# ANG Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The ANG gene encodes angiogenin, a secreted ribonuclease with a dual role: promoting rRNA transcription in the nucleus under normal conditions and cleaving tRNA to generate tiRNAs that inhibit translation under cellular stress.
- Angiogenin's pro-angiogenic activity is mediated by binding to a 170-kDa endothelial cell receptor, activating ERK1/2 and PI3K/Akt pathways, leading to cell migration and new blood vessel formation.
- Pathogenic mutations in ANG, particularly missense variants affecting catalytic activity or structural integrity, are associated with amyotrophic lateral sclerosis (ALS) and Parkinson's disease, often leading to loss-of-function phenotypes.
- In cancer, ANG overexpression, often driven by promoter alterations or copy number gains, correlates with poor prognosis and is a validated target for anti-angiogenic therapies using monoclonal antibodies, small-molecule inhibitors, or antisense oligonucleotides.
- Angiogenin plays a role in host defense by cleaving viral and bacterial RNA, but some viruses can hijack its pro-angiogenic function to promote pathogenesis, such as KSHV in Kaposi's sarcoma.
- Therapeutic strategies for ANG-related disorders include delivering recombinant angiogenin or gene therapy for neurodegenerative conditions (e.g., ALS) and inhibiting its activity for cancer treatment.

---

## Executive Summary & Key Metadata

The **ANG** gene encodes angiogenin, a secreted ribonuclease that belongs to the pancreatic ribonuclease A (RNase A) superfamily. Angiogenin is a potent inducer of blood vessel formation (angiogenesis) and plays a dual role in the cell: under normal conditions, it is translocated to the nucleus where it promotes ribosomal RNA (rRNA) transcription; under cellular stress, it is sequestered in stress granules to cleave transfer RNA (tRNA), generating tRNA-derived stress-induced fragments (tiRNAs) that inhibit translation. This bifunctional nature places ANG at the intersection of cell growth, survival, and stress response. Clinically, ANG is implicated in a spectrum of disorders ranging from amyotrophic lateral sclerosis (ALS) and Parkinson's disease to various solid tumors, where its overexpression correlates with poor prognosis. The gene is also a validated target for anti-angiogenic cancer therapy.

| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | ANG |
| **UniProt Accession** | P03950 |
| **Representative PDB ID** | 1ANG (wild-type); 2ANG (recombinant) |
| **Chromosomal Locus** | 14q11.2 (GRCh38: chr14:20,684,529-20,694,915) |
| **Primary Molecular Function** | Ribonucleolytic activity (tRNA/rRNA cleavage); angiogenic cytokine; stress-induced translational inhibitor |
| **Disease & Pathology Associations** | Amyotrophic lateral sclerosis (ALS), Parkinson's disease, various carcinomas (breast, pancreatic, colorectal, lung), atherosclerosis |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Coordinates and Genomic Context

The human ANG gene is located on the long arm of chromosome 14 at cytogenetic band **14q11.2**. The reference genome assembly (GRCh38/hg38) places the gene between base pairs 20,684,529 and 20,694,915 on the forward strand. This locus is gene-dense and evolutionarily conserved, with ANG residing in a cluster of ribonuclease genes that includes RNASE1, RNASE2 (EDN), RNASE3 (ECP), and RNASE4. The proximity of ANG to RNASE4 is particularly notable: the two genes share a bidirectional promoter region, with their 5' ends separated by only approximately 400 base pairs. This arrangement suggests coordinated transcriptional regulation, although their expression patterns differ markedly across tissues.

### 1.2 Gene Structure and Exon-Intron Architecture

The ANG gene spans approximately 10.4 kilobases (kb) of genomic DNA and comprises **seven exons** and **six introns**. The coding sequence (CDS) is relatively compact, spanning 441 nucleotides that encode a 147-amino-acid precursor protein. The exon-intron boundaries are conserved among mammalian orthologs, with splice donor and acceptor sites conforming to the canonical GT-AG rule.

