tp53bp2a is one of two zebrafish co-orthologs of human TP53BP2 (ASPP2), a large cytoplasmic scaffold protein with an N-terminal Ras-associating (ubiquitin-like) domain, a coiled-coil and a long proline-rich, largely disordered middle region, and a C-terminal module of four ankyrin repeats and an SH3 domain. In mammals this C-terminal module binds the p53 DNA-binding domain and enhances p53-dependent apoptosis, and ASPP2 also acts at apical cell junctions, where it binds Par-3 and scaffolds PP1 and YAP. In zebrafish embryos, Aspp2a (together with its paralog Aspp2b) binds Irs-1 and restrains embryonic body growth without changing developmental rate, by dampening Akt signaling; this activity needs the ankyrin repeats and SH3 domain. tp53bp2a is the predominant copy from gastrulation onward and is expressed broadly in larval and adult tissues.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002039 p53 binding | IBA GO_REF:0000033 | ACCEPT | Summary: p53 binding propagated from the PANTHER ASPP node (human ASPP2 and worm ape-1 donors). Reason: The p53-binding module of ASPP2 is the C-terminal ankyrin repeats plus SH3 domain, which contact the L2 and L3 loops of the p53 core domain. My alignment shows the four ankyrin repeats of tp53bp2a are 90.6-100% identical to human TP53BP2 and the SH3 domain is intact, so tp53bp2a sits inside the clade that inherited this function with no sign of loss. Binding of zebrafish Aspp2a to Tp53 has not itself been tested. Supporting Evidence: PMID:8875926 the SH3 domain binds the L3 loop of p53 in a manner distinct from that of previously characterized SH3-polyproline peptide complexes, and (ii) an ankyrin repeat, which forms an L-shaped structure consisting of a beta hairpin and two alpha helices, binds the L2 loop of p53 file:DANRE/tp53bp2a/tp53bp2a-bioinformatics/RESULTS.md The four ankyrin repeats are 90.6-100% identical to human TP53BP2 in both copies |
| GO:0002039 p53 binding | IEA GO_REF:0000002 | ACCEPT | Summary: p53 binding from the InterPro ASPP1/2 family signature. Reason: Same claim as the IBA row, reached from the ASPP1/2 family signature; consistent with the conserved ankyrin-SH3 module. Supporting Evidence: PMID:11684014 ASPP proteins interact with p53 and specifically enhance p53-induced apoptosis but not cell cycle arrest. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear activity propagated from human ASPP2 and ASPP1. Reason: Mammalian ASPP proteins act on p53 at pro-apoptotic promoters, so a nuclear pool is plausible, but the best-characterized sites of ASPP2 are cytoplasmic and junctional. No zebrafish localization data exist for Aspp2a. Kept as a non-core location. Supporting Evidence: PMID:11684014 ASPP enhance the DNA binding and transactivation function of p53 on the promoters of proapoptotic genes in vivo. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nucleus from the UniProt subcellular-location rule (ARBA). Reason: As for the IBA row; a minor location for this largely cytoplasmic and junctional scaffold. Supporting Evidence: PMID:11684014 ASPP enhance the DNA binding and transactivation function of p53 on the promoters of proapoptotic genes in vivo. |
| GO:0005912 adherens junction | IBA GO_REF:0000033 | ACCEPT | Summary: Adherens junction propagated from Drosophila ASPP. Reason: Junctional localization is a conserved property of ASPP2 (mouse ASPP2 maintains tight/adherens junctions and binds Par-3) and of fly ASPP. tp53bp2a keeps the domains; no zebrafish localization data. Supporting Evidence: PMID:20619750 Mechanistically, ASPP2 maintains the integrity of tight/adherens junctions. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: Generic signal transduction from the Ras-associating domain InterPro2GO mapping. Reason: Not wrong but uninformative. The one zebrafish experiment on this gene shows it dampens Akt signaling downstream of Irs-1, which is captured by the more specific term already carried by experimental evidence. Proposed replacements: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction Supporting Evidence: PMID:24362258 Aspp2a and 2b inhibit Akt signaling. This inhibition was reversed by coinjection of myr-Akt1, a constitutively active form of Akt1. |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | ACCEPT | Summary: Regulation of apoptosis from the ASPP1/2 family signature. Reason: Regulation of p53-dependent apoptosis is the defining function of the ASPP family. It is untested for zebrafish Aspp2a, but the p53-binding module is conserved. The broad term is acceptable for an IEA. Supporting Evidence: PMID:11684014 Inhibition of endogenous ASPP function suppresses the apoptotic function of endogenous p53 in response to apoptotic stimuli. |
