Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004540 RNA nuclease activity	IBA GO_REF:0000033	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0005615 obsolete extracellular space	IBA GO_REF:0000033	MODIFY	Summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region. Reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term. Proposed replacements: extracellular region Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0019731 antibacterial humoral response	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Kept as non-core. This immune/antimicrobial IBA annotation may reflect secreted RNase biology, but ANG is better characterized by RNase/stress and angiogenic functions.
GO:0045087 innate immune response	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Kept as non-core. Recent evidence supports ANG-derived tsRNAs in innate immune/inflammasome regulation, but this is context-specific. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated 5′ tsRNAs are anti-inflammatory effectors that suppress NLRP3 inflammasome activation and pyroptosis by promoting DDX3X recruitment into SGs, reducing DDX3X-NLRP3 interaction.
GO:0050830 defense response to Gram-positive bacterium	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Kept as non-core. This immune/antimicrobial IBA annotation may reflect secreted RNase biology, but ANG is better characterized by RNase/stress and angiogenic functions.
GO:0061844 antimicrobial humoral immune response mediated by antimicrobial peptide	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Kept as non-core. This immune/antimicrobial IBA annotation may reflect secreted RNase biology, but ANG is better characterized by RNase/stress and angiogenic functions.
GO:0001525 angiogenesis	IBA GO_REF:0000033	ACCEPT	Summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0003676 nucleic acid binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Generic nucleic acid binding does not describe the catalytic RNA-cleavage function.
GO:0004540 RNA nuclease activity	IEA GO_REF:0000117	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005730 nucleolus	IEA GO_REF:0000044	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0010494 cytoplasmic stress granule	IEA GO_REF:0000044	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0005515 protein binding	IPI PMID:10413501 Superadditive and subadditive effects of "hot spot" mutation...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005515 protein binding	IPI PMID:15737636 Alpha-actinin-2, a cytoskeletal protein, binds to angiogenin...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005515 protein binding	IPI PMID:17991437 Identification and characterization of follistatin as a nove...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005515 protein binding	IPI PMID:24457100 Angiogenin interacts with the plasminogen activation system ...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005515 protein binding	IPI PMID:28777577 Proteomic Analysis of Human Angiogenin Interactions Reveals ...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005730 nucleolus	IDA GO_REF:0000052	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0004521 RNA endonuclease activity	TAS Reactome:R-HSA-9708327	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0007165 signal transduction	IDA PMID:29100074 Plexin-B2 Mediates Physiologic and Pathologic Functions of A...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Broad signaling is less informative than receptor ligand, angiogenesis, and RNase/stress-response terms.
GO:0048018 receptor ligand activity	IDA PMID:29100074 Plexin-B2 Mediates Physiologic and Pathologic Functions of A...	KEEP AS NON CORE	Summary: Supported but non-core. Receptor-mediated signaling or uptake is relevant to ANG trafficking and extracellular activity, but not the central RNase mechanism. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0004540 RNA nuclease activity	IDA PMID:23047679 Structural and molecular insights into the mechanism of acti...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0005615 obsolete extracellular space	IDA PMID:23047679 Structural and molecular insights into the mechanism of acti...	MODIFY	Summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region. Reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term. Proposed replacements: extracellular region Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005634 nucleus	IDA PMID:23047679 Structural and molecular insights into the mechanism of acti...	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005737 cytoplasm	IDA PMID:23047679 Structural and molecular insights into the mechanism of acti...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Prefer specific cytosol, stress granule, nuclear, nucleolar, and extracellular localization terms.
GO:0034063 stress granule assembly	IDA PMID:23047679 Structural and molecular insights into the mechanism of acti...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:27518564 Angiogenin Promotes Hematopoietic Regeneration by Dichotomou...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:29100074 Plexin-B2 Mediates Physiologic and Pathologic Functions of A...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:32510170 Myeloid cells protect intestinal epithelial barrier integrit...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:38718836 Structural mechanism of angiogenin activation by the ribosom...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0009303 rRNA transcription	IDA PMID:27518564 Angiogenin Promotes Hematopoietic Regeneration by Dichotomou...	ACCEPT	Summary: Correct. In nucleoli, ANG promotes rRNA transcription and ribosome biogenesis under growth conditions. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0009303 rRNA transcription	IDA PMID:29100074 Plexin-B2 Mediates Physiologic and Pathologic Functions of A...	ACCEPT	Summary: Correct. In nucleoli, ANG promotes rRNA transcription and ribosome biogenesis under growth conditions. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0009303 rRNA transcription	IDA PMID:32510170 Myeloid cells protect intestinal epithelial barrier integrit...	ACCEPT	Summary: Correct. In nucleoli, ANG promotes rRNA transcription and ribosome biogenesis under growth conditions. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0010494 cytoplasmic stress granule	IDA PMID:27518564 Angiogenin Promotes Hematopoietic Regeneration by Dichotomou...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0010494 cytoplasmic stress granule	IDA PMID:29100074 Plexin-B2 Mediates Physiologic and Pathologic Functions of A...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0032055 negative regulation of translation in response to stress	IDA PMID:27518564 Angiogenin Promotes Hematopoietic Regeneration by Dichotomou...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0032055 negative regulation of translation in response to stress	IDA PMID:29100074 Plexin-B2 Mediates Physiologic and Pathologic Functions of A...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0032055 negative regulation of translation in response to stress	IDA PMID:32510170 Myeloid cells protect intestinal epithelial barrier integrit...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0032055 negative regulation of translation in response to stress	IDA PMID:38718836 Structural mechanism of angiogenin activation by the ribosom...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0043022 ribosome binding	IDA PMID:38718836 Structural mechanism of angiogenin activation by the ribosom...	ACCEPT	Summary: Correct and informative. Ribosome binding activates ANG and positions tRNA substrate for efficient anticodon-loop cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A key unresolved question in the field has been why ANG is a weak RNase as a free protein yet is biologically potent in cells. Loveland et al. (bioRxiv, posted 2023-12; version/availability in 2024) provide structural and biochemical evidence that the cytosolic 80S ribosome is the activator and specificity factor for ANG.
GO:0071425 hematopoietic stem cell proliferation	IDA PMID:27518564 Angiogenin Promotes Hematopoietic Regeneration by Dichotomou...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0004540 RNA nuclease activity	IDA PMID:3289612 Base cleavage specificity of angiogenin with Saccharomyces c...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:19332886 Angiogenin cleaves tRNA and promotes stress-induced translat...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:20129916 Angiogenin-induced tRNA-derived stress-induced RNAs promote ...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:21855800 Angiogenin-induced tRNA fragments inhibit translation initia...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:31582561 Angiogenin generates specific stress-induced tRNA halves and...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0032055 negative regulation of translation in response to stress	IDA PMID:19332886 Angiogenin cleaves tRNA and promotes stress-induced translat...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0032055 negative regulation of translation in response to stress	IDA PMID:20129916 Angiogenin-induced tRNA-derived stress-induced RNAs promote ...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0032055 negative regulation of translation in response to stress	IDA PMID:21855800 Angiogenin-induced tRNA fragments inhibit translation initia...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0032055 negative regulation of translation in response to stress	IDA PMID:31582561 Angiogenin generates specific stress-induced tRNA halves and...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0034063 stress granule assembly	IDA PMID:20129916 Angiogenin-induced tRNA-derived stress-induced RNAs promote ...	ACCEPT	Summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0043066 negative regulation of apoptotic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Supported as a non-core survival/stress-response outcome of ANG-derived tiRNAs rather than a direct molecular function. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
GO:0001525 angiogenesis	IDA PMID:3470787 Human placental ribonuclease inhibitor abolishes both angiog...	ACCEPT	Summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0004540 RNA nuclease activity	IDA PMID:11919285 Diversifying selection of the tumor-growth promoter angiogen...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0004540 RNA nuclease activity	IDA PMID:3470787 Human placental ribonuclease inhibitor abolishes both angiog...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0004549 tRNA-specific ribonuclease activity	IDA PMID:29748193 Human angiogenin is a potent cytotoxin in the absence of rib...	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0005615 obsolete extracellular space	IDA PMID:29748193 Human angiogenin is a potent cytotoxin in the absence of rib...	MODIFY	Summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region. Reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term. Proposed replacements: extracellular region Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005634 nucleus	IDA PMID:23843625 Ribonuclease/angiogenin inhibitor 1 regulates stress-induced...	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005737 cytoplasm	IDA PMID:23843625 Ribonuclease/angiogenin inhibitor 1 regulates stress-induced...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Prefer specific cytosol, stress granule, nuclear, nucleolar, and extracellular localization terms.
GO:0030139 endocytic vesicle	IDA PMID:29748193 Human angiogenin is a potent cytotoxin in the absence of rib...	KEEP AS NON CORE	Summary: Supported but non-core. Receptor-mediated signaling or uptake is relevant to ANG trafficking and extracellular activity, but not the central RNase mechanism. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0004540 RNA nuclease activity	IDA PMID:2459697 Mutagenesis of aspartic acid-116 enhances the ribonucleolyti...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0004540 RNA nuclease activity	IDA PMID:3122207 Ribonucleolytic activity of angiogenin: essential histidine,...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0004540 RNA nuclease activity	IDA PMID:8159680 Role of glutamine-117 in the ribonucleolytic activity of hum...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0004540 RNA nuclease activity	IDA PMID:8570639 A combined kinetic and modeling study of the catalytic cente...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0004540 RNA nuclease activity	IDA PMID:8622921 The C-terminal region of human angiogenin has a dual role in...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0001525 angiogenesis	IDA PMID:4074709 Isolation and characterization of angiogenin, an angiogenic ...	ACCEPT	Summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0023052 signaling	IDA PMID:2457905 Angiogenin activates endothelial cell phospholipase C.	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Broad signaling is less informative than receptor ligand, angiogenesis, and RNase/stress-response terms.
GO:0016078 tRNA decay	TAS Reactome:R-HSA-9708296	ACCEPT	Summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt.
GO:0005829 cytosol	TAS Reactome:R-HSA-9708327	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005576 extracellular region	TAS Reactome:R-HSA-5692437	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005634 nucleus	IDA PMID:25372031 Computational and functional characterization of Angiogenin ...	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0042803 protein homodimerization activity	IDA PMID:25372031 Computational and functional characterization of Angiogenin ...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0001525 angiogenesis	IDA PMID:8448182 Characterization and sequencing of rabbit, pig and mouse ang...	ACCEPT	Summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0001556 oocyte maturation	NAS PMID:11438326 Concentrations of angiogenic factors in follicular fluid and...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0001666 response to hypoxia	IDA PMID:10999833 Evidence for the presence of angiogenin in human follicular ...	KEEP AS NON CORE	Summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0009725 response to hormone	IDA PMID:10999833 Evidence for the presence of angiogenin in human follicular ...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0030426 growth cone	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0042277 peptide binding	IDA PMID:11782452 Antiplasmin activity of a peptide that binds to the receptor...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Peptide binding is too generic for ANG-specific curation.
GO:0043025 neuronal cell body	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0001525 angiogenesis	IMP PMID:17125737 Angiogenin-induced protein kinase B/Akt activation is necess...	ACCEPT	Summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0016477 cell migration	IMP PMID:17125737 Angiogenin-induced protein kinase B/Akt activation is necess...	KEEP AS NON CORE	Summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0042327 positive regulation of phosphorylation	IDA PMID:17125737 Angiogenin-induced protein kinase B/Akt activation is necess...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0032311 angiogenin-PRI complex	IDA PMID:3470787 Human placental ribonuclease inhibitor abolishes both angiog...	KEEP AS NON CORE	Summary: Supported but non-core. The angiogenin-PRI/RNH1 complex is a specific inhibitory regulatory complex for ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md RNH1/RI is the principal intracellular inhibitor that restrains ANG activity and trafficking.
GO:0032311 angiogenin-PRI complex	IPI PMID:3470787 Human placental ribonuclease inhibitor abolishes both angiog...	KEEP AS NON CORE	Summary: Supported but non-core. The angiogenin-PRI/RNH1 complex is a specific inhibitory regulatory complex for ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md RNH1/RI is the principal intracellular inhibitor that restrains ANG activity and trafficking.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:9707554 Neomycin inhibits angiogenin-induced angiogenesis.	KEEP AS NON CORE	Summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0005730 nucleolus	ISS GO_REF:0000024	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0030041 actin filament polymerization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0050714 positive regulation of protein secretion	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0001525 angiogenesis	IMP PMID:2479414 Site-directed mutagenesis of histidine-13 and histidine-114 ...	ACCEPT	Summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0003677 DNA binding	IC PMID:10649442 Human angiogenin is rapidly translocated to the nucleus of h...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: DNA binding is too generic relative to nucleolar rRNA-transcription and RNase annotations.
GO:0004519 endonuclease activity	TAS PMID:10103013 Expression of receptors for human angiogenin in vascular smo...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Use RNA endonuclease and tRNA-specific ribonuclease terms rather than generic endonuclease activity.
GO:0004540 RNA nuclease activity	IDA PMID:2424496 Characteristic ribonucleolytic activity of human angiogenin.	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0004540 RNA nuclease activity	IDA PMID:2730651 Characterization of ribonucleolytic activity of angiogenin t...	ACCEPT	Summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.
GO:0005507 copper ion binding	IDA PMID:9245697 Interaction of human angiogenin with copper modulates angiog...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0005515 protein binding	IPI PMID:2742853 Binding of placental ribonuclease inhibitor to the active si...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005515 protein binding	IPI PMID:3470787 Human placental ribonuclease inhibitor abolishes both angiog...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
GO:0005604 basement membrane	IDA PMID:15166501 Angiogenin distribution in human term placenta, and expressi...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0005615 obsolete extracellular space	IDA PMID:3663649 Isolation of angiogenin from normal human plasma.	MODIFY	Summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region. Reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term. Proposed replacements: extracellular region Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005634 nucleus	IDA PMID:10649442 Human angiogenin is rapidly translocated to the nucleus of h...	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0007154 cell communication	NAS PMID:10103013 Expression of receptors for human angiogenin in vascular smo...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Generic cell communication should not be used when specific ANG functions are available.
GO:0008201 heparin binding	IDA PMID:10103013 Expression of receptors for human angiogenin in vascular smo...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0019843 rRNA binding	TAS PMID:2457905 Angiogenin activates endothelial cell phospholipase C.	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0042592 homeostatic process	NAS PMID:15166501 Angiogenin distribution in human term placenta, and expressi...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful ANG annotation. Reason: Homeostatic process is not informative for ANG curation.
GO:0050714 positive regulation of protein secretion	IDA PMID:2646638 Angiogenin stimulates endothelial cell prostacyclin secretio...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:9122172 A putative angiogenin receptor in angiogenin-responsive huma...	KEEP AS NON CORE	Summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0003779 actin binding	IDA PMID:7679494 Actin is a binding protein for angiogenin.	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0005102 signaling receptor binding	IDA PMID:9122172 A putative angiogenin receptor in angiogenin-responsive huma...	KEEP AS NON CORE	Summary: Supported but non-core. Receptor-mediated signaling or uptake is relevant to ANG trafficking and extracellular activity, but not the central RNase mechanism. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0048662 negative regulation of smooth muscle cell proliferation	IDA PMID:10103013 Expression of receptors for human angiogenin in vascular smo...	KEEP AS NON CORE	Summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0001525 angiogenesis	TAS PMID:16567967 Influence of angiogenin on the growth of A375 human melanoma...	ACCEPT	Summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0001541 ovarian follicle development	NAS PMID:12770725 Production of vascular endothelial growth factor and angioge...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0001666 response to hypoxia	NAS PMID:15776477 Angiogenin is up-regulated in the nucleus and cytoplasm in h...	KEEP AS NON CORE	Summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0001666 response to hypoxia	IDA PMID:15979542 Hypoxia up-regulated angiogenin and down-regulated vascular ...	KEEP AS NON CORE	Summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0001666 response to hypoxia	IDA PMID:16490744 Hypoxic conditions stimulate the production of angiogenin an...	KEEP AS NON CORE	Summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG remains a canonical proangiogenic factor and tumor-associated RNase.
GO:0001890 placenta development	NAS PMID:11984825 Expression and localization of angiogenin in placenta: enhan...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0003779 actin binding	IDA PMID:11782452 Antiplasmin activity of a peptide that binds to the receptor...	KEEP AS NON CORE	Summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
GO:0005615 obsolete extracellular space	IDA PMID:16461950 Assessment of some tools for the characterization of the hum...	MODIFY	Summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region. Reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term. Proposed replacements: extracellular region Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005615 obsolete extracellular space	IDA PMID:16490744 Hypoxic conditions stimulate the production of angiogenin an...	MODIFY	Summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region. Reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term. Proposed replacements: extracellular region Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0005634 nucleus	IDA PMID:15735021 Angiogenin is translocated to the nucleus of HeLa cells and ...	ACCEPT	Summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.
GO:0009303 rRNA transcription	IMP PMID:15735021 Angiogenin is translocated to the nucleus of HeLa cells and ...	ACCEPT	Summary: Correct. In nucleoli, ANG promotes rRNA transcription and ribosome biogenesis under growth conditions. Supporting Evidence: file:human/ANG/ANG-deep-research-falcon.md ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs.