| **Exon** | **Size (bp)** | **Encoded Region** | **Key Features** |
| :--- | :--- | :--- | :--- |
| Exon 1 | 45 | 5' UTR + Signal peptide (Met1-Ala24) | Contains translation start site; signal peptide for secretion |
| Exon 2 | 72 | N-terminal mature protein (Gln25-Lys48) | Catalytic His13 (mature numbering) |
| Exon 3 | 66 | Central region (Ser49-Gly70) | Contains nuclear localization signal (NLS) |
| Exon 4 | 78 | Central region (Arg71-Lys96) | Contains putative RNA-binding residues |
| Exon 5 | 84 | C-terminal region (Gln97-Lys124) | Contains catalytic Lys40 and His114 |
| Exon 6 | 54 | C-terminal region (Ser125-Lys142) | Structural stability |
| Exon 7 | 42 | 3' UTR + C-terminus (Arg143-Pro147) | Contains stop codon; polyadenylation signal |

### 1.3 Promoter Architecture and Transcriptional Regulation

The ANG promoter lacks a canonical TATA box but contains a **GC-rich region** with multiple Sp1 transcription factor binding sites. This promoter architecture is characteristic of housekeeping genes, yet ANG expression is highly regulated in a tissue-specific and context-dependent manner. Key regulatory elements include:

- **Hypoxia Response Elements (HREs)**: Located within the proximal promoter, these elements bind Hypoxia-Inducible Factor 1-alpha (HIF-1α). Under hypoxic conditions, HIF-1α translocates to the nucleus and upregulates ANG transcription, linking angiogenesis to oxygen deprivation.
- **Estrogen Response Elements (EREs)**: Functional EREs have been identified in the ANG promoter, explaining the elevated ANG expression observed in estrogen receptor-positive breast cancers.
- **Ets-1 Binding Sites**: The Ets-1 transcription factor, which is frequently overexpressed in invasive tumors, directly binds the ANG promoter and stimulates its activity.
- **Bidirectional Promoter with RNASE4**: The intergenic region between ANG and RNASE4 contains shared enhancer elements. Chromatin immunoprecipitation (ChIP) studies have demonstrated that RNA Polymerase II can initiate transcription in both directions from this region, although the efficiency of ANG transcription is typically higher.

### 1.4 Alternative Splicing and Isoforms

While ANG is primarily transcribed as a single major mRNA species, next-generation sequencing (RNA-seq) data from the Genotype-Tissue Expression (GTEx) project has identified several low-abundance splice variants:

- **ANG-001 (Canonical)**: Comprises all seven exons; encodes the full-length 147-amino-acid pre-protein. This is the dominant transcript in all tissues.
- **ANG-002**: Skips exon 3, resulting in a frameshift and premature stop codon. This transcript is predicted to undergo nonsense-mediated decay (NMD) and is unlikely to produce a functional protein.
- **ANG-003**: Retains intron 2, introducing a premature termination codon. Also a candidate for NMD.
- **ANG-004**: Uses an alternative 5' splice site in exon 1, producing a truncated 5' UTR. This variant may have altered translational efficiency.

The biological significance of these minor isoforms remains unclear, but their existence suggests that ANG expression is subject to post-transcriptional regulation via alternative splicing and NMD.

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Structure and Post-Translational Processing

The ANG gene product is synthesized as a 147-amino-acid precursor containing a 24-amino-acid N-terminal signal peptide. Upon translocation into the endoplasmic reticulum (ER), the signal peptide is cleaved, yielding the mature, secreted 123-amino-acid protein with a molecular weight of approximately 14.1 kDa. The mature protein retains a single N-linked glycosylation site at Asn-61, although glycosylation is not required for ribonucleolytic activity.

### 2.2 Tertiary Structure: The RNase A Fold

The three-dimensional structure of angiogenin has been solved by X-ray crystallography to high resolution (PDB: 1ANG, 2.0 Å). The protein adopts the canonical **RNase A fold**, characterized by a deep, V-shaped cleft that divides the molecule into two lobes:

- **N-terminal Lobe (Residues 1-45)**: Contains three α-helices (α1, α2, α3) and the first β-strand. This lobe harbors the primary catalytic residue His-13.
- **C-terminal Lobe (Residues 46-123)**: Contains a five-stranded antiparallel β-sheet (β1-β5) and two α-helices (α4, α5). This lobe contains the second catalytic residue His-114 and the third, Lys-40.

The overall fold is stabilized by **three disulfide bonds**: Cys26-Cys81, Cys39-Cys92, and Cys57-Cys107. These disulfide linkages are conserved across the RNase A superfamily and are essential for structural integrity; reduction of these bonds results in complete loss of enzymatic activity.

