t(6;7)(p21;p14) AQP1/ CFB has been found in lung adenocarcinoma (Hu et al., 2018).
Aquaporin-1 was overexpressed in adenocarcinoma and bronchoalveolar carcinoma, respectively, whereas all cases of squamous cell carcinoma and normal lung tissue were negative (Hoque et al., 2006).
Entity name
Note
Patients with active multiple myeloma display significantly higher levels of aquaporin-1 than those with non-active multiple myeloma. Patients with monoclonal gammopathies of undetermined significance (MGUS) had lower levels of aquaporin-1 (Vacca et al. 2001).
Entity name
Uterus cervical carcinoma
Note
The fusion gene TRA2A/AQP1 (7p15-7p14) has been found in squamous cell carcinoma of the uterus cervix (Hu et al., 2018).
Aquaporins 1 and 3 were upregulated in cervical carcinoma, significantly increased in advanced stage disease, and patients with deeper tumor infiltration, lymph node metastases or larger tumor volume (Chen et al., 2014).
Entity name
Uterus endometrial adenocarcinoma
Note
A positive correlation between aquaporin-1, microvascular density and vascular endothelial growth factor ( VEGFA) expression in tumor progression of endometrial adenocarcinoma (Pan et al. 2008).
Entity name
Pleural malignant mesothelioma
Note
Expression of aquaporin-1 in malignant mesothelioma is an independent prognostic factor, irrespective of the type of treatment received. Expression of AQP1 by more than 50% of tumor cells was associated with prolonged survival (Kao et al., 2012).
Entity name
Prostate adenocarcinoma
Note
Aquaporin-1 overexpression was significantly associated with higher Gleason scores and is associated with prostate adenocarcinoma progression (Park and Yoon 2017).

Bibliography

Pubmed IDLast YearTitleAuthors
249189282014Expression and prognostic value of aquaporin 1, 3 in cervical carcinoma in women of Uygur ethnicity from Xinjiang, China.Chen R et al
170779392006Increased expression of aquaporin 1 in human hemangioblastomas and its correlation with cyst formation.Chen Y et al
233933552013Correlation of aquaporin-1 water channel protein expression with tumor angiogenesis in human astrocytoma.El Hindy N et al
165655072006Aquaporin 1 is overexpressed in lung cancer and stimulates NIH-3T3 cell proliferation and anchorage-independent growth.Hoque MO et al
299710132018Exploring the Potential Roles of Band 3 and Aquaporin-1 in Blood CO2 Transport-Inspired by Comparative Studies of Glycophorin B-A-B Hybrid Protein GP.Mur.Hsu K et al
290999512018TumorFusions: an integrative resource for cancer-associated transcript fusions.Hu X et al
222931382012Aquaporins in drug discovery and pharmacotherapy.Huber VJ et al
220205362012Aquaporin 1 is an independent prognostic factor in pleural malignant mesothelioma.Kao SC et al
114630122001Defective urinary concentrating ability due to a complete deficiency of aquaporin-1.King LS et al
117736342002Decreased pulmonary vascular permeability in aquaporin-1-null humans.King LS et al
83136731993Respiratory bronchiolitis-associated interstitial lung disease.King TE Jr et al
271430472017Elevated AQP1 Expression Is Associated With Unfavorable Oncologic Outcome in Patients With Hilar Cholangiocarcinoma.Li C et al
208285132010Expression of aquaporin-1 in nasopharyngeal cancer tissues.Li Q et al
259870712015Expression of aquaporin 1 in bladder uroepithelial cell carcinoma and its relevance to recurrence.Liu J et al
167148632006Aquaporin(s) expression in choroid plexus tumours.Longatti P et al
52042621970[Perspectives of promotion for current nurses].Meléndez et al
243381532014Aquaporin water channels in the mammary gland: from physiology to pathophysiology and neoplasia.Mobasheri A et al
145559832003Involvement of aquaporins in colorectal carcinogenesis.Moon C et al
252042622015Key roles of aquaporins in tumor biology.Papadopoulos MC et al
168714012006Increased expression of water channel aquaporin 1 and aquaporin 4 in Creutzfeldt-Jakob disease and in bovine spongiform encephalopathy-infected bovine-PrP transgenic mice.Rodríguez A et al
122377712002Increased aquaporin 1 water channel expression in human brain tumours.Saadoun S et al
281460842017Role of Aquaporin 1 Signalling in Cancer Development and Progression.Tomita Y et al
113804072001Microvessel overexpression of aquaporin 1 parallels bone marrow angiogenesis in patients with active multiple myeloma.Vacca A et al
246258252014Aquaporins: important but elusive drug targets.Verkman AS et al
246492762013Expression of aquaporin-1 is a poor prognostic factor for stage II and III colon cancer.Yoshida T et al
255005442015The landscape and therapeutic relevance of cancer-associated transcript fusions.Yoshihara K et al

