EPAS1 (Endothelial PAS Domain Protein 1)

2013-12-01   Sofie Mohlin , Arash Hamidian , Daniel Bexell , Sven Pœhlman , Caroline Wigerup 

Lund University, Center for Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404, C3, SE-223 81 Lund, Sweden





Genomic size: Starts at 46524541 and ends at 46613842.


Transcript length: The gene is comprised of 16 exons, constituting one main transcript of 5184 base pairs.


None described.


Atlas Image
Representation of the EPAS1/HIF2A protein with its specific domains specified. Critical hydroxylation sites are indicated.


The HIF-2α protein is 870 amino acids long and consists of a basic-helix-loop-helix domain, two PER-ARNT-SIM domains (A and B), an oxygen-dependent degradation domain (ODDD) and two transcriptional-activation domains (N-TAD and C-TAD). Two proline residues (P405 in ODDD and P531 in N-TAD) and an asparaginyl residue (N847 in C-TAD) are subjected to hydroxylation during physiologic oxygen tensions, regulating the stability and activity of the HIF-2α protein. Phosphorylation of HIF-2α at T844 has been reported as necessary for its transcriptional activation function (Gradin et al., 2002).


In adult human tissue, HIF-2α protein is mainly expressed in cells experiencing low oxygen levels, and the HIF-2α mRNA has been shown to be predominantly expressed in highly vascularized tissues (Tian et al., 1997). During human embryonic and fetal development, HIF-2α is transiently but specifically expressed in cells of the developing sympathetic nervous system (SNS) (Nilsson et al., 2005; Mohlin et al., 2013). In embryonic and adult mouse tissue, the expression of HIF-2α mRNA is more or less restricted to endothelial cells (Tian et al., 1997; Jain et al., 1998). In a zebrafish model, the HIF-2α transcript is expressed early in brain tissue and blood vessels, and later on HIF-2α replaces HIF-1α transcription in the notochord (Rojas et al., 2007).


HIF-2α is part of a transcriptional complex and is hence localized mainly in the nucleus upon hypoxic induction. However, HIF-2α protein can also be detected in the cytoplasm, at hypoxic conditions and foremost at more physiological oxygen conditions, as demonstrated in cultured cells in vitro and in tumor specimens in vivo (Holmquist-Mengelbier et al., 2006). These findings were recently strengthened by the demonstration of a role for HIF-2α as part of an oxygen-regulated translation initiation complex and presence of HIF-2α in the cellular polysome fraction (Uniacke et al., 2012).


At lower oxygen tensions, the hydroxylation of HIF-2α by prolyl hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) is prevented, and the HIF-2α subunit relocates to the nucleus where it forms a transcriptional complex together with its binding partner ARNT (also known as HIF-1β) and co-factors such as p300 and CBP. By binding to hypoxia response elements (HREs) in the promoter of target genes, the HIF complex initiates transcription of numerous genes involved in a variety of tumorigenic cellular processes, including angiogenesis, invasion and metastasis, growth, dedifferentiation, and apoptosis (Semenza, 2003). As mentioned under the Localization section, HIF-2α has also been demonstrated to be part of a hypoxia-regulated translation initiation complex. Hypoxia induces HIF-2α to form a complex together with RNA-binding protein RBM4 and cap-binding eIF4E2, and this complex is then recruited to a wide variety of mRNAs, promoting active translation at polysomes (Uniacke et al., 2012). In a recent report, HIF-2α was further shown to protect human hematopoietic stem/progenitor cells from endoplasmic reticulum (ER) stress-induced apoptosis and to enhance the long-term repopulating ability of these cells (Rouault-Pierre et al., 2013).


HIF-2α is part of the basic helix-loop-helix-PAS family of proteins and is structurally related to the HIF-1α and HIF-3α subunits. While HIF-3α is believed to negatively regulate the other two alpha subunits (Makino et al., 2001; Maynard et al., 2007), HIF-1α and HIF-2α share both sequence similarity and target genes. However, despite 48% primary amino acid sequence homology between HIF-1α and HIF-2α (Tian et al., 1997), it is becoming increasingly evident that these two proteins also function at distinct sites and during differential cellular conditions.