Core Functions

ANG is a regulated RNase A-family endoribonuclease whose core function is compartment-dependent RNA metabolism: ribosome-activated cytosolic tRNA cleavage during stress and nucleolar promotion of rRNA transcription under growth conditions, with secreted proangiogenic activity as a major physiological output.

Molecular Function:

tRNA-specific ribonuclease activity

Directly Involved In:

tRNA decay negative regulation of translation in response to stress rRNA transcription angiogenesis

Cellular Locations:

extracellular region nucleolus cytosol cytoplasmic stress granule

Supporting Evidence:

file:human/ANG/ANG-deep-research-falcon.md
ANG is a secreted RNase A-family endoribonuclease originally characterized as an angiogenic factor, but now understood as a **stress-responsive ribonuclease** with dual roles depending on subcellular localization: (i) **nucleolar/nuclear** functions in rRNA transcription and (ii) **cytosolic** functions in stress-induced tRNA cleavage and translational repression.
file:human/ANG/ANG-deep-research-falcon.md
A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5′ and 3′ tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30–40 nt**.
file:human/ANG/ANG-deep-research-falcon.md
ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:10103013

Expression of receptors for human angiogenin in vascular smooth muscle cells.

PMID:10413501

Superadditive and subadditive effects of "hot spot" mutations within the interfaces of placental ribonuclease inhibitor with angiogenin and ribonuclease A.

PMID:10649442

Human angiogenin is rapidly translocated to the nucleus of human umbilical vein endothelial cells and binds to DNA.

PMID:10999833

Evidence for the presence of angiogenin in human follicular fluid and the up-regulation of its production by human chorionic gonadotropin and hypoxia.

PMID:11438326

Concentrations of angiogenic factors in follicular fluid and oocyte-cumulus complex culture medium from women undergoing in vitro fertilization: association with oocyte maturity and fertilization.

PMID:11782452

Antiplasmin activity of a peptide that binds to the receptor-binding site of angiogenin.

PMID:11919285

Diversifying selection of the tumor-growth promoter angiogenin in primate evolution.

PMID:11984825

Expression and localization of angiogenin in placenta: enhanced levels at term over first trimester villi.

PMID:12770725

Production of vascular endothelial growth factor and angiogenic factor in human follicular fluid.

PMID:15166501

Angiogenin distribution in human term placenta, and expression by cultured trophoblastic cells.

PMID:15735021

Angiogenin is translocated to the nucleus of HeLa cells and is involved in ribosomal RNA transcription and cell proliferation.

PMID:15737636

Alpha-actinin-2, a cytoskeletal protein, binds to angiogenin.

PMID:15776477

Angiogenin is up-regulated in the nucleus and cytoplasm in human primary breast carcinoma and is associated with markers of hypoxia but not survival.

PMID:15979542

Hypoxia up-regulated angiogenin and down-regulated vascular cell adhesion molecule-1 expression and secretion in human placental trophoblasts.

PMID:16461950

Assessment of some tools for the characterization of the human osteoarthritic cartilage proteome.

PMID:16490744

Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture.

PMID:16567967

Influence of angiogenin on the growth of A375 human melanoma cells and the expression of basic fibroblast growth factor.

PMID:17125737

Angiogenin-induced protein kinase B/Akt activation is necessary for angiogenesis but is independent of nuclear translocation of angiogenin in HUVE cells.

PMID:17991437

Identification and characterization of follistatin as a novel angiogenin-binding protein.

PMID:19332886

Angiogenin cleaves tRNA and promotes stress-induced translational repression.

PMID:20129916

Angiogenin-induced tRNA-derived stress-induced RNAs promote stress-induced stress granule assembly.

PMID:21855800

Angiogenin-induced tRNA fragments inhibit translation initiation.

PMID:23047679

Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons.

PMID:23843625

Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival.

PMID:2424496

Characteristic ribonucleolytic activity of human angiogenin.

PMID:24457100

Angiogenin interacts with the plasminogen activation system at the cell surface of breast cancer cells to regulate plasmin formation and cell migration.

PMID:2457905

Angiogenin activates endothelial cell phospholipase C.

PMID:2459697

Mutagenesis of aspartic acid-116 enhances the ribonucleolytic activity and angiogenic potency of angiogenin.

PMID:2479414

Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis.

PMID:25372031

Computational and functional characterization of Angiogenin mutations, and correlation with amyotrophic lateral sclerosis.

PMID:2646638

Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A2.

PMID:2730651

Characterization of ribonucleolytic activity of angiogenin towards tRNA.

PMID:2742853

Binding of placental ribonuclease inhibitor to the active site of angiogenin.

PMID:27518564

Angiogenin Promotes Hematopoietic Regeneration by Dichotomously Regulating Quiescence of Stem and Progenitor Cells.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:28777577

Proteomic Analysis of Human Angiogenin Interactions Reveals Cytoplasmic PCNA as a Putative Binding Partner.

PMID:29100074

Plexin-B2 Mediates Physiologic and Pathologic Functions of Angiogenin.

PMID:29748193

Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor.

PMID:3122207

Ribonucleolytic activity of angiogenin: essential histidine, lysine, and arginine residues.

PMID:31582561

Angiogenin generates specific stress-induced tRNA halves and is not involved in tRF-3-mediated gene silencing.

PMID:32510170

Myeloid cells protect intestinal epithelial barrier integrity through the angiogenin/plexin-B2 axis.