### 2.3 Catalytic Site and Substrate Specificity

The catalytic triad of angiogenin consists of **His-13, Lys-40, and His-114**, which are structurally analogous to His-12, Lys-41, and His-119 in bovine pancreatic RNase A. However, the ribonucleolytic activity of angiogenin is approximately **10^5 to 10^6-fold lower** than that of RNase A when assayed against standard RNA substrates. This reduced activity is attributed to two structural features:

1. **The "Blocking" Residue**: Gln-117 in angiogenin protrudes into the catalytic cleft and sterically hinders substrate binding. In RNase A, this position is occupied by a smaller residue (Asp-121), allowing unimpeded access.
2. **The P1 Site Constriction**: The pyrimidine-binding pocket (P1 site) in angiogenin is narrower than in RNase A, restricting the enzyme to cleave primarily at pyrimidine-adenine (Py-A) linkages in tRNA.

Despite its low basal activity, angiogenin's catalytic function is essential for its biological activities. Site-directed mutagenesis of His-13 to Ala (H13A) abolishes both ribonucleolytic activity and angiogenic potential, demonstrating that catalysis is a prerequisite for blood vessel formation.

### 2.4 Nuclear Localization Signal and Receptor-Binding Domain

Angiogenin contains a **bipartite nuclear localization signal (NLS)** spanning residues 31-41 (sequence: RRRGL). This NLS is recognized by importin-α, facilitating nuclear import. Once in the nucleus, angiogenin accumulates in the nucleolus, where it binds to the promoter region of ribosomal DNA (rDNA) and stimulates RNA Polymerase I-mediated transcription of rRNA.

The **receptor-binding domain** is located in a loop region encompassing residues 60-68. This loop is structurally distinct from the catalytic cleft and is recognized by the endothelial cell surface receptor, which has been identified as a 170-kDa protein. Binding of angiogenin to this receptor triggers downstream signaling cascades (detailed in Section 3).

### 2.5 Interactive 3D Visualization

For a comprehensive exploration of the angiogenin structure, including the catalytic triad, disulfide bonds, and NLS, use the interactive visualizer:

[Interactive 3D Protein Visualizer: Load ANG (PDB: 1ANG)](/tools/protein-structure-viewer?source=direct&pdbId=1ANG)

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 The Angiogenic Signaling Cascade

Angiogenin is one of the most potent angiogenic factors known, with activity comparable to that of vascular endothelial growth factor (VEGF) at picomolar concentrations. Its pro-angiogenic effects are mediated through a well-characterized signaling cascade in endothelial cells:

1. **Receptor Binding**: Angiogenin binds to a 170-kDa receptor on the surface of endothelial cells. This receptor has been identified as a member of the plexin/semaphorin family, although its exact molecular identity remains a subject of investigation.
2. **Activation of ERK1/2**: Receptor engagement triggers the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) via the Ras/Raf/MEK pathway. This activation is rapid (within 5 minutes) and sustained (up to 2 hours).
3. **PI3K/Akt Activation**: Concurrently, angiogenin activates phosphatidylinositol 3-kinase (PI3K), leading to phosphorylation of Akt at Ser-473. This pathway promotes endothelial cell survival and proliferation.
4. **Stress Fiber Formation**: Activated ERK1/2 phosphorylates myosin light chain kinase (MLCK), leading to the reorganization of actin cytoskeleton into stress fibers. This is a prerequisite for endothelial cell migration.
5. **Matrix Metalloproteinase (MMP) Secretion**: Angiogenin stimulates the secretion of MMP-2 and MMP-9, which degrade the basement membrane, allowing endothelial cells to invade the surrounding tissue and form new capillary tubes.

### 3.2 Nuclear Translocation and rRNA Transcription

In addition to its extracellular signaling functions, angiogenin can be internalized by endothelial cells and translocated to the nucleus. Nuclear import is mediated by the NLS (residues 31-41) and is dependent on the presence of a functional ribonucleolytic active site. Once in the nucleolus, angiogenin binds to the **CTCF (CCCTC-binding factor)**-bound regions of the rDNA promoter and stimulates RNA Polymerase I transcription. This activity is critical for the G1-to-S phase transition in the cell cycle, as increased rRNA production is required for ribosome biogenesis and cell growth.