Functional mutations in human EPAS1 are associated with variations in hemoglobin and red blood cell concentration (Percy et al., 2008b; Beall et al., 2010; Yi et al., 2010). Percy et al. described a gain of function mutation in a family with high hemoglobin concentrations and erythrocytosis (Percy et al., 2008b). Similar mutations, all associated with small amino acid substitutions leading to protein stabilization, have been reported in other clinical cases (Gale et al., 2008; Martini et al., 2008; Percy et al., 2008a; van Wijk et al., 2010). In contrast, EPAS1 mutations associated with a loss of function and low hemoglobin concentrations have been described in healthy individuals living at high altitudes. Extensive analysis of genome-wide sequence variations and exome sequencing in Tibetans have shown that EPAS1 is a key gene mutated in Tibetan populations (Beall et al., 2010; Simonson et al., 2010; Yi et al., 2010; Peng et al., 2011). The functional consequence of EPAS1 SNPs associated with low hemoglobin concentrations is described as adaptation to low oxygen without elevated red blood cell production, thereby avoiding high blood viscosity creating cardiovascular risks.


Several studies have recently identified the first mutations in any of the HIF alpha subunits in cancer. Somatic gain-of-function mutations in exon 12 of the EPAS1 gene in two patients with paraganglioma and associated erythrocytosis results in an amino acid substitution in proximity to the PHD hydroxylation site and increased protein half-life and HIF-2α activity (Zhuang et al., 2012). Additional mutations in EPAS1 have also been identified in patients with paraganglioma and pheochromocytoma without associated erythrocytosis (Comino-Mendez et al., 2013), and in patients with somatostatinoma and paraganglioma (Yang et al., 2013).