PMID:3289612

Base cleavage specificity of angiogenin with Saccharomyces cerevisiae and Escherichia coli 5S RNAs.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:3470787

Human placental ribonuclease inhibitor abolishes both angiogenic and ribonucleolytic activities of angiogenin.

PMID:3663649

Isolation of angiogenin from normal human plasma.

PMID:38718836

Structural mechanism of angiogenin activation by the ribosome.

PMID:4074709

Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells.

PMID:7679494

Actin is a binding protein for angiogenin.

PMID:8159680

Role of glutamine-117 in the ribonucleolytic activity of human angiogenin.

PMID:8448182

Characterization and sequencing of rabbit, pig and mouse angiogenins: discernment of functionally important residues and regions.

PMID:8570639

A combined kinetic and modeling study of the catalytic center subsites of human angiogenin.

PMID:8622921

The C-terminal region of human angiogenin has a dual role in enzymatic activity.

PMID:9122172

A putative angiogenin receptor in angiogenin-responsive human endothelial cells.

PMID:9245697

Interaction of human angiogenin with copper modulates angiogenin binding to endothelial cells.

PMID:9707554

Neomycin inhibits angiogenin-induced angiogenesis.

Reactome:R-HSA-5692437

ANG binds F-actin

Reactome:R-HSA-9708296

tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis

Reactome:R-HSA-9708327

ANG cleaves tRNA to yield tRNA halves

file:human/ANG/ANG-deep-research-falcon.md

Falcon deep research report for human ANG

Suggested Experiments

Experiment: Use ANG variants defective in ribosome association or catalytic residues, then compare tRNA-half production, translation rates, and stress granule assembly after oxidative stress.

Hypothesis: Ribosome binding is required for stress-induced ANG tRNA cleavage and translation repression in cells.

Experiment: Rescue ANG-depleted endothelial cells with localization-biased ANG variants and measure rRNA transcription, endothelial proliferation/migration, and stress-induced tiRNA production.

Hypothesis: ANG angiogenic outputs are separable from cytosolic stress-response outputs by altering nuclear localization or receptor-mediated uptake.

Deep Research

Falcon

(ANG-deep-research-falcon.md)

Comprehensive Research Report: Human **ANG** (Angiogenin; RNASE5) — Functional Annotation (UniProt P03950) Falcon Edison Scientific Literature 32 citations 2026-05-11T14:46:27.314998

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Human ANG (Angiogenin; RNASE5) — Functional Annotation (UniProt P03950)

0. Identity verification (critical disambiguation)

The target gene/protein is human angiogenin, encoded by ANG (syn. RNASE5) and belonging to the RNase A (pancreatic ribonuclease) family. Multiple 2024 sources describe ANG/RNase5 as a secreted ~14 kDa RNase A-family endoribonuclease synthesized as a signal-peptide-containing precursor with a 123-aa mature protein, consistent with the UniProt context provided (P03950) and not a different “ANG” from another organism or pathway. (gotte2024effectsofpathogenic pages 4-5, mao2024researchprogresson pages 1-3)

1. Key concepts and definitions (current understanding)

1.1 What is angiogenin (ANG/RNASE5)?

ANG is a secreted RNase A-family endoribonuclease originally characterized as an angiogenic factor, but now understood as a stress-responsive ribonuclease with dual roles depending on subcellular localization: (i) nucleolar/nuclear functions in rRNA transcription and (ii) cytosolic functions in stress-induced tRNA cleavage and translational repression. (culurciello2024tailoringthestress pages 1-2, gotte2024effectsofpathogenic pages 4-5)

Protein form and family: ANG is produced with a signal peptide (reported as ~24 aa) and secreted as a mature single-chain protein of 123 aa with apparent mass ~14.1–14.4 kDa, placing it within secretory pancreatic-type RNases. (gotte2024effectsofpathogenic pages 4-5, mao2024researchprogresson pages 1-3)

1.2 Enzymatic activity: reaction and substrate specificity

Reaction class: ANG is an RNase A-family phosphodiesterase (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture. Catalytic residues summarized in recent literature include His13, Lys40, and His114. (loveland2024structuralmechanismof pages 9-12, shah2025aberranttrnaprocessing pages 44-53)

Substrate specificity:
- A central, repeatedly supported substrate in stress biology is mature cytoplasmic tRNA, cleaved within the anticodon loop to yield 5′ and 3′ tRNA halves (often called tiRNAs/tsRNAs), typically ~30–40 nt. (culurciello2024tailoringthestress pages 1-2, loveland2024structuralmechanismof pages 9-12)
- Ribosome-bound structural data indicate cleavage occurs near anticodon-loop positions 33–36, and that ANG prefers cleavage between a pyrimidine and an adenosine. (loveland2024structuralmechanismof pages 9-12)

Why isolated ANG is weakly active: Free angiogenin has markedly lower activity than canonical RNase A; one mechanistic explanation is that its C-terminal region can occlude the substrate site, and a 2024 structural study reports purified angiogenin is ≥10,000-fold less active (kcat/KM) than RNase A. (loveland2024structuralmechanismof pages 1-5, gotte2024effectsofpathogenic pages 4-5)

1.3 Localization and compartment-specific functions

ANG’s functional output depends strongly on where it acts:

Extracellular/secreted:
- ANG is secreted and can function in intercellular signaling contexts.
- Recombinant ANG added to culture medium is described as being rapidly internalized, consistent with autocrine/paracrine uptake models. (culurciello2024tailoringthestress pages 1-2)

Receptor-mediated uptake and internalization:
- ANG is reported to bind cell-surface receptors (including a ~170 kDa binding factor and syndecan-4), and a receptor-binding region around residues 60–68 has been implicated in uptake and downstream responses. (gotte2024effectsofpathogenic pages 4-5)

Nuclear/nucleolar ANG:
- ANG contains a nuclear localization sequence (NLS) 31RRRGL35 facilitating nuclear/nucleolar localization. (culurciello2024tailoringthestress pages 1-2, gotte2024effectsofpathogenic pages 4-5)
- In nucleoli, ANG is described as active in promoting rRNA transcription and thereby supporting growth/proliferation programs. (culurciello2024tailoringthestress pages 1-2, gotte2024effectsofpathogenic pages 4-5)

Cytosolic ANG during stress:
- Under stress, ANG accumulates in the cytoplasm and cleaves tRNAs to generate tiRNAs/tsRNAs that repress translation and engage stress-response assemblies (including stress granules). (culurciello2024tailoringthestress pages 1-2, gotte2024effectsofpathogenic pages 4-5)

1.4 Regulation by the ribonuclease inhibitor RNH1 (RI)

ANG is tightly regulated by the cytosolic ribonuclease inhibitor (RNH1/RI):
- Binding affinity is described as extremely high (reported Kd ~ 1 fM). (culurciello2024tailoringthestress pages 1-2, gotte2024effectsofpathogenic pages 4-5)
- Stress can enable ANG activity by promoting dissociation from RNH1, shifting ANG into functional cytosolic pathways. (culurciello2024tailoringthestress pages 1-2)
- A 2024 mechanistic study also indicates that RNase inhibitor (RNasin; an RNH1-type inhibitor) prevents ANG association with ribosomes and blocks ANG-induced tRNA fragmentation in translation lysates. (loveland2024structuralmechanismof pages 1-5, loveland2024structuralmechanismof pages 5-9)

2. Recent developments and latest research (prioritizing 2023–2024)

2.1 Major 2024 mechanistic advance: ribosomes activate angiogenin

A key unresolved question in the field has been why ANG is a weak RNase as a free protein yet is biologically potent in cells. Loveland et al. (bioRxiv, posted 2023-12; version/availability in 2024) provide structural and biochemical evidence that the cytosolic 80S ribosome is the activator and specificity factor for ANG. (loveland2024structuralmechanismof pages 1-5)

Core findings:
- Cryo-EM at ~2.8 Å reveals ANG bound in the ribosomal A site, with extensive ribosome contacts (~2200 Å², ~30% of ANG surface), and ribosome-driven rearrangement of ANG’s C-terminal tail into an RNase-A-like active conformation. (loveland2024structuralmechanismof pages 1-5, loveland2024structuralmechanismof pages 5-9)
- Ribosome-bound ANG rapidly cleaves tRNA to ~35-nt fragments, whereas isolated ANG shows minimal cleavage over long incubations. With 10 nM ANG + 20 nM 80S, fragments appear within 1 min and product accumulation is reported as >100-fold by 100 min relative to controls; the eEF1A ternary complex can further stimulate cleavage. (loveland2024structuralmechanismof pages 9-12)

Visual evidence (figure panels): The binding of ANG in the 80S A site and associated biochemical assays for ribosome-stimulated cleavage are shown in key figure panels retrieved from the paper. (loveland2024structuralmechanismof media 3b8dc74d, loveland2024structuralmechanismof media 4c901db4)

Interpretation: This ribosome-activation model provides a coherent explanation for how ANG achieves stress-conditional activation (vacant A sites increase during stress) while limiting constitutive ribonucleolysis under basal conditions. (loveland2024structuralmechanismof pages 1-5)

2.2 ANG, stress granules, and translational repression (2024 cell biology)

Culurciello et al. (Heliyon, Feb 2024) emphasize that ANG’s subcellular routing shapes its stress functions: nucleolar ANG supports rRNA transcription, whereas cytosolic ANG supports tRNA cleavage, translational arrest, and stress granule–linked outcomes. (culurciello2024tailoringthestress pages 1-2)

A notable experimental strategy in this 2024 work is engineering an NLS-attenuated variant (R31Q/R32Q) to substantially reduce nuclear localization, enabling functional dissection of “cytosol-biased” ANG in human skin cells. (culurciello2024tailoringthestress pages 1-2, culurciello2024tailoringthestress pages 8-10)

2.3 New 2024 link between ANG-generated tsRNAs and innate immunity: NLRP3 inflammasome control

Cai et al. (Cell Death & Differentiation, May 2024) connect ANG’s tRNA cleavage products to inflammatory control:

Claim: ANG-mediated 5′ tsRNAs negatively regulate NLRP3 inflammasome activation and pyroptosis by sequestering the RNA helicase DDX3X into stress granules, thereby reducing DDX3X–NLRP3 interaction. (cai2024angiogeninmediatedtsrnascontrol pages 5-7, cai2024angiogeninmediatedtsrnascontrol pages 1-5)

Experimental implementation and quantitative conditions (selected):
- In vitro macrophage system: BMDMs were primed with LPS 500 ng/mL for 4 h; sodium arsenite stress used 50 μM for 1 h. (cai2024angiogeninmediatedtsrnascontrol pages 19-26, cai2024angiogeninmediatedtsrnascontrol pages 5-7)
- tsRNA add-back: transfection of total 5′ tsRNAs at 200 nM for 2 h decreased NLRP3 activation markers (cleaved caspase-1 and GSDMD), reduced IL-1β release, and reduced ASC specks. (cai2024angiogeninmediatedtsrnascontrol pages 19-26, cai2024angiogeninmediatedtsrnascontrol pages 5-7)
- In vivo arsenite: 4 mg/kg IP with sampling at 0/6/24 h is reported in figure legends. (cai2024angiogeninmediatedtsrnascontrol pages 19-26)
- In vivo inflammation/metabolic context: Ang deficiency exacerbated LPS-induced systemic inflammation and worsened HFD-related glucose intolerance/insulin resistance; several in vivo analyses used n=8. (cai2024angiogeninmediatedtsrnascontrol pages 19-26, cai2024angiogeninmediatedtsrnascontrol pages 5-7)