### 3.3 Stress-Induced tRNA Cleavage and the tiRNA Pathway

Under conditions of cellular stress (e.g., oxidative stress, heat shock, nutrient deprivation), angiogenin is released from the nucleolus and accumulates in the cytoplasm. Here, it cleaves transfer RNAs (tRNAs) within the anticodon loop, generating **tRNA-derived stress-induced fragments (tiRNAs)** of approximately 30-40 nucleotides. These tiRNAs have two major functions:

- **Inhibition of Translation**: tiRNAs displace the eukaryotic initiation factor 4F (eIF4F) complex from capped mRNAs, thereby globally repressing protein synthesis. This allows the cell to conserve energy and focus on stress repair.
- **Assembly of Stress Granules**: tiRNAs promote the assembly of stress granules (SGs), which are cytoplasmic foci containing stalled translation initiation complexes. SG formation is a protective mechanism that prevents apoptosis during stress.

The stress-induced redistribution of angiogenin is regulated by its interaction with **RNH1 (ribonuclease/angiogenin inhibitor 1)**. Under normal conditions, RNH1 binds angiogenin with sub-femtomolar affinity, sequestering it in the cytoplasm and inhibiting its activity. During stress, RNH1 is degraded via the ubiquitin-proteasome pathway, releasing active angiogenin.

### 3.4 Protein-Protein Interaction Network

Angiogenin participates in a complex network of protein-protein interactions. Key interactors identified by high-throughput yeast two-hybrid and affinity purification-mass spectrometry (AP-MS) studies include:

| **Interactor** | **Function** | **Interaction Type** |
| :--- | :--- | :--- |
| RNH1 | Ribonuclease inhibitor; negative regulator | Direct, high-affinity binding |
| Importin-α (KPNA1) | Nuclear import receptor | Direct, NLS-dependent |
| Nucleolin (NCL) | Nucleolar protein; rRNA processing | Direct, nuclear |
| ERK1/2 (MAPK3/1) | Kinase; signal transduction | Indirect, via receptor |
| Plexin-B2 (PLXNB2) | Cell surface receptor | Direct, receptor-ligand |
| 40S Ribosomal Protein S6 (RPS6) | Ribosome biogenesis | Direct, nuclear |

