AQP5-AS1 encodes MIAC (micropeptide inhibiting actin cytoskeleton), a 51-residue endogenous micropeptide translated from a long non-coding RNA antisense to AQP5. MIAC binds aquaporin 2 directly. In head and neck squamous carcinoma cells this binding is followed by reduced SEPT2 and ITGB4 expression and loss of F-actin fibres. In renal carcinoma cells it is followed by reduced EREG and EGFR expression. MIAC overexpression or synthetic peptide suppresses tumour growth and metastasis in these models, and low MIAC expression correlates with poor survival. How AQP2 binding leads to these expression changes is unknown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:32176498 Micropeptide MIAC Inhibits HNSCC Progression by Interacting ... | REMOVE | Summary: Protein binding (IPI) with aquaporin 2, from the head and neck carcinoma study (abstract-only here), which reports direct MIAC-AQP2 interaction. No GO term describes what this binding does to AQP2, so the bare protein-binding row is removed. Removal does not mean the interaction is false. Reason: [PMID:32176498 "Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC."] Supporting Evidence: PMID:32176498 Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC. |
| GO:0005515 protein binding | IPI PMID:36117171 Micropeptide MIAC inhibits the tumor progression by interact... | REMOVE | Summary: Protein binding (IPI) with aquaporin 2, from the renal carcinoma study, which measures the interaction by MST and SPR and maps AQP2 residues Y221, L217 and E232 as binding sites by mutant pulldowns. No GO term describes what this binding does to AQP2, so the bare protein-binding row is removed. Removal does not mean the interaction is false. Reason: [PMID:36117171 "MST (D) and SPR (E) analysis of the direct intearction between MIAC and AQP2."] [PMID:36117171 "The results showed that Y221, L217, and E232 amino acid residues on AQP2 protein were important sites for binding to MIAC"] Supporting Evidence: PMID:36117171 MST (D) and SPR (E) analysis of the direct intearction between MIAC and AQP2. PMID:36117171 The results showed that Y221, L217, and E232 amino acid residues on AQP2 protein were important sites for binding to MIAC |
| GO:0007015 actin filament organization | IMP PMID:32176498 Micropeptide MIAC Inhibits HNSCC Progression by Interacting ... | MODIFY | Summary: Actin filament organization (IMP). MIAC reduces F-actin fibres in head and neck cancer cells, which the authors attribute to lower SEPT2 and ITGB4 expression downstream of AQP2 binding. MIAC has no actin-binding role, so it regulates rather than participates in actin filament organization; modified to regulation of actin filament organization, as a non-core role. Reason: [PMID:32176498 "Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC."] [file:human/AQP5-AS1/AQP5-AS1-uniprot.txt "CC aquaporin AQP2 which leads to inhibition of the expression of SEPTIN4"] Proposed replacements: regulation of actin filament organization Supporting Evidence: PMID:32176498 Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC. file:human/AQP5-AS1/AQP5-AS1-uniprot.txt CC aquaporin AQP2 which leads to inhibition of the expression of SEPTIN4 |
| GO:0042058 regulation of epidermal growth factor receptor signaling pathway | IMP PMID:36117171 Micropeptide MIAC inhibits the tumor progression by interact... | MODIFY | Summary: Regulation of epidermal growth factor receptor signaling pathway (IMP). In renal carcinoma cells MIAC, with AQP2, lowers EREG and EGFR expression and inhibits downstream PI3K/AKT and RAS/ERK activation. The direction is negative, so modified to negative regulation of the EGFR signaling pathway. Reason: [PMID:36117171 "Simultaneous overexpression of AQP2 protein and MIAC micropeptide can significantly down-regulate the expression of EREG and EGFR, and inhibiting the activation of downstream signaling pathways PI3K/AKT and RAS/ERK"] [PMID:36117171 "This study found and confirmed for the first time that MIAC directly binds to AQP2 inhibiting the expression of EREG, EGFR and the activation of downstream PI3K/AKT and mTOR signaling pathways"] Proposed replacements: negative regulation of epidermal growth factor receptor signaling pathway Supporting Evidence: PMID:36117171 Simultaneous overexpression of AQP2 protein and MIAC micropeptide can significantly down-regulate the expression of EREG and EGFR, and inhibiting the activation of downstream signaling pathways PI3K/AKT and RAS/ERK PMID:36117171 This study found and confirmed for the first time that MIAC directly binds to AQP2 inhibiting the expression of EREG, EGFR and the activation of downstream PI3K/AKT and mTOR signaling pathways |
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Download this section (compressed HTML)Q: Does MIAC change AQP2 channel activity or trafficking, and are its gene-expression effects lost in AQP2-deficient cells?
Experiment: Measure AQP2 water permeability and membrane trafficking with and without MIAC, and repeat the SEPT2/ITGB4 and EREG/EGFR expression assays in AQP2-knockout cells.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: MIAC binds AQP2, but the molecular activity behind its effects is unknown: how AQP2 binding lowers SEPT2, ITGB4, EREG and EGFR expression has not been shown, and AQP2 water-channel activity is not measured in the renal study's full text (the head and neck study is abstract-only here).
OPEN BIOLOGY MF_DARK
What is known: Established, in cancer cell lines from one research group: direct MIAC-AQP2 binding by several methods, reduced F-actin and target-gene expression, and tumour suppression in xenografts. Not established: the effect on AQP2 function, the signalling link to gene expression, and any normal physiological role.
Significance: MIAC is one of few characterized micropeptides from a lncRNA locus; its mechanism decides whether AQP2 is a functional effector or only a binding partner.
What would resolve it: Test whether MIAC alters AQP2 water permeability or trafficking, and whether its expression effects require AQP2.
Provenance (the field's own admissions):
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