Interpretation: This work expands ANG biology from translation control to stress-granule-mediated immunoregulation, positioning ANG-tsRNA pathways as potentially druggable nodes for NLRP3-driven inflammatory diseases. (cai2024angiogeninmediatedtsrnascontrol pages 1-5)

2.4 Disease genetics and expert synthesis (2024 ALS-focused review)

Gottè (Genes, Jun 2024) synthesizes evidence that heterozygous missense ANG variants are associated with ALS and that many pathogenic variants behave as loss-of-function (loss of catalytic activity, altered nuclear localization, altered stress responses), although some variants (e.g., R121H/C) have been reported with increased RNase activity. (gotte2024effectsofpathogenic pages 10-12)

This review also summarizes trafficking/regulatory features (signal peptide secretion, receptor-mediated internalization, NLS-dependent nucleolar localization, RNH1 inhibition, stress-dependent cytosolic tRNA cleavage) as the mechanistic substrate upon which ALS variants exert effects. (gotte2024effectsofpathogenic pages 4-5)

3. Current applications and real-world implementations

3.1 Biomarker implementation: cardiovascular risk prediction in type 2 diabetes (human cohort)

Gurung et al. (Cardiovascular Diabetology, Feb 2024) provide a large prospective dataset linking baseline plasma angiogenin levels to future major adverse cardiovascular events (MACE) in type 2 diabetes:

Sample size: 1,083 individuals with type 2 diabetes. (gurung2024associationofplasma pages 1-2)
Follow-up: median 9.3 years (IQR 8.4–9.8), totaling 9,513 patient-years. (gurung2024associationofplasma pages 4-5)
Events: 109 MACE (10%); crude incidence 1.15 per 100 patient-years. (gurung2024associationofplasma pages 4-5)
Assay: Proximity extension assay (Olink PEA); results as NPX (log2). Reported assay precision includes intra-assay CV ~7–8% and interassay CV ~11–14%; PEA correlated with immunoassay (Spearman r=0.85). (gurung2024associationofplasma pages 2-4, gurung2024associationofplasma pages 5-7)
Effect sizes: per 1 NPX increment (interpreted as a doubling), unadjusted HR for MACE 3.10 (95% CI 1.84–5.22); adjusted HRs 2.38 (1.34–4.23) and 1.90 (1.02–3.53) with additional renal biomarker adjustment. (gurung2024associationofplasma pages 1-2, gurung2024associationofplasma pages 4-5)

Real-world implication: ANG is already being operationalized as a circulating protein biomarker measurable by multiplex proteomic platforms for long-horizon cardiovascular risk stratification in T2D. (gurung2024associationofplasma pages 4-5)

3.2 Translational directions in oncology

A 2024 review in Heliyon summarizes evidence that ANG is frequently elevated in tumor contexts and supports angiogenesis and cancer progression programs, and discusses its potential as a biomarker and therapeutic target. While much of this review is qualitative, it consolidates receptor signaling (including Akt pathway), nuclear function (rRNA transcription), and tumor phenotypes (growth, invasion, EMT, therapy response). (mao2024researchprogresson pages 1-3)

3.3 Mechanism-guided protein engineering as a “functional switch”

The NLS-attenuation strategy (R31Q/R32Q) reported in 2024 skin-cell experiments exemplifies a practical approach to tune ANG’s nuclear vs cytosolic localization to modulate stress phenotypes—an example of mechanistically informed “cellular routing” engineering rather than global inhibition. (culurciello2024tailoringthestress pages 1-2, culurciello2024tailoringthestress pages 8-10)

4. Expert opinions and analysis (authoritative synthesis)

4.1 Consensus model emerging from 2024 literature

Across mechanistic and review sources, a convergent model is that ANG operates as a context-dependent RNase whose biological functions arise from:
1) Tight inhibition by RNH1 at baseline, (culurciello2024tailoringthestress pages 1-2)
2) Stress-conditional activation, now plausibly explained by ribosome binding in the A site and by stress-dependent availability of suitable ribosomal states, (loveland2024structuralmechanismof pages 1-5, loveland2024structuralmechanismof media 3b8dc74d)
3) A compartmental split in outputs: nucleolar rRNA transcription vs cytosolic tRNA cleavage producing tiRNAs/tsRNAs that engage translation repression, stress granules, and (as of 2024) inflammasome regulation. (culurciello2024tailoringthestress pages 1-2, cai2024angiogeninmediatedtsrnascontrol pages 5-7)

4.2 Disease interpretability of ANG variants

The ALS-focused expert synthesis emphasizes that many ANG variants reduce one or more of these core functional axes—RNase activity, localization control, or stress-response execution—supporting a mechanistic “loss-of-protective-function” framing in neurodegeneration rather than a simple toxic gain-of-function paradigm. (gotte2024effectsofpathogenic pages 10-12, gotte2024effectsofpathogenic pages 4-5)

5. Relevant statistics and quantitative data (recent studies)

Key quantitative highlights from 2024 studies (most directly actionable for functional annotation) include:

1) Ribosome activation kinetics: Ribosome-bound ANG generates ~35-nt tRNA fragments within 1 minute and shows >100-fold product accumulation by 100 min, whereas free ANG is minimally active. (loveland2024structuralmechanismof pages 9-12)

2) Inflammasome pathway experimental parameters: ANG-dependent tsRNA biology in macrophages is demonstrated under defined stress and priming conditions (e.g., arsenite 50 μM 1 h, LPS 500 ng/mL 4 h, tsRNA transfection 200 nM 2 h, in vivo arsenite 4 mg/kg IP). (cai2024angiogeninmediatedtsrnascontrol pages 19-26, cai2024angiogeninmediatedtsrnascontrol pages 5-7)

3) Prospective human biomarker statistics: In 1,083 T2D participants followed for 9.3 years, a doubling of plasma ANG (1 NPX) associated with MACE risk with adjusted HRs ~1.90–2.38 depending on covariate sets, with 109 events and crude incidence 1.15/100 patient-years. (gurung2024associationofplasma pages 4-5)

Evidence map / quick-reference table

The table below consolidates key concepts, mechanisms, and translational evidence with URLs, dates, and quantitative details.