| GO:0043009 chordate embryonic development | IMP PMID:24362258 Aspp2 negatively regulates body growth but not developmental... | MODIFY | Summary: Knockdown of aspp2a altered embryonic growth in zebrafish. Reason: The paper's finding is specific: Aspp2a restrains body growth while developmental rate (timing) is unchanged. "Chordate embryonic development" is broad and implies a developmental-timing role the authors explicitly exclude. Negative regulation of multicellular organism growth states the claim. I have only the abstract; the refinement follows the title and abstract, not a disagreement with the curator. Proposed replacements: negative regulation of multicellular organism growth Supporting Evidence: PMID:24362258 Here, we show that zebrafish Aspp2a and Aspp2b negatively regulate embryonic growth without affecting developmental rate. |
| GO:0048471 perinuclear region of cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Perinuclear cytoplasm propagated from rat Tp53bp2. Reason: Consistent with a largely cytoplasmic protein; not a site of any characterized function and not tested in zebrafish. The best-characterized ASPP2 site is the apical junction. Supporting Evidence: PMID:25360797 Here we report that the tumour suppressor ASPP2 forms an apical-lateral polarity complex at the level of tight junctions in polarised epithelial cells |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:24362258 Aspp2 negatively regulates body growth but not developmental... | ACCEPT | Summary: Aspp2a inhibits Akt signaling in zebrafish embryos; the effect is reversed by constitutively active Akt1. Reason: Direct zebrafish evidence on this copy, with an epistasis test (myr-Akt1) and a mechanism (binding to Irs-1). Abstract only in cache; accepted, deferring to the curator who read the full text. Supporting Evidence: PMID:24362258 Aspp2a and 2b inhibit Akt signaling. This inhibition was reversed by coinjection of myr-Akt1, a constitutively active form of Akt1. PMID:24362258 Zebrafish Aspp2a and Aspp2b physically bound with Irs-1, and the growth inhibitory effects of ASPP2/Aspp2 depend on the presence of their ankyrin repeats and SH3 domains. |
| GO:0072332 intrinsic apoptotic signaling pathway by p53 class mediator | IBA GO_REF:0000033 | ACCEPT | Summary: p53-mediated intrinsic apoptosis, propagated from human ASPP2 and ASPP1. Reason: This is the ancestral ASPP function (enhancing p53 transactivation of pro-apoptotic genes), and the p53-binding module is conserved in tp53bp2a. Not yet tested in zebrafish. Supporting Evidence: PMID:11684014 ASPP enhance the DNA binding and transactivation function of p53 on the promoters of proapoptotic genes in vivo. |
| GO:0043560 insulin receptor substrate binding | IPI PMID:24362258 Aspp2 negatively regulates body growth but not developmental... | NEW | Summary: Zebrafish Aspp2a binds Irs-1. Reason: Physical interaction with Irs-1 reported for both zebrafish copies, and the growth phenotype needs the ankyrin-SH3 module; this is the only molecular interaction shown for the zebrafish protein and it explains the Akt phenotype. Abstract only; assay details not visible. Supporting Evidence: PMID:24362258 Zebrafish Aspp2a and Aspp2b physically bound with Irs-1, and the growth inhibitory effects of ASPP2/Aspp2 depend on the presence of their ankyrin repeats and SH3 domains. |
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Download this section (compressed HTML)Q: Does zebrafish Aspp2a bind Tp53 and enhance p53-dependent apoptosis (for example after DNA damage), and does it differ from Aspp2b in doing so?
Q: Why does tp53bp2b expression drop during gastrulation and organogenesis while tp53bp2a stays high, and does gar TP53BP2 show a single continuous profile?
Q: Does Aspp2a localize to apical junctions in zebrafish epithelia, as mammalian ASPP2 does?
Experiment: Make stable tp53bp2a and tp53bp2b mutants (including promoter-less alleles to avoid transcriptional adaptation) and double mutants; measure body length, Akt phosphorylation and Irs-1 binding.
Hypothesis: tp53bp2a and tp53bp2b are redundant growth regulators.
Type: genetic interaction
Experiment: Test tp53bp2a mutants for reduced p53-dependent apoptosis after irradiation, with tp53 mutants as controls.
Hypothesis: Aspp2a keeps the ancestral p53 cofactor function.
Type: loss of function
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