Three decades of research on angiogenin: a review and perspective

Abstract

As a member of the vertebrate-specific secreted ribonucleases, angiogenin (ANG) was first isolated and identified solely by its ability to induce new blood vessel formation, and now, it has been recognized to play important roles in various physiological and pathological processes through regulating cell proliferation, survival, migration, invasion, and/or differentiation. ANG exhibits very weak ribonucleolytic activity that is critical for its biological functions, and exerts its functions through activating different signaling transduction pathways in different target cells. A series of recent studies have indicated that ANG contributes to cellular nucleic acid metabolism. Here, we comprehensively review the results of studies regarding the structure, mechanism, and function of ANG over the past three decades. Moreover, current problems and future research directions of ANG are discussed. The understanding of the function and mechanism of ANG in a wide context will help to better delineate its roles in diseases, especially in cancer and neurodegenerative diseases.

Keywords: RNA metabolism; angiogenesis; angiogenin; neurodegeneration disease; tumorigenesis.

Figure 1.

Gene structure of angiogenin (ANG) and the ribonuclease 4 (RNASE4) locus in mammalian whole-genome sequences The locus usually contains four exons, three introns, and two promoters. The exons containing the coding regions of ANG and RNASE4 are indicated by gray arrows. The chromatin and nucleotide numbering of the locus are indicated below the chromatin line.

Figure 2.

Schematic representation of the crystal structure of human ANG at a resolution of 1.8 Å The file with PDB ID IB1I (human ANG) [160] was retrieved from protein data bank and visualized with Cn3D. ANG consists of 123 amino acid residues with two α-helices (green tubular arrow), seven β-sheets (yellow sheet arrow), and three disulfide bonds (red line). The protein contains three main catalytic residues (His-13, Lys-40, and His-114) that compose the catalytic center (P1) at which phosphodiester bond cleavage occurs. NLS and receptor-binding site are colored by yellow. Further details can be found in the text.

Figure 3.

Schematic representation of the mechanisms of action of ANG Secreted ANG undergoes receptor-mediated endocytosis from the cell surface to the inside of the cell where it accumulates in the nucleoli under growth conditions or in the cytoplasm under stress conditions. First, the extracellular ANG activates signal transduction pathways including SAPK/JNK, ERK1/2, and PI3K/AKT pathways, in different cells and cell conditions, although full pathway investigations have yet to be performed. The interaction between ANG and cell-surface complex could lead to ECM degradation and matrix metalloproteinase activation that promote cell migration and invasion. Second, the cytoplasmic ANG cleaves the tRNA to form tiRNA in response to stress, while the 5′-tiRNA interacts with the translational silencer YB-1 to inhibit translational initiation by recruiting eIF4G/A from uncapped mRNAs. ANG also inhibits the serine-15 phosphorylation of p53 and the subsequent binding of Mdm2, resulting in ubiquitination of p53. In addition, cytoplasmic ANG can optimize stress fiber assembly and focal adhesion formation to accommodate cell migration. Third, the nuclear ANG contributes to the rRNA transcription/procession and mRNA transcription under growth conditions. Further details can be found in the text. SAPK/JNK, stress-associated protein kinase/c-Jun N-terminal kinase; ERK1/2, extracellular signal-related kinase 1/2; YB-1, Y box binding protein 1; eIF4, eukaryotic initiation factor-4; Mdm2, MDM2 protooncogene, E3 ubiquitin protein ligase; RNH1, human placental ribonuclease inhibitor; ECM, extracellular matrix; LR, lipid raft; uPAR, urokinase plasminogen activator receptor; uPA, urokinase plasminogen activator; A2, annexin A2; S100, calpactin S100-A10; VT, vitronectin; PLSG, plasminogen; PLN, plasmin; PLSCR1, phospholipid scramblase 1.

Figure 4.

Schematic representation of ANG mutations identified to date in ALS and PD patients All the reported human ANG mutations are shown. Newly synthesized ANG has 147 amino acids and contains several conserved domains: signal peptide, receptor-binding site, RNase A canonical domain, catalytic site, and NLS. Numbers under the protein line indicate the boundaries of each domain. Mutations identified in ALS (black and blue) and PD (orange) patients are shown above the protein line.