Topic	Key finding (1-2 sentences)	Quantitative details	Primary source (authors, journal, date)	URL
Identity and definition of ANG/RNASE5	Human ANG encodes angiogenin, also called RNase 5, a secreted RNase A-family endoribonuclease produced as a signal-peptide-containing precursor and functioning in angiogenesis, stress adaptation, and RNA metabolism. Its comparatively weak free-enzyme RNase activity reflects partial occlusion of the substrate-binding cleft despite conservation of catalytic residues. (gotte2024effectsofpathogenic pages 4-5, mao2024researchprogresson pages 1-3, loveland2024structuralmechanismof pages 1-5)	Mature protein is 123 aa; apparent mass about 14.1-14.4 kDa; signal peptide 24 aa. Free angiogenin is reported as at least 10,000-fold less active (kcat/KM) than RNase A. (gotte2024effectsofpathogenic pages 4-5, mao2024researchprogresson pages 1-3, loveland2024structuralmechanismof pages 1-5)	Gotte, Genes, Jun 2024; Mao et al., Heliyon, May 2024; Loveland et al., bioRxiv, Dec 2024	https://doi.org/10.3390/genes15060738 ; https://doi.org/10.1016/j.heliyon.2024.e30654 ; https://doi.org/10.1101/2023.12.11.570495
Catalytic center and substrate specificity	ANG is an RNase A-family phosphodiesterase with catalytic residues including His13, Lys40, His114; under stress it preferentially cleaves mature cytoplasmic tRNAs at the anticodon loop, generating 5′ and 3′ tRNA halves/tiRNAs (tsRNAs) that repress translation. Structural work places cleavage near anticodon-loop positions 33-36, with preference for cleavage between a pyrimidine and adenosine. (culurciello2024tailoringthestress pages 1-2, gotte2024effectsofpathogenic pages 4-5, loveland2024structuralmechanismof pages 9-12)	Ribosome-bound ANG produces about 35-nt tRNA fragments; isolated ANG shows almost no tRNAAla cleavage over 100 min, whereas ribosome-bound ANG cleaves rapidly within 1 min. (loveland2024structuralmechanismof pages 9-12)	Culurciello et al., Heliyon, Feb 2024; Gotte, Genes, Jun 2024; Loveland et al., bioRxiv, Dec 2024	https://doi.org/10.1016/j.heliyon.2024.e24556 ; https://doi.org/10.3390/genes15060738 ; https://doi.org/10.1101/2023.12.11.570495
Ribosome activation mechanism	A major 2024 mechanistic advance is that the cytosolic 80S ribosome is the activator and specificity factor for ANG. Cryo-EM shows ANG bound in the ribosomal A site, where ribosome contacts remodel its C-terminal tail into an RNase-A-like active conformation and orient the enzyme toward incoming tRNA. (loveland2024structuralmechanismof pages 1-5, loveland2024structuralmechanismof pages 5-9, loveland2024structuralmechanismof media 3b8dc74d)	Cryo-EM structures were solved at about 2.8-3.0 Å. ANG contacts roughly 2200 Å² of ribosome surface (~30% of ANG solvent-accessible area); catalytic activation is described as several orders of magnitude. (loveland2024structuralmechanismof pages 1-5, loveland2024structuralmechanismof pages 5-9)	Loveland et al., bioRxiv, Dec 2024	https://doi.org/10.1101/2023.12.11.570495
Ribosome-stimulated tRNA cleavage time course	Biochemical assays show that ribosome binding converts minimally active ANG into a fast tRNA nuclease. Delivery of aminoacyl-tRNA by eEF1A ternary complex further enhances cleavage, indicating that the ribosome positions substrate for efficient anticodon-loop attack. (loveland2024structuralmechanismof pages 9-12, loveland2024structuralmechanismof pages 27-31, loveland2024structuralmechanismof media 4c901db4)	With 10 nM ANG + 20 nM 80S + 250 nM tRNA, ~35-nt fragments appear within 1 min and product accumulation exceeds 100-fold by 100 min versus ANG alone; Ala-tRNAAla cleavage in structural assays was nearly saturated within 25 s. (loveland2024structuralmechanismof pages 9-12, loveland2024structuralmechanismof pages 23-27, loveland2024structuralmechanismof pages 27-31)	Loveland et al., bioRxiv, Dec 2024	https://doi.org/10.1101/2023.12.11.570495
Translation repression and stress granules	ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response. 5′ tiRNAs can displace eIF4G from mRNA on ribosomes, promote stress-granule (SG) assembly, and some 5′ tiRNAs can form G-quadruplexes linked to neuroprotection. (culurciello2024tailoringthestress pages 1-2, gotte2024effectsofpathogenic pages 4-5)	In rabbit reticulocyte lysate, ANG inhibits translation at 70-140 nM and this is reversed by RNasin/RNH1, which also prevents accumulation of 30-40 nt tRNA fragments. (loveland2024structuralmechanismof pages 1-5, loveland2024structuralmechanismof pages 5-9)	Culurciello et al., Heliyon, Feb 2024; Gotte, Genes, Jun 2024; Loveland et al., bioRxiv, Dec 2024	https://doi.org/10.1016/j.heliyon.2024.e24556 ; https://doi.org/10.3390/genes15060738 ; https://doi.org/10.1101/2023.12.11.570495
Localization: secretion, uptake, nucleus/nucleolus, cytosol	ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. Nucleolar ANG promotes rRNA transcription and ribosome biogenesis, whereas cytosolic ANG under stress cleaves tRNAs and participates in translational arrest/SG programs. (gotte2024effectsofpathogenic pages 4-5, culurciello2024tailoringthestress pages 1-2)	Reported receptor-binding region includes residues 60-68; nuclear localization signal is 31RRRGL35. Recombinant ANG added to culture medium is described as rapidly internalized. (gotte2024effectsofpathogenic pages 4-5, culurciello2024tailoringthestress pages 1-2)	Gotte, Genes, Jun 2024; Culurciello et al., Heliyon, Feb 2024	https://doi.org/10.3390/genes15060738 ; https://doi.org/10.1016/j.heliyon.2024.e24556
Regulation by RNH1/RI	RNH1/RI is the principal intracellular inhibitor that restrains ANG activity and trafficking. Stress or altered protein interactions can release ANG from RNH1, enabling cytosolic tRNA cleavage; conversely, RNH1/RNasin also blocks ribosome association of ANG. (gotte2024effectsofpathogenic pages 4-5, culurciello2024tailoringthestress pages 1-2, loveland2024structuralmechanismof pages 9-12, loveland2024structuralmechanismof pages 5-9)	ANG-RNH1 binding affinity is reported around Kd ~1 fM. RNasin prevents ANG co-pelleting with ribosomes and restores translation in lysate assays. (culurciello2024tailoringthestress pages 1-2, loveland2024structuralmechanismof pages 5-9, loveland2024structuralmechanismof pages 20-23)	Culurciello et al., Heliyon, Feb 2024; Gotte, Genes, Jun 2024; Loveland et al., bioRxiv, Dec 2024	https://doi.org/10.1016/j.heliyon.2024.e24556 ; https://doi.org/10.3390/genes15060738 ; https://doi.org/10.1101/2023.12.11.570495
Nuclear trafficking control	ANG contains an NLS and post-translational changes can bias nuclear import. A 2024 skin-cell study used an R31Q/R32Q NLS-attenuated variant to reduce nuclear localization and probe how shifting ANG toward the cytoplasm reshapes stress responses. (culurciello2024tailoringthestress pages 1-2, culurciello2024tailoringthestress pages 8-10)	NLS-mutated variant targets residues Arg31/Arg32 within 31RRRGL35. The study was designed to substantially limit nuclear localization rather than abolish uptake/secretion. (culurciello2024tailoringthestress pages 1-2, culurciello2024tailoringthestress pages 8-10)	Culurciello et al., Heliyon, Feb 2024	https://doi.org/10.1016/j.heliyon.2024.e24556
NLRP3 inflammasome regulation	ANG-generated 5′ tsRNAs are anti-inflammatory effectors that suppress NLRP3 inflammasome activation and pyroptosis by promoting DDX3X recruitment into SGs, reducing DDX3X-NLRP3 interaction. Thus ANG connects RNA cleavage/stress-granule biology to innate immune control. (cai2024angiogeninmediatedtsrnascontrol pages 5-7, cai2024angiogeninmediatedtsrnascontrol pages 1-5)	In BMDMs, sodium arsenite (50 μM, 1 h) induced tsRNAs and inflammasome activation; transfected total 5′ tsRNAs (200 nM, 2 h) reduced cleaved caspase-1/GSDMD, IL-1β release, and ASC specks. In vivo arsenite was 4 mg/kg IP; LPS priming in BMDMs was 500 ng/mL for 4 h. (cai2024angiogeninmediatedtsrnascontrol pages 19-26, cai2024angiogeninmediatedtsrnascontrol pages 5-7)	Cai et al., Cell Death & Differentiation, May 2024	https://doi.org/10.1038/s41418-024-01311-8
In vivo inflammatory and metabolic phenotypes	ANG deficiency worsens systemic and metabolic inflammation, supporting a physiological protective role for ANG-mediated tsRNAs. In mouse models, loss of Ang increased inflammasome-dependent cytokines and aggravated insulin resistance on high-fat diet. (cai2024angiogeninmediatedtsrnascontrol pages 19-26, cai2024angiogeninmediatedtsrnascontrol pages 7-9, cai2024angiogeninmediatedtsrnascontrol pages 5-7)	In vivo study details include 8-week-old male mice, arsenite 4 mg/kg IP with sampling at 0/6/24 h, and 14-week HFD experiments; LPS systemic inflammation outcomes included higher serum IL-1β and IL-18 in Ang-/- mice, with n=8 for in vivo cytokine/GTT/ITT analyses. (cai2024angiogeninmediatedtsrnascontrol pages 19-26, cai2024angiogeninmediatedtsrnascontrol pages 5-7)	Cai et al., Cell Death & Differentiation, May 2024	https://doi.org/10.1038/s41418-024-01311-8
Cancer/angiogenesis pathways	ANG remains a canonical proangiogenic factor and tumor-associated RNase. In endothelial and tumor contexts it promotes neovascularization, survival, proliferation, migration, invasion, EMT, and can signal through receptors including Tie-2 and FHL3, with nuclear ANG contributing to rRNA transcription required for growth. (mao2024researchprogresson pages 1-3, gotte2024effectsofpathogenic pages 4-5)	Mao et al. summarize 26 ANG-responsive miRNAs in endothelial cells; receptor-binding/nuclear-translocation regions are highlighted structurally but the review is mainly qualitative rather than effect-size driven. (mao2024researchprogresson pages 1-3)	Mao et al., Heliyon, May 2024; Gotte, Genes, Jun 2024	https://doi.org/10.1016/j.heliyon.2024.e30654 ; https://doi.org/10.3390/genes15060738
Neuroprotection and ALS relevance	ANG is widely regarded as a neuroprotective RNase, and many ALS-associated ANG variants appear to be loss-of-function, impairing ribonucleolytic activity, nuclear trafficking, SG biology, or tiRNA-dependent protection. Reviews from 2024 emphasize ANG as a mechanistically important but still underexploited ALS gene. (gotte2024effectsofpathogenic pages 10-12, gotte2024effectsofpathogenic pages 4-5)	Gotte 2024 notes that some variants such as R121H/C may show increased RNase activity, but many ALS-linked mutants have partial or impaired function; no single pooled 2024 penetrance estimate is provided. (gotte2024effectsofpathogenic pages 10-12)	Gotte, Genes, Jun 2024	https://doi.org/10.3390/genes15060738
Cardiovascular biomarker evidence	In type 2 diabetes, higher circulating ANG was associated with future major adverse cardiovascular events, supporting translational interest in ANG as a plasma biomarker. This is one of the clearest 2024 human quantitative datasets for ANG. (gurung2024associationofplasma pages 1-2, gurung2024associationofplasma pages 4-5, gurung2024associationofplasma pages 5-7)	n=1,083 participants; median follow-up 9.3 years (9,513 patient-years); 109 MACE events (10%); crude incidence 1.15/100 patient-years. Per 1 NPX increase (doubling by Olink PEA), HR for MACE was 3.10 (95% CI 1.84-5.22) unadjusted, 2.38 (95% CI 1.34-4.23) adjusted model 1, and 1.90 (95% CI 1.02-3.53) after additional renal adjustment; assay correlation with immunoassay Spearman r=0.85. (gurung2024associationofplasma pages 1-2, gurung2024associationofplasma pages 2-4, gurung2024associationofplasma pages 4-5, gurung2024associationofplasma pages 5-7)	Gurung et al., Cardiovascular Diabetology, Feb 2024	https://doi.org/10.1186/s12933-024-02156-8

Table: This table compiles the core biology, mechanisms, localization, and translational evidence for human ANG/RNASE5, emphasizing 2024 studies with quantitative details. It is useful as a quick reference for functional annotation and evidence-backed interpretation of ANG biology.

Limitations of this report

Some quantitative effect sizes in Cai et al. 2024 (e.g., exact fold-changes in cytokines or densitometry values) are presented primarily in figures; the extracted text provides experimental conditions, sample sizes, and significance statements but not all numeric fold changes. (cai2024angiogeninmediatedtsrnascontrol pages 19-26, cai2024angiogeninmediatedtsrnascontrol pages 5-7)
Loveland et al. is a bioRxiv preprint (mechanistically influential and highly cited), so interpretations should be checked against the final peer-reviewed version when available. (loveland2024structuralmechanismof pages 1-5)

References (with URLs and publication dates)

Loveland AB et al. “Structural mechanism of angiogenin activation by the ribosome.” bioRxiv. Posted 2023-12; available/cited in 2024. https://doi.org/10.1101/2023.12.11.570495 (loveland2024structuralmechanismof pages 1-5)
Cai J et al. “Angiogenin-mediated tsRNAs control inflammation and metabolic disorder by regulating NLRP3 inflammasome.” Cell Death & Differentiation. 2024-05. https://doi.org/10.1038/s41418-024-01311-8 (cai2024angiogeninmediatedtsrnascontrol pages 5-7)
Culurciello R et al. “Tailoring the stress response of human skin cells by substantially limiting the nuclear localization of angiogenin.” Heliyon. 2024-02. https://doi.org/10.1016/j.heliyon.2024.e24556 (culurciello2024tailoringthestress pages 1-2)
Gurung RL et al. “Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes.” Cardiovascular Diabetology. 2024-02. https://doi.org/10.1186/s12933-024-02156-8 (gurung2024associationofplasma pages 4-5)
Gottè G. “Effects of Pathogenic Mutants of the Neuroprotective RNase 5-Angiogenin in Amyotrophic Lateral Sclerosis (ALS).” Genes. 2024-06. https://doi.org/10.3390/genes15060738 (gotte2024effectsofpathogenic pages 10-12)
Mao M et al. “Research progress on the structure, function, and use of angiogenin in malignant tumours.” Heliyon. 2024-05. https://doi.org/10.1016/j.heliyon.2024.e30654 (mao2024researchprogresson pages 1-3)