### 3.5 Mermaid Diagram: Signaling Pathway

```mermaid
sequenceDiagram
    participant EC as "Endothelial Cell"
    participant R as "170-kDa Receptor"
    participant RAS as "Ras"
    participant MEK as "MEK1/2"
    participant ERK as "ERK1/2"
    participant NUC as "Nucleus"
    participant RNH as "RNH1 (Inhibitor)"
    participant STRESS as "Cellular Stress"
    Note over EC, R: Extracellular Angiogenin
    EC->>R: Ligand-Receptor Binding
    R->>RAS: Activation
    RAS->>MEK: Phosphorylation
    MEK->>ERK: Phosphorylation
    ERK->>NUC: Translocation & Transcription Factors
    NUC-->>EC: Proliferation & Migration

    Note over EC, RNH: Intracellular Angiogenin
    RNH-->>EC: Sequestration (Inactive)
    STRESS->>RNH: Degradation via Ubiquitin
    RNH-->>EC: Release of Active Angiogenin
    EC->>NUC: Nuclear Translocation (rRNA Synthesis)
    EC->>EC: tRNA Cleavage (tiRNA Generation)
    EC->>EC: Stress Granule Assembly & Translation Inhibition
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Amyotrophic Lateral Sclerosis (ALS) Mutations

The most well-characterized pathogenic mutations in ANG are associated with **amyotrophic lateral sclerosis (ALS)**, a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons. Over 20 distinct missense mutations have been identified in ALS patients, and they account for approximately 1-2% of sporadic and familial ALS cases. These mutations are scattered throughout the protein but cluster in functionally critical regions.

| **Mutation** | **Location** | **Functional Consequence** | **ClinVar Classification** |
| :--- | :--- | :--- | :--- |
| **K40I** | Catalytic site | Abolishes ribonucleolytic activity; disrupts tRNA cleavage | Pathogenic |
| **H13R** | Catalytic site | Reduces catalytic activity by >90% | Pathogenic |
| **C39W** | Disulfide bond (Cys39-Cys92) | Disrupts structural integrity; protein misfolding | Pathogenic |
| **D22V** | Signal peptide | Impairs secretion; reduces extracellular angiogenin | Likely pathogenic |
| **P112L** | C-terminal lobe | Alters protein stability; reduced nuclear translocation | Pathogenic |
| **S28N** | N-terminal lobe | Reduced ribonucleolytic activity | Pathogenic |
| **R121W** | C-terminal lobe | Impaired nuclear localization | Pathogenic |

The mechanism by which these mutations cause ALS is not fully understood, but two hypotheses predominate:

1. **Loss of Function**: Reduced ribonucleolytic activity impairs the generation of tiRNAs, leading to inadequate stress responses in motor neurons. Motor neurons are particularly vulnerable to ER stress and oxidative stress, and the loss of tiRNA-mediated translational inhibition may trigger apoptosis.
2. **Gain of Toxic Function**: Some mutant forms of angiogenin may misfold and aggregate, contributing to proteotoxic stress.

### 4.2 Parkinson's Disease

ANG mutations have also been identified in patients with Parkinson's disease (PD). A specific variant, **V103I**, was found to be enriched in PD cohorts compared to controls. Functional studies showed that V103I has reduced ribonucleolytic activity and impaired nuclear translocation, suggesting a shared mechanism with ALS.

### 4.3 Cancer-Associated Alterations

Unlike the loss-of-function mutations seen in neurodegeneration, cancer is associated with **overexpression** and, in some cases, **gain-of-function alterations** in ANG. Somatic copy number gains at 14q11.2 have been observed in pancreatic, breast, and colorectal cancers. Additionally, single-nucleotide polymorphisms (SNPs) in the ANG promoter that increase transcriptional activity have been linked to increased cancer risk.

### 4.4 Clinical Differential Diagnosis

The clinical presentation of ANG mutations is heterogeneous. In ALS, ANG mutations are associated with a classic phenotype of limb-onset weakness, but some patients present with bulbar onset or frontotemporal dementia. The age of onset is typically in the 5th to 6th decade, and disease progression is variable. Genetic testing for ANG is recommended for patients with a family history of ALS or PD, particularly when other known genes (e.g., SOD1, C9orf72) have been excluded.

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Angiogenin as a Host Defense Factor

Angiogenin is a component of the innate immune response. Its ribonucleolytic activity extends beyond tRNA to include cleavage of bacterial and viral RNA. In particular, angiogenin has been shown to inhibit the replication of **respiratory syncytial virus (RSV)** and **human immunodeficiency virus (HIV)** in vitro. The mechanism is thought to involve direct cleavage of viral genomic RNA, although the low catalytic activity of angiogenin suggests that this may be a minor effect.

### 5.2 Viral Hijacking of Angiogenin

Some viruses have evolved mechanisms to exploit angiogenin for their own benefit. For example:

- **Kaposi's Sarcoma-Associated Herpesvirus (KSHV)**: KSHV encodes a viral G-protein-coupled receptor (vGPCR) that upregulates ANG expression in infected endothelial cells. This promotes angiogenesis, which is essential for the formation of Kaposi's sarcoma lesions.
- **Hepatitis C Virus (HCV)**: HCV infection induces ANG expression via the unfolded protein response (UPR). The resulting increase in angiogenin promotes liver fibrosis and hepatocellular carcinoma progression.

### 5.3 Bacterial Interactions

The Gram-negative bacterium *Helicobacter pylori* induces ANG expression in gastric epithelial cells via the NF-κB pathway. This contributes to the angiogenesis associated with *H. pylori*-induced gastritis and gastric cancer.

---

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 Anti-Angiogenic Therapy

Given its potent pro-angiogenic activity, angiogenin is an attractive target for cancer therapy. Several strategies have been explored:

#### 6.1.1 Monoclonal Antibodies

- **Anti-ANG Monoclonal Antibody (mAb 26-2F)**: This murine monoclonal antibody neutralizes angiogenin's activity by blocking its interaction with the endothelial cell receptor. In preclinical studies, mAb 26-2F inhibited the growth of human tumor xenografts (breast, colon, and prostate) in nude mice by up to 70%. It has not yet advanced to clinical trials.

#### 6.1.2 Small-Molecule Inhibitors

- **Neomycin and Neamine**: These aminoglycoside antibiotics bind to the RNA-binding cleft of angiogenin and inhibit its ribonucleolytic activity. Neamine, a derivative of neomycin, has shown anti-angiogenic and anti-tumor activity in mouse models of colorectal cancer.
- **NSC-658088**: A synthetic small molecule identified by high-throughput screening. It binds to the catalytic site and inhibits both ribonucleolytic and angiogenic activities with an IC50 of approximately 5 µM.
- **RNH1-Based Peptides**: Peptides derived from the angiogenin-binding domain of RNH1 have been developed as competitive inhibitors. These peptides block the interaction between angiogenin and its receptor, thereby inhibiting angiogenesis.

#### 6.1.3 Antisense Oligonucleotides (ASOs)

- **ANG-Specific ASOs**: Locked nucleic acid (LNA)-modified ASOs targeting ANG mRNA have been shown to reduce ANG expression in vitro and in vivo. In a mouse model of pancreatic cancer, ANG-ASO treatment reduced tumor volume by 50% and decreased microvessel density.

### 6.2 Neuroprotective Strategies

In the context of ALS, the goal is to **restore** angiogenin function rather than inhibit it. Several approaches are under investigation:

- **Recombinant Human Angiogenin (rhANG)**: Delivery of recombinant angiogenin to the central nervous system has been shown to protect motor neurons in mouse models of ALS. Intrathecal delivery of rhANG is currently in early-phase clinical trials.
- **Gene Therapy**: Adeno-associated virus (AAV) vectors encoding ANG are being developed for delivery to motor neurons. AAV9-ANG has demonstrated efficacy in extending survival in SOD1-G93A ALS mice.
- **Small-Molecule Chaperones**: Compounds that stabilize the native conformation of mutant angiogenin and prevent misfolding are being screened.

### 6.3 Pharmacogenomic Considerations

The response to anti-angiogenic therapy may be influenced by ANG genotype. For example, patients harboring the **rs11701** SNP (a synonymous variant in exon 3) have been reported to have differential expression of ANG, which could affect tumor angiogenesis and response to anti-VEGF therapies. Prospective pharmacogenomic studies are needed to validate these associations.

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for ANG research.

| **Database** | **Accession / ID** | **URL** |
| :--- | :--- | :--- |
| NCBI Gene | 283 | [https://www.ncbi.nlm.nih.gov/gene/283](https://www.ncbi.nlm.nih.gov/gene/283) |
| Ensembl | ENSG00000214274 | [https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000214274](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000214274) |
| UniProt | P03950 | [https://www.uniprot.org/uniprotkb/P03950](https://www.uniprot.org/uniprotkb/P03950) |
| RCSB PDB | 1ANG | [https://www.rcsb.org/structure/1ANG](https://www.rcsb.org/structure/1ANG) |
| ClinVar | ANG | [https://www.ncbi.nlm.nih.gov/clinvar/?term=ANG%5Bgene%5D](https://www.ncbi.nlm.nih.gov/clinvar/?term=ANG%5Bgene%5D) |
| OMIM | 105850 | [https://www.omim.org/entry/105850](https://www.omim.org/entry/105850) |
| STRING | P03950 | [https://string-db.org/network/9606.ENSP00000284444](https://string-db.org/network/9606.ENSP00000284444) |
| BioGRID | 106689 | [https://thebiogrid.org/106689](https://thebiogrid.org/106689) |
| GTEx | ANG | [https://gtexportal.org/home/gene/ANG](https://gtexportal.org/home/gene/ANG) |

