Plexin-B2 Mediates Physiologic and Pathologic Functions of Angiogenin

Abstract

SUMMARY Angiogenin (ANG) is a secreted ribonuclease (RNase) with cell type- and context-specific roles in growth, survival, and regeneration. Although these functions require receptor-mediated endocytosis and appropriate subcellular localization, the identity of the cell surface receptor remains undefined. Here, we show that plexin-B2 (PLXNB2) is the functional receptor for ANG in endothelial, cancer, neuronal, and normal hematopoietic and leukemic stem and progenitor cells. Mechanistically, PLXNB2 mediates intracellular RNA processing that contribute to cell growth, survival, and regenerative capabilities of ANG. Antibodies generated against the ANG binding site on PLXNB2 restricts ANG activity in vitro and in vivo, resulting in inhibition of established xenograft tumors, ANG-induced neurogenesis and neuroprotection, levels of pro-self-renewal transcripts in hematopoietic and patient-derived leukemic stem/progenitor cells, and reduced progression of leukemia in vivo. PLXNB2 is therefore required for the physiological and pathological functions of ANG and has significant therapeutic potential in solid and hematopoietic cancers and neurodegenerative diseases.

Angiogenin promotes colorectal cancer metastasis via tiRNA production

“…Recent advances indicate that the subcellular localization and ribonucleolytic activity of ANG are essential to its biological functions . Mechanistically, ANG accumulates in the nucleus where it regulates rRNA and mRNA transcriptions to promote cell proliferation under growth conditions, while ANG translocates to the cytosol where it specifically cleaves the anticodon loop of tRNAs to yield 5′ and 3′ halves (termed as tRNA‐derived stress‐induced small RNA, tiRNA) under stress conditions, resulting in protein‐translation reprogramming and thereby promoting cell survival . The expression level, ribonuclease activity and cytoplasmic localization of ANG are positively correlated with tiRNA production .…”

“…7 Mechanistically, ANG accumulates in the nucleus where it regulates rRNA and mRNA transcriptions to promote cell proliferation under growth conditions, 8,9 while ANG translocates to the cytosol where it specifically cleaves the anticodon loop of tRNAs to yield 5 0 and 3 0 halves (termed as tRNA-derived stress-induced small RNA, tiRNA) under stress conditions, resulting in protein-translation reprogramming and thereby promoting cell survival. [10][11][12][13] The expression level, ribonuclease activity and cytoplasmic localization of ANG are positively correlated with tiRNA production. 11,14 However, although ANG has been reported to be upregulated in sera and tissues of CRC patients, [15][16][17] and to promote HT-29 cell adhesion in vitro, 18 its authentic role in CRC progression has not been explored.…”

Chemosensitization of prostate cancer stem cells in mice by angiogenin and plexin-B2 inhibitors

“…ANG has been shown to be progressively upregulated in prostate cancer 8,16,17,19,45 and plays a role in the transition from androgen-dependent to castration-resistant, hormone-refractory phenotype 21,45 . PLXNB2 has also been shown to be upregulated in prostate cancer and be inversely correlated with patient survival 14 . Expression levels of ANG ( Supplementary Fig 5a) and PLXNB2 ( Supplementary Fig.…”

“…We have reported that bone marrow niche-secreted ANG 7 promotes quiescence of primitive HSPCs by enhancing tiRNA production, which leads to restricted protein synthesis in these cells, whereas, in more differentiated MyePros, ANG promotes 47S rRNA transcription thereby stimulating protein synthesis and cell proliferation 6 . The differential functions of ANG in primitive stem cells and in differentiated cells are both mediated by plexin-B2 (PLXNB2), a recently identified functional ANG receptor that is both necessary and sufficient for the physiological and pathological functions of ANG in multiple cell types 14 .…”

Identification of the cis‑molecular neighbours of the immune checkpoint protein�B7‑H4 in the breast cancer cell‑line SK‑BR‑3 by proteomic proximity labelling

“…CD4 T-cells (30). Another plexin identified as being in close proximity to B7-H4 on the cell surface, PLXNB2, is required for the physiological and pathological functions of angiogenin (ANG) and has significant therapeutic potential in solid and hematopoietic cancers and neurodegenerative diseases (31). In addition, quantitative SILAC demonstrated increased expression of Enox1 that has previously been implicated in immune regulation: As a candidate gene for the autoimmune disease myasthenia gravis (32), and as a biomarker of response to an anti-IL6 mAb in rheumatoid arthritis (33).…”