References

(gotte2024effectsofpathogenic pages 4-5): Giovanni Gotte. Effects of pathogenic mutants of the neuroprotective rnase 5-angiogenin in amyotrophic lateral sclerosis (als). Genes, 15:738, Jun 2024. URL: https://doi.org/10.3390/genes15060738, doi:10.3390/genes15060738. This article has 0 citations.
(mao2024researchprogresson pages 1-3): Mingwen Mao, Weina Chen, and Dong Ye. Research progress on the structure, function, and use of angiogenin in malignant tumours. Heliyon, 10:e30654, May 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e30654, doi:10.1016/j.heliyon.2024.e30654. This article has 9 citations.
(culurciello2024tailoringthestress pages 1-2): Rosanna Culurciello, Ilaria Di Nardo, Andrea Bosso, Francesca Tortora, Romualdo Troisi, Filomena Sica, Angela Arciello, Eugenio Notomista, and Elio Pizzo. Tailoring the stress response of human skin cells by substantially limiting the nuclear localization of angiogenin. Heliyon, 10:e24556, Feb 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e24556, doi:10.1016/j.heliyon.2024.e24556. This article has 6 citations.
(loveland2024structuralmechanismof pages 9-12): Anna B. Loveland, Cha San Koh, Robin Ganesan, Allan Jacobson, and Andrei A. Korostelev. Structural mechanism of angiogenin activation by the ribosome. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2023.12.11.570495, doi:10.1101/2023.12.11.570495. This article has 48 citations.
(shah2025aberranttrnaprocessing pages 44-53): A Shah. Aberrant trna processing contributes to cellular toxicity and impaired proteostasis in als. Unknown journal, 2025.
(loveland2024structuralmechanismof pages 1-5): Anna B. Loveland, Cha San Koh, Robin Ganesan, Allan Jacobson, and Andrei A. Korostelev. Structural mechanism of angiogenin activation by the ribosome. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2023.12.11.570495, doi:10.1101/2023.12.11.570495. This article has 48 citations.
(loveland2024structuralmechanismof pages 5-9): Anna B. Loveland, Cha San Koh, Robin Ganesan, Allan Jacobson, and Andrei A. Korostelev. Structural mechanism of angiogenin activation by the ribosome. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2023.12.11.570495, doi:10.1101/2023.12.11.570495. This article has 48 citations.
(loveland2024structuralmechanismof media 3b8dc74d): Anna B. Loveland, Cha San Koh, Robin Ganesan, Allan Jacobson, and Andrei A. Korostelev. Structural mechanism of angiogenin activation by the ribosome. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2023.12.11.570495, doi:10.1101/2023.12.11.570495. This article has 48 citations.
(loveland2024structuralmechanismof media 4c901db4): Anna B. Loveland, Cha San Koh, Robin Ganesan, Allan Jacobson, and Andrei A. Korostelev. Structural mechanism of angiogenin activation by the ribosome. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2023.12.11.570495, doi:10.1101/2023.12.11.570495. This article has 48 citations.
(culurciello2024tailoringthestress pages 8-10): Rosanna Culurciello, Ilaria Di Nardo, Andrea Bosso, Francesca Tortora, Romualdo Troisi, Filomena Sica, Angela Arciello, Eugenio Notomista, and Elio Pizzo. Tailoring the stress response of human skin cells by substantially limiting the nuclear localization of angiogenin. Heliyon, 10:e24556, Feb 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e24556, doi:10.1016/j.heliyon.2024.e24556. This article has 6 citations.
(cai2024angiogeninmediatedtsrnascontrol pages 5-7): Jiangxue Cai, Chenxuan Li, Suyuan Liu, Meiling Tan, Yiran Sun, Xiaoxiao Sun, Miaoxin Yang, and Bin He. Angiogenin-mediated tsrnas control inflammation and metabolic disorder by regulating nlrp3 inflammasome. Cell death and differentiation, 31:1057-1069, May 2024. URL: https://doi.org/10.1038/s41418-024-01311-8, doi:10.1038/s41418-024-01311-8. This article has 26 citations and is from a domain leading peer-reviewed journal.
(cai2024angiogeninmediatedtsrnascontrol pages 1-5): Jiangxue Cai, Chenxuan Li, Suyuan Liu, Meiling Tan, Yiran Sun, Xiaoxiao Sun, Miaoxin Yang, and Bin He. Angiogenin-mediated tsrnas control inflammation and metabolic disorder by regulating nlrp3 inflammasome. Cell death and differentiation, 31:1057-1069, May 2024. URL: https://doi.org/10.1038/s41418-024-01311-8, doi:10.1038/s41418-024-01311-8. This article has 26 citations and is from a domain leading peer-reviewed journal.
(cai2024angiogeninmediatedtsrnascontrol pages 19-26): Jiangxue Cai, Chenxuan Li, Suyuan Liu, Meiling Tan, Yiran Sun, Xiaoxiao Sun, Miaoxin Yang, and Bin He. Angiogenin-mediated tsrnas control inflammation and metabolic disorder by regulating nlrp3 inflammasome. Cell death and differentiation, 31:1057-1069, May 2024. URL: https://doi.org/10.1038/s41418-024-01311-8, doi:10.1038/s41418-024-01311-8. This article has 26 citations and is from a domain leading peer-reviewed journal.
(gotte2024effectsofpathogenic pages 10-12): Giovanni Gotte. Effects of pathogenic mutants of the neuroprotective rnase 5-angiogenin in amyotrophic lateral sclerosis (als). Genes, 15:738, Jun 2024. URL: https://doi.org/10.3390/genes15060738, doi:10.3390/genes15060738. This article has 0 citations.
(gurung2024associationofplasma pages 1-2): Resham L. Gurung, Sylvia Liu, Jian-Jun Liu, Yiamunaa M., Huili Zheng, Clara Chan, Keven Ang, Tavintharan Subramaniam, Chee Fang Sum, and Su Chi Lim. Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes. Cardiovascular Diabetology, Feb 2024. URL: https://doi.org/10.1186/s12933-024-02156-8, doi:10.1186/s12933-024-02156-8. This article has 10 citations and is from a peer-reviewed journal.
(gurung2024associationofplasma pages 4-5): Resham L. Gurung, Sylvia Liu, Jian-Jun Liu, Yiamunaa M., Huili Zheng, Clara Chan, Keven Ang, Tavintharan Subramaniam, Chee Fang Sum, and Su Chi Lim. Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes. Cardiovascular Diabetology, Feb 2024. URL: https://doi.org/10.1186/s12933-024-02156-8, doi:10.1186/s12933-024-02156-8. This article has 10 citations and is from a peer-reviewed journal.
(gurung2024associationofplasma pages 2-4): Resham L. Gurung, Sylvia Liu, Jian-Jun Liu, Yiamunaa M., Huili Zheng, Clara Chan, Keven Ang, Tavintharan Subramaniam, Chee Fang Sum, and Su Chi Lim. Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes. Cardiovascular Diabetology, Feb 2024. URL: https://doi.org/10.1186/s12933-024-02156-8, doi:10.1186/s12933-024-02156-8. This article has 10 citations and is from a peer-reviewed journal.
(gurung2024associationofplasma pages 5-7): Resham L. Gurung, Sylvia Liu, Jian-Jun Liu, Yiamunaa M., Huili Zheng, Clara Chan, Keven Ang, Tavintharan Subramaniam, Chee Fang Sum, and Su Chi Lim. Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes. Cardiovascular Diabetology, Feb 2024. URL: https://doi.org/10.1186/s12933-024-02156-8, doi:10.1186/s12933-024-02156-8. This article has 10 citations and is from a peer-reviewed journal.
(loveland2024structuralmechanismof pages 27-31): Anna B. Loveland, Cha San Koh, Robin Ganesan, Allan Jacobson, and Andrei A. Korostelev. Structural mechanism of angiogenin activation by the ribosome. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2023.12.11.570495, doi:10.1101/2023.12.11.570495. This article has 48 citations.
(loveland2024structuralmechanismof pages 23-27): Anna B. Loveland, Cha San Koh, Robin Ganesan, Allan Jacobson, and Andrei A. Korostelev. Structural mechanism of angiogenin activation by the ribosome. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2023.12.11.570495, doi:10.1101/2023.12.11.570495. This article has 48 citations.
(loveland2024structuralmechanismof pages 20-23): Anna B. Loveland, Cha San Koh, Robin Ganesan, Allan Jacobson, and Andrei A. Korostelev. Structural mechanism of angiogenin activation by the ribosome. bioRxiv, Dec 2024. URL: https://doi.org/10.1101/2023.12.11.570495, doi:10.1101/2023.12.11.570495. This article has 48 citations.
(cai2024angiogeninmediatedtsrnascontrol pages 7-9): Jiangxue Cai, Chenxuan Li, Suyuan Liu, Meiling Tan, Yiran Sun, Xiaoxiao Sun, Miaoxin Yang, and Bin He. Angiogenin-mediated tsrnas control inflammation and metabolic disorder by regulating nlrp3 inflammasome. Cell death and differentiation, 31:1057-1069, May 2024. URL: https://doi.org/10.1038/s41418-024-01311-8, doi:10.1038/s41418-024-01311-8. This article has 26 citations and is from a domain leading peer-reviewed journal.

Citations

loveland2024structuralmechanismof pages 9-12
culurciello2024tailoringthestress pages 1-2
gotte2024effectsofpathogenic pages 4-5
loveland2024structuralmechanismof pages 1-5
cai2024angiogeninmediatedtsrnascontrol pages 19-26
cai2024angiogeninmediatedtsrnascontrol pages 1-5
gotte2024effectsofpathogenic pages 10-12
gurung2024associationofplasma pages 1-2
gurung2024associationofplasma pages 4-5
mao2024researchprogresson pages 1-3
cai2024angiogeninmediatedtsrnascontrol pages 5-7
shah2025aberranttrnaprocessing pages 44-53
loveland2024structuralmechanismof pages 5-9
culurciello2024tailoringthestress pages 8-10
gurung2024associationofplasma pages 2-4
gurung2024associationofplasma pages 5-7
loveland2024structuralmechanismof pages 27-31
loveland2024structuralmechanismof pages 23-27
loveland2024structuralmechanismof pages 20-23
cai2024angiogeninmediatedtsrnascontrol pages 7-9
https://doi.org/10.3390/genes15060738
https://doi.org/10.1016/j.heliyon.2024.e30654
https://doi.org/10.1101/2023.12.11.570495
https://doi.org/10.1016/j.heliyon.2024.e24556
https://doi.org/10.1038/s41418-024-01311-8
https://doi.org/10.1186/s12933-024-02156-8
https://doi.org/10.3390/genes15060738,
https://doi.org/10.1016/j.heliyon.2024.e30654,
https://doi.org/10.1016/j.heliyon.2024.e24556,
https://doi.org/10.1101/2023.12.11.570495,
https://doi.org/10.1038/s41418-024-01311-8,
https://doi.org/10.1186/s12933-024-02156-8,