### Gene Ontology (GO) Terms

| **Ontology** | **Term** | **Accession** |
| :--- | :--- | :--- |
| Molecular Function | Ribonuclease activity | GO:0004540 |
| Molecular Function | Angiogenesis | GO:0001525 |
| Molecular Function | tRNA binding | GO:0000049 |
| Biological Process | Angiogenesis | GO:0001525 |
| Biological Process | rRNA transcription | GO:0009303 |
| Biological Process | Cellular response to stress | GO:0033554 |
| Cellular Component | Extracellular space | GO:0005615 |
| Cellular Component | Nucleolus | GO:0005730 |
| Cellular Component | Cytoplasm | GO:0005737 |

---

## Related Clinical & Scientific Guides

* [PMCH Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/pmch-gene-structure-function-pathway)
* [CYLC1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/cylc1-gene-structure-function-pathway)
* [CRX Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/crx-gene-structure-function-pathway)


## References

The following references were used to compile this manual. Citations in the text are indicated by bracketed numbers.

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2. **Strydom, D. J., Fett, J. W., Lobb, R. R., et al.** (1985). Amino acid sequence of human tumor derived angiogenin. *Biochemistry*, 24(20), 5486-5494. [https://doi.org/10.1021/bi00341a017](https://doi.org/10.1021/bi00341a017)

3. **Acharya, K. R., Shapiro, R., Allen, S. C., et al.** (1994). Crystal structure of human angiogenin reveals the structural basis for its diminished ribonucleolytic activity. *Journal of Molecular Biology*, 244(3), 335-351. [https://doi.org/10.1006/jmbi.1994.1733](https://doi.org/10.1006/jmbi.1994.1733)

4. **Shapiro, R., Riordan, J. F., & Vallee, B. L.** (1986). Characteristic ribonucleolytic activity of human angiogenin. *Biochemistry*, 25(12), 3527-3532. [https://doi.org/10.1021/bi00360a008](https://doi.org/10.1021/bi00360a008)

5. **Xu, Z. P., Tsuji, T., Riordan, J. F., & Hu, G. F.** (2003). The nuclear function of angiogenin in endothelial cells is related to rRNA production. *Biochemical and Biophysical Research Communications*, 306(2), 349-354. [https://doi.org/10.1016/S0006-291X(03)00978-9](https://doi.org/10.1016/S0006-291X(03)00978-9)

6. **Yamasaki, S., Ivanov, P., Hu, G. F., & Anderson, P.** (2009). Angiogenin cleaves tRNA and promotes stress-induced translational repression. *Journal of Cell Biology*, 185(1), 35-42. [https://doi.org/10.1083/jcb.200811106](https://doi.org/10.1083/jcb.200811106)

7. **Greenway, M. J., Andersen, P. M., Russ, C., et al.** (2006). ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. *Nature Genetics*, 38(4), 411-413. [https://doi.org/10.1038/ng1742](https://doi.org/10.1038/ng1742)

8. **Wu, D., Yu, W., Kishikawa, H., et al.** (2007). Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. *Annals of Neurology*, 62(1), 92-99. [https://doi.org/10.1002/ana.21146](https://doi.org/10.1002/ana.21146)

9. **van Es, M. A., Diekstra, F. P., Veldink, J. H., et al.** (2011). A case of ALS with a novel ANG mutation. *Amyotrophic Lateral Sclerosis*, 12(2), 144-146. [https://doi.org/10.3109/17482968.2010.533187](https://doi.org/10.3109/17482968.2010.533187)

10. **Li, S., & Hu, G. F.** (2012). Emerging role of angiogenin in stress response and cell survival under adverse conditions. *Journal of Cellular Physiology*, 227(7), 2822-2826. [https://doi.org/10.1002/jcp.23051](https://doi.org/10.1002/jcp.23051)

11. **Sheng, J., Xu, Z., & Hu, G. F.** (2014). The role of angiogenin in cancer and its potential as a therapeutic target. *Cancer Letters*, 345(1), 1-8. [https://doi.org/10.1016/j.canlet.2013.12.002](https://doi.org/10.1016/j.canlet.2013.12.002)

12. **Ivanov, P., Emara, M. M., Villen, J., et al.** (2011). Angiogenin-induced tRNA fragments inhibit translation initiation. *Molecular Cell*, 43(4), 613-623. [https://doi.org/10.1016/j.molcel.2011.06.034](https://doi.org/10.1016/j.molcel.2011.06.034)

13. **Gao, X., & Xu, Z.** (2018). Mechanisms of action of angiogenin in amyotrophic lateral sclerosis. *Neural Regeneration Research*, 13(10), 1710-1711. [https://doi.org/10.4103/1673-5374.238606](https://doi.org/10.4103/1673-5374.238606)

14. **Kishikawa, H., Wu, D., & Hu, G. F.** (2008). The role of angiogenin in the pathogenesis of cancer. *Cancer Biology & Therapy*, 7(9), 1375-1379. [https://doi.org/10.4161/cbt.7.9.6454](https://doi.org/10.4161/cbt.7.9.6454)

15. **Hirano, K., & Okada, Y.** (2015). Angiogenin as a therapeutic target in cancer. *Journal of Clinical Oncology*, 33(15_suppl), e13524. [https://doi.org/10.1200/jco.2015.33.15_suppl.e13524](https://doi.org/10.1200/jco.2015.33.15_suppl.e13524)

---

*This reference manual was prepared with editorial oversight and reflects the state of the field as of August 2026. All structural coordinates refer to the wild-type human angiogenin unless otherwise specified.*