Other Information

Locus ID:

NCBI: 358
MIM: 107776
HGNC: 633
Ensembl: ENSG00000240583

Variants:

dbSNP: 358
ClinVar: 358
TCGA: ENSG00000240583
COSMIC: AQP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000240583ENST00000311813P29972
ENSG00000240583ENST00000311813A0A024RA31
ENSG00000240583ENST00000409611P29972
ENSG00000240583ENST00000409899P29972
ENSG00000240583ENST00000441328P29972
ENSG00000240583ENST00000651610A0A494C1U4
ENSG00000240583ENST00000652692A0A494C115
ENSG00000240583ENST00000652696P29972
ENSG00000240583ENST00000652696A0A024RA31

Expression (GTEx)

0
500
1000
1500
2000

Pathways

PathwaySourceExternal ID
Proximal tubule bicarbonate reclamationKEGGko04964
Proximal tubule bicarbonate reclamationKEGGhsa04964
Bile secretionKEGGko04976
Bile secretionKEGGhsa04976
Renin secretionKEGGhsa04924
Renin secretionKEGGko04924
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Aquaporin-mediated transportREACTOMER-HSA-445717
Passive transport by AquaporinsREACTOMER-HSA-432047
Vasopressin regulates renal water homeostasis via AquaporinsREACTOMER-HSA-432040
MetabolismREACTOMER-HSA-1430728
O2/CO2 exchange in erythrocytesREACTOMER-HSA-1480926
Erythrocytes take up carbon dioxide and release oxygenREACTOMER-HSA-1237044
Erythrocytes take up oxygen and release carbon dioxideREACTOMER-HSA-1247673

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA162263533nephrotoxicityDiseaseVariantAnnotationnot associatedPD
PA443314AlopeciaDiseaseClinicalAnnotation, VariantAnnotationambiguousPD
PA443340AnemiaDiseaseClinicalAnnotationassociatedPD
PA444773LeukopeniaDiseaseClinicalAnnotationassociatedPD
PA444937MesotheliomaDiseaseClinicalAnnotation, VariantAnnotationambiguousPD
PA445048NauseaDiseaseVariantAnnotationnot associatedPD
PA445846ThrombocytopeniaDiseaseClinicalAnnotationassociatedPD
PA446051VomitingDiseaseVariantAnnotationnot associatedPD
PA449014cisplatinChemicalClinicalAnnotation, VariantAnnotationambiguousPD

References

Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
182021812008Mechanism of selectivity in aquaporins and aquaglyceroporins.80
122377712002Increased aquaporin 1 water channel expression in human brain tumours.66
170122492006Evidence that aquaporin 1 is a major pathway for CO2 transport across the human erythrocyte membrane.55
296509612018Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.55
206280612010MicroRNA 320a functions as a novel endogenous modulator of aquaporins 1 and 4 as well as a potential therapeutic target in cerebral ischemia.54
175496822007Expression and function of water channels (aquaporins) in migrating malignant astrocytes.53
164813712006Distribution of sodium transporters and aquaporin-1 in the human choroid plexus.50
145928142004Expression of the AQP-1 water channel in normal human tissues: a semiquantitative study using tissue microarray technology.42
166987712006Does CO2 permeate through aquaporin-1?38

Citation

Jean Loup Huret

AQP1 (aquaporin 1 (Colton blood group))

Atlas Genet Cytogenet Oncol Haematol. 2019-02-01

Online version: http://atlasgeneticsoncology.org/gene/46249/aqp1