📄 View Raw YAML

id: P03950
gene_symbol: ANG
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ANG encodes angiogenin/RNase 5, a secreted RNase A-family endoribonuclease. Its core activity is regulated RNA cleavage, especially ribosome-activated cleavage of mature cytoplasmic tRNAs under stress to generate tiRNA/tsRNA halves, together with nucleolar stimulation of rRNA transcription and established proangiogenic functions.
existing_annotations:
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0005615
    label: obsolete extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region.
    action: MODIFY
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term.
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
    proposed_replacement_terms:
    - id: GO:0005576
      label: extracellular region
- term:
    id: GO:0019731
    label: antibacterial humoral response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Kept as non-core. This immune/antimicrobial IBA annotation may reflect secreted RNase biology, but ANG is better characterized by RNase/stress and angiogenic functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Kept as non-core. Recent evidence supports ANG-derived tsRNAs in innate immune/inflammasome regulation, but this is context-specific.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "ANG-generated **5\u2032 tsRNAs** are anti-inflammatory effectors that suppress **NLRP3 inflammasome** activation and pyroptosis by promoting **DDX3X recruitment into SGs**, reducing DDX3X-NLRP3 interaction."
- term:
    id: GO:0050830
    label: defense response to Gram-positive bacterium
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Kept as non-core. This immune/antimicrobial IBA annotation may reflect secreted RNase biology, but ANG is better characterized by RNase/stress and angiogenic functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0061844
    label: antimicrobial humoral immune response mediated by antimicrobial peptide
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Kept as non-core. This immune/antimicrobial IBA annotation may reflect secreted RNase biology, but ANG is better characterized by RNase/stress and angiogenic functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Generic nucleic acid binding does not describe the catalytic RNA-cleavage function.
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10413501
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15737636
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17991437
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24457100
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28777577
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0004521
    label: RNA endonuclease activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708327
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IDA
  original_reference_id: PMID:29100074
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Broad signaling is less informative than receptor ligand, angiogenesis, and RNase/stress-response terms.
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IDA
  original_reference_id: PMID:29100074
  review:
    summary: Supported but non-core. Receptor-mediated signaling or uptake is relevant to ANG trafficking and extracellular activity, but not the central RNase mechanism.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:23047679
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0005615
    label: obsolete extracellular space
  evidence_type: IDA
  original_reference_id: PMID:23047679
  review:
    summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region.
    action: MODIFY
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term.
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
    proposed_replacement_terms:
    - id: GO:0005576
      label: extracellular region
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23047679
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23047679
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Prefer specific cytosol, stress granule, nuclear, nucleolar, and extracellular localization terms.
- term:
    id: GO:0034063
    label: stress granule assembly
  evidence_type: IDA
  original_reference_id: PMID:23047679
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:27518564
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:29100074
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:32510170
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:38718836
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0009303
    label: rRNA transcription
  evidence_type: IDA
  original_reference_id: PMID:27518564
  review:
    summary: Correct. In nucleoli, ANG promotes rRNA transcription and ribosome biogenesis under growth conditions.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0009303
    label: rRNA transcription
  evidence_type: IDA
  original_reference_id: PMID:29100074
  review:
    summary: Correct. In nucleoli, ANG promotes rRNA transcription and ribosome biogenesis under growth conditions.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0009303
    label: rRNA transcription
  evidence_type: IDA
  original_reference_id: PMID:32510170
  review:
    summary: Correct. In nucleoli, ANG promotes rRNA transcription and ribosome biogenesis under growth conditions.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: IDA
  original_reference_id: PMID:27518564
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0010494
    label: cytoplasmic stress granule
  evidence_type: IDA
  original_reference_id: PMID:29100074
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IDA
  original_reference_id: PMID:27518564
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IDA
  original_reference_id: PMID:29100074
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IDA
  original_reference_id: PMID:32510170
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IDA
  original_reference_id: PMID:38718836
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IDA
  original_reference_id: PMID:38718836
  review:
    summary: Correct and informative. Ribosome binding activates ANG and positions tRNA substrate for efficient anticodon-loop cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: A key unresolved question in the field has been why ANG is a weak RNase as a free protein yet is biologically potent in cells. Loveland et al. (bioRxiv, posted 2023-12; version/availability in 2024) provide structural and biochemical evidence that the **cytosolic 80S ribosome is the activator and specificity factor for ANG**.
- term:
    id: GO:0071425
    label: hematopoietic stem cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:27518564
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:3289612
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:19332886
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:20129916
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:21855800
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:31582561
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IDA
  original_reference_id: PMID:19332886
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IDA
  original_reference_id: PMID:20129916
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IDA
  original_reference_id: PMID:21855800
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IDA
  original_reference_id: PMID:31582561
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0034063
    label: stress granule assembly
  evidence_type: IDA
  original_reference_id: PMID:20129916
  review:
    summary: Correct. ANG-derived tiRNAs/tsRNAs repress translation and participate in stress granule-linked stress responses.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Supported as a non-core survival/stress-response outcome of ANG-derived tiRNAs rather than a direct molecular function.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG-generated tiRNAs/tsRNAs repress protein synthesis and help organize the stress response.
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:3470787
  review:
    summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:11919285
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:3470787
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:29748193
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0005615
    label: obsolete extracellular space
  evidence_type: IDA
  original_reference_id: PMID:29748193
  review:
    summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region.
    action: MODIFY
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term.
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
    proposed_replacement_terms:
    - id: GO:0005576
      label: extracellular region
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23843625
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23843625
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Prefer specific cytosol, stress granule, nuclear, nucleolar, and extracellular localization terms.
- term:
    id: GO:0030139
    label: endocytic vesicle
  evidence_type: IDA
  original_reference_id: PMID:29748193
  review:
    summary: Supported but non-core. Receptor-mediated signaling or uptake is relevant to ANG trafficking and extracellular activity, but not the central RNase mechanism.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:2459697
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:3122207
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:8159680
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:8570639
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:8622921
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:4074709
  review:
    summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0023052
    label: signaling
  evidence_type: IDA
  original_reference_id: PMID:2457905
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Broad signaling is less informative than receptor ligand, angiogenesis, and RNase/stress-response terms.
- term:
    id: GO:0016078
    label: tRNA decay
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708296
  review:
    summary: Correct and core. ANG cleaves mature cytoplasmic tRNAs in the anticodon loop to generate tiRNA/tsRNA halves.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708327
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5692437
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25372031
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:25372031
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:8448182
  review:
    summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0001556
    label: oocyte maturation
  evidence_type: NAS
  original_reference_id: PMID:11438326
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IDA
  original_reference_id: PMID:10999833
  review:
    summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0009725
    label: response to hormone
  evidence_type: IDA
  original_reference_id: PMID:10999833
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0042277
    label: peptide binding
  evidence_type: IDA
  original_reference_id: PMID:11782452
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Peptide binding is too generic for ANG-specific curation.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:17125737
  review:
    summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0016477
    label: cell migration
  evidence_type: IMP
  original_reference_id: PMID:17125737
  review:
    summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0042327
    label: positive regulation of phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:17125737
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0032311
    label: angiogenin-PRI complex
  evidence_type: IDA
  original_reference_id: PMID:3470787
  review:
    summary: Supported but non-core. The angiogenin-PRI/RNH1 complex is a specific inhibitory regulatory complex for ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**RNH1/RI** is the principal intracellular inhibitor that restrains ANG activity and trafficking.'
- term:
    id: GO:0032311
    label: angiogenin-PRI complex
  evidence_type: IPI
  original_reference_id: PMID:3470787
  review:
    summary: Supported but non-core. The angiogenin-PRI/RNH1 complex is a specific inhibitory regulatory complex for ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**RNH1/RI** is the principal intracellular inhibitor that restrains ANG activity and trafficking.'
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:9707554
  review:
    summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0030041
    label: actin filament polymerization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0050714
    label: positive regulation of protein secretion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:2479414
  review:
    summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IC
  original_reference_id: PMID:10649442
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: DNA binding is too generic relative to nucleolar rRNA-transcription and RNase annotations.
- term:
    id: GO:0004519
    label: endonuclease activity
  evidence_type: TAS
  original_reference_id: PMID:10103013
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Use RNA endonuclease and tRNA-specific ribonuclease terms rather than generic endonuclease activity.
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:2424496
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:2730651
  review:
    summary: Correct. ANG is an RNase A-family RNA endoribonuclease that catalyzes RNA backbone cleavage.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: '**Reaction class**: ANG is an RNase A-family **phosphodiesterase** (EC 3.1.27.- in UniProt context), catalyzing RNA backbone cleavage via the canonical RNase A catalytic architecture.'
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IDA
  original_reference_id: PMID:9245697
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:2742853
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:3470787
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Retain interaction evidence conceptually, but replace generic protein binding with specific binding, complex, receptor, ribosome, and RNase annotations.
- term:
    id: GO:0005604
    label: basement membrane
  evidence_type: IDA
  original_reference_id: PMID:15166501
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0005615
    label: obsolete extracellular space
  evidence_type: IDA
  original_reference_id: PMID:3663649
  review:
    summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region.
    action: MODIFY
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term.
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
    proposed_replacement_terms:
    - id: GO:0005576
      label: extracellular region
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:10649442
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0007154
    label: cell communication
  evidence_type: NAS
  original_reference_id: PMID:10103013
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Generic cell communication should not be used when specific ANG functions are available.
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IDA
  original_reference_id: PMID:10103013
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0019843
    label: rRNA binding
  evidence_type: TAS
  original_reference_id: PMID:2457905
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0042592
    label: homeostatic process
  evidence_type: NAS
  original_reference_id: PMID:15166501
  review:
    summary: Correct or plausible but too broad for useful ANG annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: Homeostatic process is not informative for ANG curation.
- term:
    id: GO:0050714
    label: positive regulation of protein secretion
  evidence_type: IDA
  original_reference_id: PMID:2646638
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:9122172
  review:
    summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IDA
  original_reference_id: PMID:7679494
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IDA
  original_reference_id: PMID:9122172
  review:
    summary: Supported but non-core. Receptor-mediated signaling or uptake is relevant to ANG trafficking and extracellular activity, but not the central RNase mechanism.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0048662
    label: negative regulation of smooth muscle cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:10103013
  review:
    summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: TAS
  original_reference_id: PMID:16567967
  review:
    summary: Correct. ANG is a canonical proangiogenic factor, with angiogenic outcomes linked to its secreted/nuclear RNase biology.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0001541
    label: ovarian follicle development
  evidence_type: NAS
  original_reference_id: PMID:12770725
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: NAS
  original_reference_id: PMID:15776477
  review:
    summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IDA
  original_reference_id: PMID:15979542
  review:
    summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0001666
    label: response to hypoxia
  evidence_type: IDA
  original_reference_id: PMID:16490744
  review:
    summary: Supported as a non-core angiogenic or vascular cell-response context downstream of ANG activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG remains a canonical **proangiogenic** factor and tumor-associated RNase.
- term:
    id: GO:0001890
    label: placenta development
  evidence_type: NAS
  original_reference_id: PMID:11984825
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IDA
  original_reference_id: PMID:11782452
  review:
    summary: Supported or plausible for ANG, but non-core relative to regulated RNase activity, tRNA cleavage, nucleolar rRNA transcription, and angiogenesis. This context-specific annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
- term:
    id: GO:0005615
    label: obsolete extracellular space
  evidence_type: IDA
  original_reference_id: PMID:16461950
  review:
    summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region.
    action: MODIFY
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term.
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
    proposed_replacement_terms:
    - id: GO:0005576
      label: extracellular region
- term:
    id: GO:0005615
    label: obsolete extracellular space
  evidence_type: IDA
  original_reference_id: PMID:16490744
  review:
    summary: The biological localization is extracellular, but this GO term is obsolete and should be replaced by extracellular region.
    action: MODIFY
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    reason: GO:0005615 is obsolete; GO:0005576 extracellular region is the current supported localization term.
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
    proposed_replacement_terms:
    - id: GO:0005576
      label: extracellular region
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:15735021
  review:
    summary: Correct. ANG has compartment-dependent function across extracellular, nuclear/nucleolar, and cytosolic stress-response pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
- term:
    id: GO:0009303
    label: rRNA transcription
  evidence_type: IMP
  original_reference_id: PMID:15735021
  review:
    summary: Correct. In nucleoli, ANG promotes rRNA transcription and ribosome biogenesis under growth conditions.
    action: ACCEPT
    additional_reference_ids:
    - file:human/ANG/ANG-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/ANG/ANG-deep-research-falcon.md
      supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:10103013
  title: Expression of receptors for human angiogenin in vascular smooth muscle cells.
  findings: []
- id: PMID:10413501
  title: Superadditive and subadditive effects of "hot spot" mutations within the interfaces of placental ribonuclease inhibitor with angiogenin and ribonuclease A.
  findings: []
- id: PMID:10649442
  title: Human angiogenin is rapidly translocated to the nucleus of human umbilical vein endothelial cells and binds to DNA.
  findings: []
- id: PMID:10999833
  title: Evidence for the presence of angiogenin in human follicular fluid and the up-regulation of its production by human chorionic gonadotropin and hypoxia.
  findings: []
- id: PMID:11438326
  title: 'Concentrations of angiogenic factors in follicular fluid and oocyte-cumulus complex culture medium from women undergoing in vitro fertilization: association with oocyte maturity and fertilization.'
  findings: []
- id: PMID:11782452
  title: Antiplasmin activity of a peptide that binds to the receptor-binding site of angiogenin.
  findings: []
- id: PMID:11919285
  title: Diversifying selection of the tumor-growth promoter angiogenin in primate evolution.
  findings: []
- id: PMID:11984825
  title: 'Expression and localization of angiogenin in placenta: enhanced levels at term over first trimester villi.'
  findings: []
- id: PMID:12770725
  title: Production of vascular endothelial growth factor and angiogenic factor in human follicular fluid.
  findings: []
- id: PMID:15166501
  title: Angiogenin distribution in human term placenta, and expression by cultured trophoblastic cells.
  findings: []
- id: PMID:15735021
  title: Angiogenin is translocated to the nucleus of HeLa cells and is involved in ribosomal RNA transcription and cell proliferation.
  findings: []
- id: PMID:15737636
  title: Alpha-actinin-2, a cytoskeletal protein, binds to angiogenin.
  findings: []
- id: PMID:15776477
  title: Angiogenin is up-regulated in the nucleus and cytoplasm in human primary breast carcinoma and is associated with markers of hypoxia but not survival.
  findings: []
- id: PMID:15979542
  title: Hypoxia up-regulated angiogenin and down-regulated vascular cell adhesion molecule-1 expression and secretion in human placental trophoblasts.
  findings: []
- id: PMID:16461950
  title: Assessment of some tools for the characterization of the human osteoarthritic cartilage proteome.
  findings: []
- id: PMID:16490744
  title: Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture.
  findings: []
- id: PMID:16567967
  title: Influence of angiogenin on the growth of A375 human melanoma cells and the expression of basic fibroblast growth factor.
  findings: []
- id: PMID:17125737
  title: Angiogenin-induced protein kinase B/Akt activation is necessary for angiogenesis but is independent of nuclear translocation of angiogenin in HUVE cells.
  findings: []
- id: PMID:17991437
  title: Identification and characterization of follistatin as a novel angiogenin-binding protein.
  findings: []
- id: PMID:19332886
  title: Angiogenin cleaves tRNA and promotes stress-induced translational repression.
  findings: []
- id: PMID:20129916
  title: Angiogenin-induced tRNA-derived stress-induced RNAs promote stress-induced stress granule assembly.
  findings: []
- id: PMID:21855800
  title: Angiogenin-induced tRNA fragments inhibit translation initiation.
  findings: []
- id: PMID:23047679
  title: Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons.
  findings: []
- id: PMID:23843625
  title: Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival.
  findings: []
- id: PMID:2424496
  title: Characteristic ribonucleolytic activity of human angiogenin.
  findings: []
- id: PMID:24457100
  title: Angiogenin interacts with the plasminogen activation system at the cell surface of breast cancer cells to regulate plasmin formation and cell migration.
  findings: []
- id: PMID:2457905
  title: Angiogenin activates endothelial cell phospholipase C.
  findings: []
- id: PMID:2459697
  title: Mutagenesis of aspartic acid-116 enhances the ribonucleolytic activity and angiogenic potency of angiogenin.
  findings: []
- id: PMID:2479414
  title: Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis.
  findings: []
- id: PMID:25372031
  title: Computational and functional characterization of Angiogenin mutations, and correlation with amyotrophic lateral sclerosis.
  findings: []
- id: PMID:2646638
  title: Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A2.
  findings: []
- id: PMID:2730651
  title: Characterization of ribonucleolytic activity of angiogenin towards tRNA.
  findings: []
- id: PMID:2742853
  title: Binding of placental ribonuclease inhibitor to the active site of angiogenin.
  findings: []
- id: PMID:27518564
  title: Angiogenin Promotes Hematopoietic Regeneration by Dichotomously Regulating Quiescence of Stem and Progenitor Cells.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:28777577
  title: Proteomic Analysis of Human Angiogenin Interactions Reveals Cytoplasmic PCNA as a Putative Binding Partner.
  findings: []
- id: PMID:29100074
  title: Plexin-B2 Mediates Physiologic and Pathologic Functions of Angiogenin.
  findings: []
- id: PMID:29748193
  title: Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor.
  findings: []
- id: PMID:3122207
  title: 'Ribonucleolytic activity of angiogenin: essential histidine, lysine, and arginine residues.'
  findings: []
- id: PMID:31582561
  title: Angiogenin generates specific stress-induced tRNA halves and is not involved in tRF-3-mediated gene silencing.
  findings: []
- id: PMID:32510170
  title: Myeloid cells protect intestinal epithelial barrier integrity through the angiogenin/plexin-B2 axis.
  findings: []
- id: PMID:3289612
  title: Base cleavage specificity of angiogenin with Saccharomyces cerevisiae and Escherichia coli 5S RNAs.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:3470787
  title: Human placental ribonuclease inhibitor abolishes both angiogenic and ribonucleolytic activities of angiogenin.
  findings: []
- id: PMID:3663649
  title: Isolation of angiogenin from normal human plasma.
  findings: []
- id: PMID:38718836
  title: Structural mechanism of angiogenin activation by the ribosome.
  findings: []
- id: PMID:4074709
  title: Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells.
  findings: []
- id: PMID:7679494
  title: Actin is a binding protein for angiogenin.
  findings: []
- id: PMID:8159680
  title: Role of glutamine-117 in the ribonucleolytic activity of human angiogenin.
  findings: []
- id: PMID:8448182
  title: 'Characterization and sequencing of rabbit, pig and mouse angiogenins: discernment of functionally important residues and regions.'
  findings: []
- id: PMID:8570639
  title: A combined kinetic and modeling study of the catalytic center subsites of human angiogenin.
  findings: []
- id: PMID:8622921
  title: The C-terminal region of human angiogenin has a dual role in enzymatic activity.
  findings: []
- id: PMID:9122172
  title: A putative angiogenin receptor in angiogenin-responsive human endothelial cells.
  findings: []
- id: PMID:9245697
  title: Interaction of human angiogenin with copper modulates angiogenin binding to endothelial cells.
  findings: []
- id: PMID:9707554
  title: Neomycin inhibits angiogenin-induced angiogenesis.
  findings: []
- id: Reactome:R-HSA-5692437
  title: ANG binds F-actin
  findings: []
- id: Reactome:R-HSA-9708296
  title: tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis
  findings: []
- id: Reactome:R-HSA-9708327
  title: ANG cleaves tRNA to yield tRNA halves
  findings: []
- id: file:human/ANG/ANG-deep-research-falcon.md
  title: Falcon deep research report for human ANG
  findings: []
core_functions:
- description: 'ANG is a regulated RNase A-family endoribonuclease whose core function is compartment-dependent RNA metabolism: ribosome-activated cytosolic tRNA cleavage during stress and nucleolar promotion of rRNA transcription under growth conditions, with secreted proangiogenic activity as a major physiological output.'
  supported_by:
  - reference_id: file:human/ANG/ANG-deep-research-falcon.md
    supporting_text: 'ANG is a secreted RNase A-family endoribonuclease originally characterized as an angiogenic factor, but now understood as a **stress-responsive ribonuclease** with dual roles depending on subcellular localization: (i) **nucleolar/nuclear** functions in rRNA transcription and (ii) **cytosolic** functions in stress-induced tRNA cleavage and translational repression.'
  - reference_id: file:human/ANG/ANG-deep-research-falcon.md
    supporting_text: "A central, repeatedly supported substrate in stress biology is **mature cytoplasmic tRNA**, cleaved **within the anticodon loop** to yield **5\u2032 and 3\u2032 tRNA halves** (often called **tiRNAs/tsRNAs**), typically ~**30\u201340 nt**."
  - reference_id: file:human/ANG/ANG-deep-research-falcon.md
    supporting_text: ANG is secreted and can be re-internalized by cells through receptor-mediated uptake; once internalized, its localization determines function. **Nucleolar ANG** promotes rRNA transcription and ribosome biogenesis, whereas **cytosolic ANG** under stress cleaves tRNAs and participates in translational arrest/SG programs.
  molecular_function:
    id: GO:0004549
    label: tRNA-specific ribonuclease activity
  directly_involved_in:
  - id: GO:0016078
    label: tRNA decay
  - id: GO:0032055
    label: negative regulation of translation in response to stress
  - id: GO:0009303
    label: rRNA transcription
  - id: GO:0001525
    label: angiogenesis
  locations:
  - id: GO:0005576
    label: extracellular region
  - id: GO:0005730
    label: nucleolus
  - id: GO:0005829
    label: cytosol
  - id: GO:0010494
    label: cytoplasmic stress granule
proposed_new_terms: []
suggested_questions:
- question: Which ANG functions require ribosome-activated tRNA cleavage versus nucleolar rRNA transcription in specific human cell types?
  experts: []
- question: Which receptor-mediated uptake routes determine ANG partitioning between extracellular signaling, cytosolic stress responses, and nucleolar growth programs?
  experts: []
suggested_experiments:
- hypothesis: Ribosome binding is required for stress-induced ANG tRNA cleavage and translation repression in cells.
  description: Use ANG variants defective in ribosome association or catalytic residues, then compare tRNA-half production, translation rates, and stress granule assembly after oxidative stress.
- hypothesis: ANG angiogenic outputs are separable from cytosolic stress-response outputs by altering nuclear localization or receptor-mediated uptake.
  description: Rescue ANG-depleted endothelial cells with localization-biased ANG variants and measure rRNA transcription, endothelial proliferation/migration, and stress-induced tiRNA production.