Implicated in

Entity name
Renal clear cell carcinoma
The predominant loss of von Hippel Lindau in clear cell renal cell carcinoma (ccRCC), results in defective targeting of HIF-α proteins for degradation at normoxia (Gnarra et al., 1994). Therefore, both HIF-1α and HIF-2α accumulate irrespective of oxygen levels in VHL-defective cells and are abundantly expressed in cells of ccRCC origin (Krieg et al., 2000). For unknown reasons, the expression of HIF-2α is more prominent than that of HIF-1α in RCC cell lines and tumors and HIF-1α expression is often lost in RCC cell lines (Maxwell et al., 1999; Krieg et al., 2000). Regulation of HIF target genes in RCC cell lines are more dependent on HIF-2α than on HIF-1α and silencing of HIF-2α in VHL-deficient cells suppress tumor growth, suggesting an important role for HIF-2α in renal carcinoma (Kondo et al., 2003; Carroll et al., 2006).
Entity name
Paraganglioma and pheochromocytoma derive from the chromaffin cell lineage of the sympathetic nervous system, and notably, genes involved in the hypoxic response (e.g. VHL and SDH genes) are frequently mutated in these tumors (Neumann et al., 2002). Recently, somatic mutations in the EPAS1 gene itself were discovered in two paraganglioma patients, describing the first cases of EPAS1 mutations in any cancer type (Zhuang et al., 2012). These gain-of-function mutations lead to increased protein half-life and HIF-2α activity, in turn resulting in up-regulation of HIF-2α downstream target genes, presumably explaining the clinical presentation in these patients. In a follow-up study, two additional EPAS1 mutations were discovered in patients presenting with polycythemia and somatostatinoma or paraganglioma (Yang et al., 2013). These novel mutations lead to disruption of the ODD domain-PHD2 interaction and thereby result in less ubiquitination and higher activity of the HIF-2α protein. In another study, 7 out of 41 examined patients with pheochromocytoma or paraganglioma presented with somatic EPAS1 mutations, and interestingly, three of these cases were also accompanied by an exclusive gain of chromosome 2p (Comino-Mendez et al., 2013).
Entity name
In the childhood tumor neuroblastoma, HIF-2α positive tumor cells have been identified in a perivascular niche, suggesting a non-hypoxic driven expression (Pietras et al., 2008). The HIF-2α positive cells display an immature tumor stem cell-like phenotype and their presence in neuroblastoma specimens correlate to poor overall survival (Holmquist-Mengelbier et al., 2006; Noguera et al., 2009). In neuroblastoma cell lines, HIF-2α is expressed at hypoxic conditions (1% oxygen) and at near end-capillary physiological oxygen levels (5% oxygen) (Jogi et al., 2002; Holmquist-Mengelbier et al., 2006). At prolonged hypoxic conditions, HIF-2α is continuously expressed in contrast to its homologue HIF-1α. In addition, overexpression of HIF-2α in a mouse neuroblastoma cell line promoted in vivo tumor angiogenesis, while mutant HIF-2α cells formed tumors that were highly necrotic (Favier et al., 2007).
Entity name
Knockdown of HIF-2α expression can reduce vascularization but accelerate tumor growth of human glioblastoma cells pointing to a role for HIF-2α as a tumor suppressor in glioblastoma (Acker et al., 2005). In contrast, recent work has focused on HIF-2α as a putative glioblastoma cancer stem cell (CSC) marker. Specifically, HIF-2α protein expression co-localizes with CD133 in a fraction of tumor cells (McCord et al., 2009) and with cancer stem cell markers in glioma specimens (Li et al., 2009). Glioblastoma putative CSCs respond to hypoxia by induction of HIF2-α (Li et al., 2009; Seidel et al., 2010), and inhibiting HIF2-α in glioblastoma CSCs decreases self-renewal, proliferation and survival in vitro and tumor-initiating capacity in vivo (Li et al., 2009). In addition, elevated HIF2A mRNA levels are associated with poor prognosis in glioma patients (Li et al., 2009).
Entity name
Breast cancer
HIF-2α is expressed and associates with high vascular density, high c-erbB-2 expression and extensive nodal metastasis in breast cancer (Giatromanolaki et al., 2006). In a slightly larger study, HIF-2α was associated with ABCG2 expression, histology grade and Ki67 expression in invasive ductal carcinoma (Xiang et al., 2012). Importantly, in two separate breast cancer cohorts, HIF-2α correlate to reduced recurrence-free survival, breast-cancer specific survival and presence of distal metastasis (Helczynska et al., 2008).
Knockdown of HIF-2α in CD34+ acute myeloid leukemia (AML) cells reduce engraftment ability in irradiated mice (Rouault-Pierre et al., 2013). The HIF-2α deficient cells are more susceptible to apoptosis as a result of increased ROS and ER-induced stress indicating that HIF-2α is important for AML cell survival.
Entity name
Other tumor types
Expression of the HIF-2α protein has also been reported in other solid tumor types including colorectal cancer (Yoshimura et al., 2004), prostate cancer (Boddy et al., 2005), non-small cell lung cancer (Giatromanolaki et al., 2001), squamous cell head-and-neck cancer (Koukourakis et al., 2002), nodular malignant melanoma (Giatromanolaki et al., 2003) and endometrial adenocarcinoma (Sivridis et al., 2002).
Entity name
Sites of inflammation are often hypoxic due to vascular damage and large infiltration of cells. In order to operate under this condition, cells of the innate immunity adapt by expressing the HIF proteins (Fang et al., 2009; Imtiyaz and Simon, 2010). HIF-2α has been directly coupled to the regulation of proinflammatory cytokine expression in activated macrophages (Fang et al., 2009; Imtiyaz et al., 2010). Furthermore, HIF-2α has been detected in bone marrow-derived macropahges (BMDMs) and tumor associated macrophages (TAMs) of various human cancers (Talks et al., 2000). Importantly, HIF-2α is essential for TAM migration into tumor lesions (Imtiyaz et al., 2010), which in turn will promote progression and metastasis of tumor cells (Pollard, 2004).
Erythrocytosis, see section on germinal mutations.
Entity name
The four available HIF2A knockout mice display substantial differences in phenotype, presumably due to strain background. The first knockout mouse was created on a 129/SvJ background, and resulted in embryonic lethality due to circulatory failure during midgestation (Tian et al., 1997). Two of the following knockout studies demonstrated a role for HIF-2α in vascular development. HIF2A deficient embryos from an ICR/129Sv background die in utero and display severe post-vasculogenic defects (Peng et al., 2000), while HIF2A deficient mice on 129/Sv x Swiss background display lowered VEGF levels (Compernolle et al., 2002). The latter mice are embryonically lethal due to respiratory distress syndrome and cardiac failure (Compernolle et al., 2002). HIF-2α is also important in normal hematopoiesis, as demonstrated by creating adult HIF2A knockout mice by crossing of heterozygous 129S6/SvEvTac EPAS1 and heterozygous C57BL/6J EPAS1 knockout mice (Scortegagna et al., 2003b). These adult HIF2A deficient mice suffer from cardiac hypertrophy, hepatomegaly, oxidative stress and pancytopenia (Scortegagna et al., 2003a). In summary, HIF2A knockout studies demonstrate important roles for HIF-2α in catecholamine synthesis, reactive oxygen species (ROS) homeostasis and vascular remodeling during development.


