ARPP21 (ARPP-21, TARPP) is a cytoplasmic R3H-domain RNA-binding protein, first identified as a cAMP-regulated phosphoprotein that PKA phosphorylates and that is enriched in dopamine-innervated striatal neurons. It binds uridine-rich sequences in 3' UTRs and acts as a positive post-transcriptional regulator, interacting with the translation initiation complex eIF4F. In neurons it opposes the miRNA it hosts, miR-128, by co-regulating shared target mRNAs, and promotes dendritic branching. In thymocytes it promotes the expression of target mRNAs that support TCR repertoire diversity. A short isoform has been proposed to inhibit calmodulin-dependent enzymes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | MODIFY | Summary: Nucleic acid binding (IEA, InterPro R3H domain). ARPP21 binds RNA directly through its R3H domain, recognizing uridine-rich sequences with high specificity for 3' UTRs (iCLIP). Modified to mRNA 3'-UTR binding. Reason: The 3'-UTR specificity data (iCLIP in inducible ARPP21 lines, R3H binding in thymocytes) come from mouse work; the human assertion is a homology call resting on the conserved R3H domain. [PMID:29581509 "Here we use iCLIP to characterize ARPP21 recognition of uridine-rich sequences with high specificity for 3'UTRs."] [PMID:38467629 "Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs."] Proposed replacements: mRNA 3'-UTR binding Supporting Evidence: PMID:29581509 Here we use iCLIP to characterize ARPP21 recognition of uridine-rich sequences with high specificity for 3'UTRs. PMID:38467629 Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasm (IBA). Tagged ARPP21 is almost exclusively cytoplasmic and granular. Endogenous ARPP21 is in the somatodendritic compartment of cortical neurons and moves to stress granules under arsenite. Core location. Reason: [PMID:29581509 "Anti-FLAG staining revealed almost exclusively granular, cytoplasmic localization of both full-length proteins (Fig."] [PMID:29581509 "We could also demonstrate relocalization of endogenous ARPP21 present in the somatodendritic compartment of primary cortical neurons to eIF3Ξ·-positive SGs upon arsenite treatment (Fig."] Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002695700 SUPPORTS TRANSFER ARPP21 node; seeded by Mouse Arpp21 (UniProtKB:Q9DCB4, MGI:107562), whose donor IDA cytoplasm is from PMID:29581509. Supporting Evidence: PMID:29581509 Anti-FLAG staining revealed almost exclusively granular, cytoplasmic localization of both full-length proteins (Fig. PMID:29581509 We could also demonstrate relocalization of endogenous ARPP21 present in the somatodendritic compartment of primary cortical neurons to eIF3Ξ·-positive SGs upon arsenite treatment (Fig. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasm (IEA). Tagged ARPP21 is almost exclusively cytoplasmic and granular. Endogenous ARPP21 is in the somatodendritic compartment of cortical neurons and moves to stress granules under arsenite. Core location. Reason: [PMID:29581509 "Anti-FLAG staining revealed almost exclusively granular, cytoplasmic localization of both full-length proteins (Fig."] [PMID:29581509 "We could also demonstrate relocalization of endogenous ARPP21 present in the somatodendritic compartment of primary cortical neurons to eIF3Ξ·-positive SGs upon arsenite treatment (Fig."] Supporting Evidence: PMID:29581509 Anti-FLAG staining revealed almost exclusively granular, cytoplasmic localization of both full-length proteins (Fig. PMID:29581509 We could also demonstrate relocalization of endogenous ARPP21 present in the somatodendritic compartment of primary cortical neurons to eIF3Ξ·-positive SGs upon arsenite treatment (Fig. |