ANG

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Human ANG (Angiogenin; RNASE5) — Functional Annotation (UniProt P03950)

0. Identity verification (critical disambiguation)

1. Key concepts and definitions (current understanding)

1.1 What is angiogenin (ANG/RNASE5)?

1.2 Enzymatic activity: reaction and substrate specificity

1.3 Localization and compartment-specific functions

1.4 Regulation by the ribonuclease inhibitor RNH1 (RI)

2. Recent developments and latest research (prioritizing 2023–2024)

2.1 Major 2024 mechanistic advance: ribosomes activate angiogenin

2.2 ANG, stress granules, and translational repression (2024 cell biology)

2.3 New 2024 link between ANG-generated tsRNAs and innate immunity: NLRP3 inflammasome control

2.4 Disease genetics and expert synthesis (2024 ALS-focused review)

3. Current applications and real-world implementations

3.1 Biomarker implementation: cardiovascular risk prediction in type 2 diabetes (human cohort)

3.2 Translational directions in oncology

3.3 Mechanism-guided protein engineering as a “functional switch”

4. Expert opinions and analysis (authoritative synthesis)

4.1 Consensus model emerging from 2024 literature

4.2 Disease interpretability of ANG variants

5. Relevant statistics and quantitative data (recent studies)

Evidence map / quick-reference table

Limitations of this report

References (with URLs and publication dates)

Citations

📄 View Raw YAML