Pubmed IDLast YearTitleAuthors
160984662005Genetic evidence for a tumor suppressor role of HIF-2alpha.Acker T et al
205345442010Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders.Beall CM et al
162783852005The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer.Boddy JL et al
167782022006Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway.Carroll VA et al
234183102013Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.Comino-Méndez I et al
120531762002Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice.Compernolle V et al
194547492009Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.Fang HY et al
176557542007HIF2 alpha reduces growth rate but promotes angiogenesis in a mouse model of neuroblastoma.Favier J et al
186504732008Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation.Gale DP et al
165407352006Hypoxia-inducible factor-2 alpha (HIF-2 alpha) induces angiogenesis in breast carcinomas.Giatromanolaki A et al
79156011994Mutations of the VHL tumour suppressor gene in renal carcinoma.Gnarra JR et al
119836972002The transcriptional activation function of the HIF-like factor requires phosphorylation at a conserved threonine.Gradin K et al
190108932008Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.Helczynska K et al
170975632006Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype.Holmquist-Mengelbier L et al
206442542010Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation.Imtiyaz HZ et al
95455581998Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse.Jain S et al
120114612002Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.Jögi A et al
146915542003Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth.Kondo K et al
121281202002Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer.Koukourakis MI et al
111147202000Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function.Krieg M et al
194774292009Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.Li Z et al
117348562001Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression.Makino Y et al
185087872008A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis.Martini M et al
103532511999The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.Maxwell PH et al
179988052007Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression.Maynard MA et al
193725782009Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro.McCord AM et al
234795102013HIF2A and IGF2 expression correlates in human neuroblastoma cells and normal immature sympathetic neuroblasts.Mohlin S et al
120008162002Germ-line mutations in nonsyndromic pheochromocytoma.Neumann HP et al
156523562005HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia.Nilsson H et al
199037922009HIF-1alpha and HIF-2alpha are differentially regulated in vivo in neuroblastoma: high HIF-1alpha correlates negatively to advanced clinical stage and tumor vascularization.Noguera R et al
108805632000The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling.Peng J et al
210304262011Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas.Peng Y et al
183788522008Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis.Percy MJ et al
181849612008A gain-of-function mutation in the HIF2A gene in familial erythrocytosis.Percy MJ et al
181893312008High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche.Pietras A et al
147080272004Tumour-educated macrophages promote tumour progression and metastasis.Pollard JW et al
169976372007Cloning of hif-1alpha and hif-2alpha and mRNA expression pattern during development in zebrafish.Rojas DA et al
240956762013HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress.Rouault-Pierre K et al
127501632003The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice.Scortegagna M et al
203751332010A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha.Seidel S et al
131303032003Targeting HIF-1 for cancer therapy.Semenza GL et al
204668842010Genetic evidence for high-altitude adaptation in Tibet.Simonson TS et al
122096912002Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma.Sivridis E et al
109341462000The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages.Talks KL et al
90000511997Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.Tian H et al
226782942012An oxygen-regulated switch in the protein synthesis machinery.Uniacke J et al
224529962012Hypoxia-inducible factor-2a is associated with ABCG2 expression, histology-grade and Ki67 expression in breast invasive ductal carcinoma.Xiang L et al
233619062013Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas.Yang C et al
205956112010Sequencing of 50 human exomes reveals adaptation to high altitude.Yi X et al
156236392004Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression.Yoshimura H et al
229312602012Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia.Zhuang Z et al
200071412010Erythrocytosis associated with a novel missense mutation in the HIF2A gene.van Wijk R et al

Other Information

Locus ID:

NCBI: 2034
MIM: 603349
HGNC: 3374
Ensembl: ENSG00000116016


dbSNP: 2034
ClinVar: 2034
TCGA: ENSG00000116016


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Renal cell carcinomaKEGGko05211
Pathways in cancerKEGGhsa05200
Renal cell carcinomaKEGGhsa05211
Signal TransductionREACTOMER-HSA-162582
Developmental BiologyREACTOMER-HSA-1266738
Transcriptional regulation of pluripotent stem cellsREACTOMER-HSA-452723
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to hypoxiaREACTOMER-HSA-2262749
Regulation of Hypoxia-inducible Factor (HIF) by oxygenREACTOMER-HSA-1234174
Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor AlphaREACTOMER-HSA-1234162
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor AlphaREACTOMER-HSA-1234176
Regulation of gene expression by Hypoxia-inducible FactorREACTOMER-HSA-1234158
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 ExpressionREACTOMER-HSA-8849473


Pubmed IDYearTitleCitations
209654232010Hypoxia-inducible factors and the response to hypoxic stress.644
205956112010Sequencing of 50 human exomes reveals adaptation to high altitude.455
146455462003Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation.449
194774292009Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.447
118236432002Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.373
159648222005Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.332
152472322004Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor.329
205345442010Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders.251
205345442010Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders.251
170975632006Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype.238


Sofie Mohlin ; Arash Hamidian ; Daniel Bexell ; Sven Pœhlman ; Caroline Wigerup

EPAS1 (Endothelial PAS Domain Protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-12-01

Online version: http://atlasgeneticsoncology.org/gene/44088/epas1-(endothelial-pas-domain-protein-1)