| GO:0050775 positive regulation of dendrite morphogenesis | ISO PMID:29581509 The RNA-binding protein ARPP21 controls dendritic branching ... | NEW | Summary: Positive regulation of dendrite morphogenesis (NEW, ISO from mouse Arpp21). In mouse cortical neurons, ARPP21 knockdown reduces dendritic complexity and ectopic ARPP21 increases it. ARPP21 promotes translation of shared targets of its host miRNA miR-128, through eIF4F. ARPP21 itself binds the target mRNAs, so it performs the regulatory step. Reason: [PMID:29581509 "This molecular antagonism is reflected in inverse activities during dendritogenesis: miR-128 overexpression or knockdown of ARPP21 reduces dendritic complexity; ectopic ARPP21 leads to an increase."] [PMID:29581509 "Protein-protein interaction data and functional assays suggest that ARPP21 acts as a positive post-transcriptional regulator by interacting with the translation initiation complex eIF4F."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9DCB4 SUPPORTS TRANSFER Mouse Arpp21 (UniProtKB:Q9DCB4, MGI:107562); knockdown, rescue and overexpression by in utero electroporation in mouse cortex (PMID:29581509). MGI has not annotated this process to Arpp21, so the ISO rests directly on the paper's mouse experiments rather than on an existing MGI GO row. Supporting Evidence: PMID:29581509 This molecular antagonism is reflected in inverse activities during dendritogenesis: miR-128 overexpression or knockdown of ARPP21 reduces dendritic complexity; ectopic ARPP21 leads to an increase. PMID:29581509 Protein-protein interaction data and functional assays suggest that ARPP21 acts as a positive post-transcriptional regulator by interacting with the translation initiation complex eIF4F. |
| GO:0045727 positive regulation of translation | ISO PMID:29581509 The RNA-binding protein ARPP21 controls dendritic branching ... | NEW | Summary: Positive regulation of translation (NEW, ISO from mouse Arpp21 work). Tethering ARPP21 to a reporter 3' UTR raises reporter output, and the increase depends on eIF4G. Because eIF4G knockdown leaves reporter mRNA levels unchanged, the authors attribute the effect to translational efficiency. ARPP21 co-precipitates eIF4G and eIF4A1 independently of RNA. ARPP21 binds the target mRNA and engages eIF4F, so it does the regulatory work itself. The parent term is used rather than GO:0045948 positive regulation of translational initiation, because initiation-step specificity is inferred from eIF4G dependence rather than measured. Reason: [PMID:29581509 "ARPP21 tethering results in increased GFP fluorescence of the MS2-binding site reporter (4X-MS2-BS-GFP) compared to tethering of the MS2 protein alone."] [PMID:29581509 "ARPP21 activity in the tethering assay is reduced after eIF4G knockdown."] [PMID:29581509 "This suggests that the translational efficiency and not the stability of the tethered mRNA may be responsible for the observed differences in reporter expression."] [PMID:29581509 "Protein-protein interaction data and functional assays suggest that ARPP21 acts as a positive post-transcriptional regulator by interacting with the translation initiation complex eIF4F."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9DCB4 SUPPORTS TRANSFER Mouse Arpp21 (UniProtKB:Q9DCB4, MGI:107562); a mouse study (MS2 tethering in 293T cells with mouse reporters). The cached text does not state the species of the tethered ARPP21 construct, so ISO from mouse is the conservative evidence code. The R3H and C-terminal regions are conserved. Supporting Evidence: PMID:29581509 ARPP21 tethering results in increased GFP fluorescence of the MS2-binding site reporter (4X-MS2-BS-GFP) compared to tethering of the MS2 protein alone. PMID:29581509 ARPP21 activity in the tethering assay is reduced after eIF4G knockdown. PMID:29581509 This suggests that the translational efficiency and not the stability of the tethered mRNA may be responsible for the observed differences in reporter expression. PMID:29581509 Protein-protein interaction data and functional assays suggest that ARPP21 acts as a positive post-transcriptional regulator by interacting with the translation initiation complex eIF4F. |
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Download this section (compressed HTML)Q: Does PKA phosphorylation of ARPP21 at Ser55 change its RNA binding or eIF4F interaction, linking dopamine signalling to its post-transcriptional role?
Q: Does human TARPP (isoform 1), detected at protein level in immature thymocytes, promote RAG1 expression as mouse Arpp21 does, and should the Rag1/TCR-diversity role be annotated once human or direct mechanistic data exist?
Experiment: Compare 3' UTR binding (iCLIP) and target-mRNA translation for phospho-mimetic and phospho-dead Ser55 ARPP21 in striatal neurons.
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